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From Wikipedia, the free encyclopedia

autophagy related protein 8
The crystal structure of microtubule-associated protein light chain 3, a mammalian homologue of Saccharomyces cerevisiae Atg8.[1]
Identifiers
OrganismS. cerevisiae strain S288c (Baker's yeast)
SymbolAtg8
Alt. symbolsApg8, Aut7, Cvt5
Entrez852200
RefSeq (mRNA)NM_001178318
RefSeq (Prot)NP_009475
UniProtP38182
Other data
ChromosomeVII: 0.16 - 0.16 Mb
Search for
StructuresSwiss-model
DomainsInterPro

Autophagy-related protein 8 (Atg8) is a ubiquitin-like protein required for the formation of autophagosomal membranes. The transient conjugation of Atg8 to the autophagosomal membrane through a ubiquitin-like conjugation system is essential for autophagy in eukaryotes. Even though there are homologues in animals (see for example GABARAP, GABARAPL1, GABARAPL2, MAP1LC3A, MAP1LC3B, MAP1LC3B2, and MAP1LC3C), this article mainly focuses on its role in lower eukaryotes such as Saccharomyces cerevisiae.

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  • Tom Kelley, David Kelley: "Creative Confidence" | Talks at Google
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Transcription

[MUSIC PLAYING] FREDERIK G. PFERDT: Welcome to a very creative afternoon and an Authors AtGoogle Talk. My name is Frederik. Please join me in welcoming David and Tom Kelley. [APPLAUSE] FREDERIK G. PFERDT: They've just published recently a book, "Creative Confidence: Unleashing the Creative Potential Within Us All." And I actually had the pleasure of having lunch with Tom and David. And David asked me, I think the second question, so what are we going to do here? Google is already very creative. So let us come back to that question later on. So, Tom, you published various books around innovation, "The Art of Innovation," "The Ten Faces of Innovation," bestselling books. TOM KELLEY: Uh, huh. FREDERIK G. PFERDT: So what motivated you to really publish this book around creative confidence now? TOM KELLEY: Sure. So this book is actually quite different than my other books. It focuses more on the individual. It's more about creativity per se and stuff like that. So it has a business audience, but it actually speaks to a broader audience. So we're a "New York Times" bestseller as of two days ago. And it's not in the business category. It's in the advice category, which is quite different. But why'd I write this book? And really, the answer is, you know, two chairs away from me is my brother. Back in 2007, David was sick. David had throat cancer. And they only gave him a 40% chance of survival. And, wow, in that situation, you confront a lot of demons, you know. And that was hanging over our heads for a long time. I spent most of the year with him in '07. And after chemo and radiation, and eventually surgery, toward the end of the year, at least a possibility arose, became more tangible, that he was going to survive, And, you know, you can see, he's there. That's the answer six years later, And so we had talked about the future all year. And so late in 2007, then we did. We felt like we had permission to talk about the future. And so as we did that, we made two promises to each other. David and I have worked together for almost 30 years. And the two promises were, one, that we would take a trip together. Because, oddly, we have never traveled together as adults. Our big trip was in 1967. We drove from Ohio to California, you know, the promised land. And so in our work at IDEO, if one of us goes to a meeting in Grand Rapids or wherever, the other one doesn't have to go, right? And so we don't travel together. So promise number one is to do a trip together. And that became this really fun trip to Tokyo and Kyoto, two places that I really like. And, oh, I got to pick. So I picked. But then, the other promise was that we would do a project together. David and I are not very good at leisure. You know, we're couldn't just hang out for some months together or play golf or I don't know. Just not in our DNA. And so if you want to spend time together, you got to think of something to work on together. And so we said we'd do a project. And at that time we didn't know what the project would be. But the project became a book. It became the book called "Creative Confidence" that is sitting right there. DAVID KELLEY: Yeah, I actually highly recommend being diagnosed with a terminal disease. Just-- [LAUGHTER] DAVID KELLEY: --don't get a terminal disease. But if you could fake yourself into really believing that for a while, it's kind of cathartic. It'll straighten you right up. You'll do all kinds of different things. [LAUGHTER] FREDERIK G. PFERDT: Speaking of different things you did in your life, David, you founded a very successful company called IDEO. You also started an educational institution called the Stanford d.school. So you also started a revolution around innovation and innovators in general and using design thinking as a framework to really push that forward. Can you speak a little bit about what you have learned throughout the years, about innovation in general but also about innovators? DAVID KELLEY: Yeah. Well, you know, I mean, we think of IDEO as a successful company, you know, as this little thing. When you come here, and it would fit in one cafeteria, it doesn't feel that big a deal. There's a couple things. So one, I'm really proud of IDEO. You know, you get a bunch of designers together and then give them a really difficult problem-- you know, fix the educational system in Peru, or improve the experience of checking into the Mayo Clinic, or whatever-- and they come up with really wonderful, new to the world, viable solutions. And that feels really good. And at the d.school-- d.school's successful beyond my wildest dreams-- and you see people flip from thinking of themselves as not creative to thinking of themselves as creative. And it impacts their entire life, the number of people that kind of come to me and say, this thing's changed my life, as an educator, it feels great, especially since for the first kind of 20 years of my academic career, I was the design guy. So when somebody important in the university came to see me, they wanted to know, where did you get those shoes, or where I get cool glasses, you know? Now, they're coming with strategic questions about what's the future of higher education, and can we work on that? So I'm just saying it surprised me and it's really exciting. We could go on and on about that. But if you just want to think about the highlights of what we found, the first thing is that being human-centered results in new innovation. So if you think that there's lots of companies and people working on coming up with new business ideas and then trying to understand how people might accept them. And then, there's lots of people coming up with technology ideas and trying to figure out how the business side of that might work and how people might accept that. And we found that, for us, for design types, the best approach is to come in from the human side, like what do people value, what's meaningful for people, and then go out and try to find technologies and business solutions to those problems. So that seems to be, for us, the number one thing. This empathy for people is the best way to lead to innovation. And the other thing is that this is a team sport, this innovation. I mean, there's the lone genius. I mean, if you've got Leonardo da Vinci on your team, you're set, you know. [LAUGHTER] DAVID KELLEY: But if you don't, then it's really important to have a team that's very diverse and that they work together. They have had different experiences. And they have different points of views. And then, if you can get them to work together and build on each other's ideas rather than just kind of show how smart you are by saying what's wrong with the other person's idea, if you can get to build on them. And what happened at the d.school, I believe-- lots of things happened at the d.school-- but the thing I believe is that we'd been trying to do multidisciplinary stuff at the university for a long time but, you may know, if you've been in a university, that it's the opposite of that. It's in deep silos. And people are winning Nobel Prizes. And I would hope that they would keep doing that. I'm not trying to talk people out of going deep. I think that's very important. But we kind of miss things in between these deep silos of knowledge. And so what we found is that by having people from different disciplines, you get to these kind of big ideas that are between disciplines by using methods like design thinking and having these diverse teams that can build on each other. So that's the basic thing that's happened. FREDERIK G. PFERDT: You both write in your book that you want to make the world a better place through embracing creative confidence in our lives. At Google, we have a similar mission on making the world a better place through technology. So where do you see the parallels in what you're trying to achieve and what we're trying to achieve with technology. TOM KELLEY: Sure. I mean, those two are not in conflict in any way, right? What we're seeing is this trend, this kind of maker trend, that we've experienced both in our teams and in the world at large, in which new technologies put creative tools in everybody's hands. You know, there's that old line about, in the 20th century, kids watch TV. In the 21st century, kids make TV. I think they're talking about YouTube when they say that, right? And so I think the two go hand in hand. I mean, we just maybe approach it from a slightly different direction. But one of the things that we've latched on to early on is a year or two ago there was an Adobe study called "State of Create," in which they, you know, with an interest not unlike yours-- they want to use technology to help people in their focus on creativity-- and so they ask 5,000 people in five different countries about their beliefs surrounding creativity-- one about the link between creativity and economic development. And 80% of people said, unlocking creativity is critical to economic development, which we thought was great. But really interesting was the follow-on question. And they said, well, how about you? How about you as an individual? Do you have a chance to live up to your creative potential? In other words, do you have a chance to bring your whole self to work? And across the world, only 25% of the people said yes to that. And so we think it's a worthy goal. I mean, it's a worthy question, for us and for you, of how might we unlock the creativity of the other 75%, right? And so you might approach that question from a slightly different direction than us. But I think we're both quite interested in how to change the world in that way. DAVID KELLY: You just have 42,000 people on it. We have five. [LAUGHTER] FREDERIK G. PFERDT: So coming back to that question, so how would you actually recommend organizations going about unlocking the potential of creative people in their organizations? DAVID KELLEY: Yeah. I'm not sure this applies to Google, as I said before, but what we find is that you have to have support from the top of the company that the experiments are allowed to happen. But it's all really about small experiments. It's all about starting a bunch of little brush fires in different places in the company and hoping that they kind of, you know, catch on and grow together. So we, in all of our exec eds at the d.school, from the minute the people come to go through our program and learn our methods and stuff, we focus on what are they going to do when they get back? I mean, how do you implement when you get back, and how are you going to protect these ideas and stuff? Because one of the things, and early on, is that people would have this cathartic experience. Then they'd go back. And the mass of the place, the habit of the place they were going to, was just too extreme for them to catch hold, right? And so we spend a lot of time trying to understand how you kind of come up with these ideas in a way that can be accepted by the rest of the organization. TOM KELLEY: Yeah. You know, in cultures there's a really important moment we've discovered. And I personally have worked with 1,500 clients, and David, I'm sure, a lot more. And there's a really important moment in which a not yet perfect idea gets put on the table. And people look really closely to see how do leaders especially react to that. You know, you've probably heard those stories about the tyrant boss who, you bring in the unfinished thing, and they say, how would our organization be worse if you weren't here tomorrow, you know, that kind of, like, get out of my office, because you haven't thought through every detail of this idea yet. But in great cultures, in creative cultures, the first instinct is to build on the idea. There's a skill we call squinting, in which you ignore the surface details and you look at the shape of the idea and try to figure out how could you make it better. And if the leaders of an organization are squinters, you know, are the kind of people who look past the surface details, what we found is, there's a better idea flow within the company. More ideas come up, because you don't have to self-edit. You don't have to wait until your idea is perfect. You bring it out in its embryonic form and say, well, I'm thinking about this, because you're allowed to kind of think out loud about things. You know, here in the Valley, ask any venture capitalist, and they will tell you that all other things equal, the VC firm with the better deal flow wins, right, because they're picking from 1,000 instead of picking from five possibilities. And so we think it's true with companies with idea flow. If you're the kind of company-- and I know that in many ways you are-- if you're the kind of company in which ideas get circulated all of the time-- and many fall by the wayside, because they're not yet perfect or because they don't pan out-- you still have this rich culture of ideas to choose from. What we found is that those are the companies that succeed and sustain in the long run. FREDERIK G. PFERDT: So let's move from an organizational level to an individual level. I think that's very interesting. So what prevents, actually, people for having those creative breakthroughs? So is there a routine, especially like if, maybe, you have a personal routine you want to share about David or David wants to share about Tom, like how you actually train the creative muscle, if that's even possible. So some people do meditation, and they would go work out. So what are you doing? DAVID KELLEY: Well, again-- I don't know about Google and that it makes sense now about Google-- but what's really going on in these people that aren't confident in their creative ability is something happened to them when they were kids, and they opted out of thinking of themselves as creative. They think of themselves only as analytical, which is fine. We're not saying don't be analytical. We're saying be creative, as well. And so what happens is they develop this fear of kind of owning an idea. Like you don't want to be the person who came up with that idea, because then as it goes through the company, and if it doesn't work, then you are labeled with that idea. So it's that kind of fear of being judged. And so, I mean, whatever it is-- I mean, I don't understand Google's culture-- but whatever it is, there's fears that can be alleviated by this process we call guided mastery. And some of you may have seen my TED Talk. I talked about this guy that I really kind of got to enjoy at Stanford. His name is Albert Bandura. If you're a psychology major, you know who Albert Bandura is. He's like the most cited psychologist in the world, living. Freud probably has more citations somewhere. And when I met him, he was talking about this kind of curing phobias. Now, lots of people that we run into have this fear of being judged. And it turns out, it's the same deal as far as how you get around it, how you change the way you think of that, of yourself. And so he was curing snakes and spiders phobias and stuff like that. And the way he did it, in this thing called guided mastery, is he takes people through a series of small steps, you know, baby steps. And each one, they're successful at it. So you're looking at the snake through the mirror. And then 15 steps later, you're standing at the door, your hand being held. Then you get to a welder's glove. And eventually, you touch the snake. But there's a guy who's got a near 100% cure rate of people with these kind of phobias. And they've had these phobias their whole lives, and they're not going outside or going on a hike because there might be a snake there. And he can cure them through this guided mastery. So what we feel, when you talk about the individual, we know, at the d.school and IDEO, anyplace, if we take people who have this fear of being judged or of failing or whatever in the workplace, and we can take them through a series of successes-- we give them a small project just like when you were at the d.school. You know, we have a small project that you can be somewhat successful at. And then we increase the complexity and the scope and the team size and all of that stuff. And it's not that long, after a few projects, that you're thinking, oh, my, god, I am a creative person. So for the book, we interviewed 100 people, most of them from the d.school, and just talking about their extraordinary transformation by gaining this feeling in their bodies of being creative. And so it's pretty amazing to watch how this can be transformative to the individual. FREDERIK G. PFERDT: You spoke a little bit about this beginner's mind or child's mind, and you quoted, I think, a lot of times, that you should really embrace that in everything you're doing. So what would you actually recommend for parents then? Because I saw that in your book, you also dedicate your book to your parents. What would you recommend-- that's the first question for you-- for parents, what they should do with their kids? But secondly, how did your parents influence you throughout your lives? TOM KELLEY: Sure. You know, this parenting thing is hard, as you've probably noticed. Those kids don't come with instruction sets. It's sometimes hard to know, is this where I'm supposed to be firm? Is this where I'm supposed to be laissez-faire, or whatever? But just think about our parents. It wasn't that they were artists or something. It wasn't that they got out the finger paints with us every day. It was that they give us a lot of space to do things, that they weren't quick to judge us or to kind of reign us in when we got a little creative. You know, David and I took a lot of stuff apart as kids, including the family piano. And many of those things never went back together. A piano, once you take it apart, it's actually kind of beautiful. Those 88 hammers, David's got those up on his wall. But nobody ever played that piano afterwards. And the parents never complained. And so I think it's just kind of permission to misbehave a little bit, permission to be creative. And you have this sort of nurturing environment that says, and it's still going to be OK, right? And so that's really what our parents did for us. And that's what I've tried to do for my kids. DAVID KELLEY: It could be called benign neglect, right? So we got away with it. The one I remember the most, or that I've been told the most it was hardest to take, was, so, I was 12. I got a brand new red Schwinn bicycle. You can imagine, that's a big gift. We're, you know, relatively not that well-heeled a family. And so a Schwinn bike was a big deal. And somehow the next day I took it out and sandblasted it and painted it fluorescent green. And so, I can imagine, that was a little hard to look the other way. TOM KELLEY: Well, speaking of fluorescent green, so, OK, that was David's bike. And so it's kind of his to do whatever he wanted to. But he came home from college-- he went to Carnegie Mellon as an undergrad-- and he came home from college freshman year, and he got four shades of green paint, including fluorescent green, and painted a stripe, like four feet high and 40 feet long, against the back wall of the house. And you can imagine a parent in a small town in Ohio being not sure about that, right? But that green stripe's still there all these years later. DAVID KELLEY: Yeah, you're mostly too young. But this was the era of super graphics, right? FREDERIK G. PFERDT: So what changed about David? [LAUGHTER] TOM KELLEY: You can Google that. FREDERIK G. PFERDT: Great. What changed about David over the years, then? You spoke about when he was 12. But what's really now when you say, oh, David, that's really why you're childlike, not childish? TOM KELLEY: Sure. So there's that great quote from Picasso. He says, every child is an artist, and the challenge is to remain an artist after you grow up. So David and I were quite different as kids. And the thing about David is he had indication, there were tells even as a small child, that he was going to be creative, that he was going to become a designer one day or something, whereas I was the opposite. You couldn't have spotted it in me. And so I think that-- for a lot of you, you might have fit David's pattern more as kids-- but the fact that I could cross over that line, I think is good news for lots of people out in the business community and beyond. Because I wanted to be a lawyer, for God's sake. What was I thinking? I'm not sure. I got the GMAT, abandoned that, but got an MBA, worked for an accounting firm, worked five years doing spreadsheets-- first by hand, because we didn't have those computer things, and then on the early laptop machines-- and so at age 35, no indication, right, that I was going to have a chance to have a creative life. And so this is good news. Because you can decide today. You can change later in life. And so I just basically immersed myself in the creative environment at IDEO and gained creative confidence in that process. And so, you know, yeah, you could spot the stuff in David, but, yeah, hard to tell in some of the rest of us. FREDERIK G. PFERDT: So two more questions. And then, I want to open it up for the Googlers to ask questions to you. The first one is, when you think about what's next-- so in the next five to 10 years-- I think that's a time frame we as Googlers think, like it's way in the future, but it's still something you can somehow guess what's going on-- so what are your plans? You started a successful company. You started a successful educational institution. You wrote various books really successfully. So what's next? TOM KELLEY: You know, I bet David's got his own answer. But for me, this book is out, and it's done, and books are so hard. I'm not sure I'm doing another one. So the idea is out in the world now. But I feel like it's got a pretty long run, this idea of creative confidence, that dealing with the 75%. And so I've been working on innovations, you know, the products, the services, the digital experiences for 30 years. And I was thinking, the next decade or so, that I would focus more, or at least as much, on innovators, on inspiring individuals-- especially early in their careers, because they have so much promise coming up-- to get in touch with their creative confidence so they can make a bigger impact on the world and have more fun at work. You know, we did those 100 interviews. And it is so much fun to be around those people who have gained creative confidence basically around the fourth grade, a lot of them. And it happens for kids a lot there. They decided they weren't creative, and their world gets smaller when they make that decision. They kind of opt out of stuff. And then, everybody we interviewed, everybody-- and it wasn't a random sampling of the universe. We sought them out-- but all 100 of the people we interviewed had decided at some point that they were creative. And, wow, just the look in their eyes. They're fun to be around. And in the process, it's stuff isn't even limited by creativity. They are taking on bigger challenges. They are more resilient in the face of obstacles, more perseverance. They're just cool. I mean, they're just fun to be around. DAVID KELLEY: Yeah. So for me, it's about scaling this thing. So some really interesting challenges with scaling. It seems like scaling keeps coming up as the problem everywhere. And for us, even if I just look at Stanford, the university would like every student to have that as a trait, that they're confident in their creative ability, that Stanford is known as a place where the kids have that confidence and they use that tool all the time. Just that alone, how do you know? There's a few thousand students who go through d.school, maybe, a year-- but how do you get to the a large percentage of a university? And it's the same way with the relationships we have with other outside universities and stuff. And, also, my main focus, as a kind of a second thing, is K-12 education. And so we're doing things. Like, in Peru, we're trying to understand how to change all of Peru's educational system because it's particularly bad. And then, OK, how does that apply to the US? Because the US thing-- we've been working in K-12 for a while-- and as I told you about the brush fire problem-- p we got a few brush fires going, but nothing's that big a deal. And so trying to scale by seeing what we can do as the different experiments and then how you scale them. And so we're making progress. I mean, there's lots of good news out there. But I don't think we've found that kind of cleverness about what makes something really scale, especially in K-12. FREDERIK G. PFERDT: So Googlers in general, I think, are really passionate about working on big, audacious goals. So what would be one big, audacious goal or problem for you which a lot of people should actually work on in the next three or four years? DAVID KELLEY: Well, I don't know if you know. I've been going to TED for 20 years or so. And the biggest, the most watched TED Talk is Ken Robinson's. And in that, he said that he thought in schools, creativity was as important as literacy. And we're a long way from believing that. But I really think that through technology and through doing things like project-based learning and stuff, I think that's the audacious goal. I mean, there's plenty of other ones. But from my perspective, or from our perspective, and the same thing at Stanford, how do you get creative confidence into as many kids as you possibly can? Because when we do succeed, you just see how it's transformative. TOM KELLY: Yeah, and for me I would say the big goal would be cracking the code on behavior change. You know, so much of what we do, all of our social innovation work, and even our work in health care and things like that, we're trying to change behavior of the constituents that matter to us. They're not always customers, even. And that's really hard. People cling to their old patterns even when their old patterns aren't the best for them. And so, for example, I did a work with the water in developing countries. We're in India trying to get people to drink the safe water, the filtered water, the water that won't make them sick. But they've been drinking that other water for generations. And so the old way to do that, the attempted behavior change approach to that, is you send a social worker into the village, and they talk about the germ theory of disease, you know, fascinating stuff, right? And they're explaining why you shouldn't really drink that water from the well, at least untreated. You should get this other water, which is not free, right? Now, we're talking about families for whom any new expense means trading off something else. They're living very close to the Earth. And so they'll be there, really, with their best interests at heart, trying to convince this community to go for the safe water. And then, someone will raise their hand. And apparently it happens a fair amount. Someone will raise their hand and says something like, well, you know, my mother gave me water from that well. You're not saying my mom is wrong, are you? And if you're that social worker in that little village in India and that question comes up, I would urge you to just leave immediately. There is no beating that question. You're not going to change behavior in that village that day. Because we're very conscious, we're hiring behavioral economists, we're very interested in this behavior change, what we do is we show up in the village with our own generator, because you can't trust the power supply, and a projector and a white sheet that becomes our screen. And during the day, we hand out pamphlets. And then we start with singing and dancing, because you know, if you advertise germ theory of disease, not everybody shows up, right? And so singing and dancing, we've got a crowd. And then, with the crowd assembled-- and it's pretty much the whole village, because what else is going on that night, right, you know, they're not watching reruns of anything, because there's no TVs, right, and so we got the attention of the whole village-- we hook up a microscope to that projector. And we show them a drop of the water they've been drinking for generations. And we don't have to check in advance. It is alive with small animals. It is really scary to see your filthy water in that way. And then, we go to some local supplier of the safe water, and we put a drop of that on it. And it's not always perfect, by the way. But it's always way, way better than this really scary looking water with the animals in it, very small animals. And then we ask a different question. And the behavioral economists call this choice architecture, which is the ability to frame the question in a way that people make answers that are true to their belief system. And so now they've seen the unsafe water. They've seen the safe water. And we say, never mind your mom. Your mom did the best she could. We address them as parents. And we say, OK, now that you have seen it, now that you have seen the water in this new way, which water do you want your children to drink? And if you can frame that question in that way, people will change. People will give up a little something else in order to have the safe water for their families. And so to do that with diet and exercise, to do that with planning for retirement or saving for college or the thousand other things, energy usage, or recycling, or other things, that's a big thing to crack the code on. FREDERIK G. PFERDT: Right. Thank you. So we have a microphone over here. If you want to please start lining up and ask your questions. AUDIENCE: Hi. FREDERIK G. PFERDT: Yes. AUDIENCE: So I have a question that's actually kind of on the opposite end of the spectrum of what you've been talking about. And that's being overwhelmed by the opportunity to be creative and come up with ideas. I think I speak for a lot of people. Perhaps I've just been fortunate. But in my role and experience at Google, I've been a lot of situations where there's support for creativity and the opportunity to create ideas creates just an overwhelming set of options. And teams can just spin and spin and spin coming up with ideas, all of them great. But you run out of time and even energy to reduce them to actual practicing get things done from that perspective. So curious as to what your experience in a place like the d.school, where likely there is a lot of that going on, is how do you stop that, and how do you just move forward with an idea or a select set of ideas and get them working? TOM KELLEY: Right. So I totally believe you that that's a problem at Google. And I'm going to go on record and say in the other 99.9% of client organizations I work with, this is not their problem. But nevertheless, you have this issue. And so what we would recommend in a situation like that is find the quickest, cheapest way you can prototype the alternative ideas. Because in the prototype, you kind of bring them to life a little more, so that it gets just a little more tangible in a way that reasonable people-- that would be customers, maybe-- could look at it and say, oh, I would totally go for that or, like, oh, no, I would never use that, right? And so if you have lots of ideas but you can prototype them all up to a level in which you can get good feedback from it, then the kind of winners will start to emerge. DAVID KELLEY: And you probably do that. But the thing has to do with empathy. We really believe that even at Google, you're not deep enough involved with the people that you're trying to make raving fans. I mean, my experience at the d.school-- you asked about the d.school. I can tell you-- yeah, there's tons of ideas. There's so many ideas. But we just keep going deeper and deeper with the people we care about, with the extreme users, with the central personas, the stuff. And it just seems that they just more quickly resonate with some things than they do the others. And then, in this prototyping way, like you take the pulse news reader or whatever, what those guys did it at the d.school-- it's like the users will take you in the right place. I mean, you're trying to go to a really special place with a group of people. And we at the d.school just double down on trying to understand them more. Because we have a tendency to go back to our offices or our teams and sit around and talk to each other. And so by being out there in the messiness of people where they're going to use this it seems like is the only thing we really have. TOM KELLEY: We're doing a lot of work with open innovation out in the world. It's called OpenIDEO. The current challenge is actually about creative confidence. But we'll ask a question. People submit ideas. And then they participate. The open innovation community participates, in evaluating the ideas. And we've now worked with companies. There's other people unrelated to us doing this internally, where it's open innovation, but it's only open within the company in which the collective community of the company judges and says, wow, we really like this idea. So you've got more than just what your boss likes. You've got what the whole community believes has value for the future. AUDIENCE: I was just going to ask, I think in "The Ten Faces of Innovation" you discussed the group of, I think, it was fifth graders that you worked with, or five-year-olds. I forget what the number was. I was just wondering how that's been going since then, if that's something you guys still use? TOM KELLEY: So this is a question about an old book. Fifth graders we worked with. Don't know. But that prompts a story, which is one of the favorites. Of the 100 people we interviewed, there's this teacher, teaches the fifth grade. Her name is Marcy Barton. And she has been teaching for 42 years. And so I'm sure you've had those kind of teachers, 42 years in. They developed their syllabus 41 years ago. And they've been in full implementation/repetition mode ever since. And that doesn't quite describe Marcy. So Marcy comes to the d.school. She comes to a two-day program for educators. And by the way, I am going to sound like a paid spokesperson for the d.school. I'm not a Stanford guy at all. I'm a Berkeley guy, right? But Marcy is an amazing person. She comes to the d.school for this two-day program. And based on that two days, she basically changes her life. She reinvents her curriculum from scratch after that two-day seminar. And she does all project-based learning with her kids now. And so instead of standing at the board and talking about immigration in the New World, she turns the desks upside down and puts the kids inside and wraps it with craft paper. And now they're in they're in the ship going go into the New World. And they write their constitution while they're in the ship. And then, when they get there, they use their math skills and make a perfect scale model of the community. And everything is a project. And her kids have done remarkably well. And Marcy, at one point in the interview, she says, my kids are wonderfully more creative and they're engaged. And she says, and write this down. And I'm thinking, Marcy, we're taping this interview. But anyhow, she still wants us to write. And she says, and tell those parents, my kids do better on the standardized tests, too. She says, of course, they do better on the standardized tests. She says, my kids are engaged every single day of the school year. And so Marcy says, in the interview, this design thinking stuff she picked up at the d.school, she says, this is the cornerstone of my career and my life. And so that's Marcy story. But it's so ridiculously unbelievable that David and I had to take three steps back and think, OK, how are we going to explain this to anybody? So here's our theory. There's an old saying, sometimes attributed to Plutarch, but there's another possible source for it, where someone once said that education is not the filling of a vessel, it's the lighting of a fire, which is not entirely true. Because in the airline magazine, when it says you can learn Mandarin in five days, that is bull. You cannot learn Mandarin in five days. And here's why. Because it's the filling of a vessel. It's vocabulary. It's grammar. It's tonality. It's really, really hard. But with Marcy, at the d.school, she didn't fill any vessels. She lit a fire. She had almost everything she needed and just had this one more spark that set it all off. And so, anyhow, my favorite fifth grade teacher in the world now, even though we met fairly recently. DAVID KELLEY: Yeah, I'll talk to five-year-olds. Because he didn't know if it was five or fifth grade, so he did fifth grade. I'll talk to five-year-olds. So one of the things we really found out, that was really interesting, is that teachers never have time to give the same problem, even if they're project-based learning, they don't have time to give the same problem over again. And It turns out that there's so much learning in becoming expert in doing the same project over and over again. So you give them the project. And then everybody in the class comes up with their ideas. And then you've learned so much, you become more expert. Because you have your ideas, and you've worked on it. And then, you have all of the other ideas or something, and then you do it again. So we've been experimenting. We experimented with that, where the same project is given three times. And so I'll just tell you my favorite kindergarten class. And the problem we give them is redesigning your bedroom. Fairly vigorous, anyway. So everybody comes back. And they come back. And they've got their little models. And they're made out of pipe cleaners and pieces of cardboard and stuff. I want to make a long story short. This one little girl has the design. They said, what's this? And she says, well, here is it. So we had them do need finding and all this stuff. And she'd gone out. And her bedroom had a place for the family car to pull next to her bed. Because her need was, when we come home late at night and I'm asleep, Dad has to carry me all the way from the garage into the bed. So in her design, the door to the car opens-- she had a little thing-- and she rolls out right out of the car into the bed, right? [LAUGHTER] DAVID KELLEY: Anyway, so then we do another round, another around. And by the end, every kid-- that's the killer app, right-- every kid's thing has a place for the car to park next to their particular bed. [LAUGHTER] FREDERIK G. PFERDT: Great. More questions? AUDIENCE: Was there any difference when you did the survey across the different countries, or that survey you had mentioned, in terms of culturally whether the US or any one country is really behind or really ahead and what the driver may have been? TOM KELLEY: Sure. You gotta look at the whole survey. I was interested in the overall response. But when you look at the individual country responses, it's fascinating. Because, basically, every country thinks that they are the most creative country in the world, right, though no one else thinks they are. But the exception to that is Japan. Everybody thinks that Japan is creative except Japanese people. And so there's just this weird kind of asymmetry to the belief systems from country to country. But that gets at this very central theme in our book, which is that creative confidence is the combination of the natural ability to come up with breakthrough ideas and the courage to act on them. And so I've spent a ton of my life in Japan. I think it's a tremendously creative country. And sometimes, in modern Japan, people don't have the courage to stand up and say, this is a good idea. They feel like they have to self-edit, they can't express their creativity. And so, I think, a huge opportunity there. But, yeah, country by country, it's quite interesting to see how they see themselves so differently than other countries see them. DAVID KELLEY: And we do user research all over the world constantly. And I mean, people are completely different in their desires. So I remember. a vacuum cleaner company asked us to design a world vacuum cleaner, like one vacuum cleaner that they could sell everywhere in the world. And it was hilarious, because you go around and talk to people about vacuum cleaners, you realize just how different the cultures are. You know, there are places in Asia where they wanted a really technical vacuum cleaner that counted dust mites and was quiet and small and stuff. And people in the United States want some big piece of metal that makes a loud sucking noise, right? And so it was not possible to do a world product, at least in this, physical things. You guys have a better chance of that. AUDIENCE: Have you guys had any instances where the design approach didn't work or it failed? And then, what did you guys do about it? TOM KELLEY: Sure. Have we had failures? Yeah, you bet we have. I mean, this is the essence of our approach. If you're not failing, wow, you're just not taking any risks. It's like, I want to learn to ski, but I never want to fall down, right? Good luck with that. And so lots of failures along the way. We were just doing a social innovation project in Ghana that had to do with, let's just call it, sanitation issues so as not to turn off the whole crowd. But anyhow, the sanitation issue is public sanitation issues. And we had this idea that we'd put up signs all over the community and that we would draw maps of where the big issues were by having people call in and say, over there, there's a problem, over there. And so we put these signs up all over the community, call in. And we got zero phone calls. I mean, well, in fact, the phone rang. But nobody was ever there. It's like, what the heck? I mean, how are we going to get data this way, right? And then, we were outsiders. We didn't fully understand. We hadn't done all of the design research we needed to understand the community we were working in. And it turns out-- I guess, this is true in many parts of Africa-- an incoming phone call on your cellphone is free. An outgoing phone call is the one you pay for, right? So nobody is going to pay for a phone call to tell you about sanitation issues. And so there is this practice very common in that part of the world called flashing. And flashing is when you call someone just enough to make their phone ring and record your caller ID number, and then you hang up. And if they want to talk to you-- in other words, if they want to pay for the phone call-- then they'll call you back. And so we went and changed all of the signs all over and said, don't call this number, flash this number. And then, we got all kinds of data, right? But shame on us for not having figured it out. I mean, we could have printed those signs once instead of twice. But we were naive just as that outsider in the Indian village didn't fully understand all of the things that were making those family decisions. We didn't understand the local community enough to get it right the first time. DAVID KELLEY: Let me go on record as saying IDEO doesn't fail at the end very often. In the beginning, it's a technique. At the end, we tend to-- TOM KELLEY: Well, there was that whole phase called pen-based computers, many of you too young to remember. But we and all of our clients failed in that phase. Nobody wanted those things. DAVID KELLEY: Well, one of my favorite discussions about failure is about one of my buddies named John Cassidy. John Cassidy is a wonderful guy. He teaches at the d.school now. But he started a company called Klutz Press. You know, Klutz Press is books that you see in toy stores with stuff. Well, his first project was called "Juggling for the Complete Klutz." And it's a long story. And he thought he was in the juggling business. And he never came out with a book for five more years. But then he figured he was in the book business, and he's done very well. But he was in the juggling business when he started. Anyway, I got this book. I didn't know Cass at the time. But seemed like a good idea, you know, juggling. I could impress the girls at parties or something if I could juggle. And so I want to do that. Well, the whole first half of the book is about failing, about dropping the ball on the floor. It's called the drop. He does nothing in this book but desensitize you to the ball dropping on the floor. He has lots of ways to do that. But the ball hitting the floor is just not a big deal. It's not something that your brain is trying to prevent, because it's so normal. And so, then, when that happens, it's incredibly easy to learn how to juggle, because it's just not that mechanically difficult. But what's happening is your brain's constantly worried about or trying to keep you from dropping the ball on the ground. And so it's a great example of how you can get over that kind of fear that you might make a mistake. And then you can accomplish things that seem particularly difficult. TOM KELLEY: You know, a great microculture in the world that has got the right attitude about failure is the gaming culture. I mean, you think about gaming, it's about failure. I tell a story in the book about my son Sean who, Christmas Day a few years back, got the Tony Hawk skateboarding game. And those of you who have played it may know, it's got a skateboard inside. It's got a full-size skateboard that you stand on. And it controls the game. And he's there in front of three generations of Kelleys, right, trying out his new game. And on-screen, his avatar-- you know, his character on-screen, is smashing into the wall, like, a couple of hundred times. And unlike some other video games, he's also physically falling off of the skateboard and nearly breaking the glass coffee table and stuff like that. And I'm sitting there watching him for, like, half an hour. And it suddenly occurs to me, this is amazing, right? I mean, he's got the whole family watching him fail time after time after time, and he's not the tiniest bit embarrassed. So how is it that in the gaming culture, you have this what Jane McGonigal calls urgent optimism. It's like, OK, that failed. Better try again, as opposed to, in real life, where you say, oh, that failed. I'm marked for life, right? And so, if we can have a little bit more of the gaming culture, the best parts of the gaming culture, out here in the physical world, that would be a good thing. FREDERIK G. PFERDT: Great. I think that's a great note to end on, to encourage everybody over the weekend at least to try a game-- [LAUGHTER] FREDERIK G. PFERDT: --fail a couple of times, even if it's juggling. We have books which David and Tom might sign the back for a special price. And thanks, everybody, for coming. And have a great weekend. [APPLAUSE] TOM KELLEY: All right. [APPLAUSE] [MUSIC PLAYING]

Structure

Atg8 is a monomer of 117 aminoacids and a molecular weight of 13,6kDa. It consists of a 5-stranded β-sheet, which is enclosed by two α-helices at one side and one α-helix at the other side and exhibits a conserved GABARAP domain.[2] Even though Atg8 does not show a clear sequence homology to ubiquitin, its crystal structure reveals a conserved ubiquitin-like fold.[3][4]

Function

In autophagy

Atg8 is one of the key molecular components involved in autophagy, the cellular process mediating the lysosome/vacuole-dependent turnover of macromolecules and organelles.[5] Autophagy is induced upon nutrient depletion or rapamycin treatment and leads to the response of more than 30 autophagy-related (ATG) genes known so far, including ATG8. How exactly ATG proteins are regulated is still under investigation, but it is clear that all signals reporting on the availability of carbon and nitrogen sources converge on the TOR signalling pathway and that ATG proteins are downstream effectors of this pathway.[6] In case nutrient supplies are sufficient, the TOR signaling pathway hyperphosphorylates certain Atg proteins, thereby inhibiting autophagosome formation. After starvation autophagy is induced through the activation of Atg proteins both on the protein modification and the transcriptional level.

Atg8 is especially important in macroautophagy which is one of three distinct types of autophagy characterized by the formation of double-membrane enclosed vesicles that sequester portions of the cytosol, the so-called autophagosomes. The outer membrane of these autophagosomes subsequently fuses with the lysosome/vacuole to release an inter single membrane (autophagic body) destined for degradation.[5] During this process, Atg8 is particularly crucial for autophagosome maturation (lipidation).[7]

Like most Atg proteins, Atg8 is localized in the cytoplasm and at the PAS under nutrient-rich conditions, but becomes membrane-associated in case of autophagy induction. It then localizes to the site of autophagosome nucleation, the phagophore-assembly site (PAS).[2] Nucleation of the phagophore requires the accumulation of a set of Atg proteins and of class III phosphoinositide 3-kinase complexes on the PAS. The subsequent recruitment of Atg8 and other autophagy-related proteins is believed to trigger vesicle expansion in a concerted manner, presumably by providing the driving force for membrane curvature.[8] The transient conjugation of Atg8 to the membrane lipid phosphatidylethanolamine is essential for phagophore expansion as its mutation leads to defects in autophagosome formation.[9] It is distributed symmetrically on both sides of the autophagosome and it is assumed that there is a quantitative correlation between the amount of Atg8 and the vesicle size.[10][11][12][13]

After finishing vesicle expansion, the autophagosome is ready for fusion with the lysosome and Atg8 can either be released from the membrane for recycling (see below) or gets degraded in the autolysosome if left uncleaved.

ATG8 is also required for a different autophagy-related process called the cytoplasm-to-vacuole targeting (Cvt) pathway.[14] This yeast-specific process acts constitutively under nutrient-rich conditions and selectively transports hydrolases such as aminopeptidase I to the yeast vacuole. The Cvt pathway also requires Atg8 localised to the PAS for the formation of Cvt vesicles which then fuse with the vacuole to deliver hydrolases necessary for degradation.

Post-translational modification and regulatory cycle

Atg8 exists in a cytoplasmic and in a membrane-associated form.[15] Membrane association is achieved by coupling Atg8 to phosphatidylethanolamine (PE) which is a lipid constituent of plasma membranes. This post-translational modification process, called lipidation, is performed by the Atg8 conjugation system comprising the cysteine protease ATG4 (belonging to the caspase family), as well as the proteins ATG7, ATG3 and the ATG5-ATG12 complex.[16]

The Atg8 conjugation system works in analogy to the ubiquitination system. However, it is Atg8 itself that represents the ubiquitin-like protein (Ubl) being transferred to PE, while ATG7 functions like an E1 enzyme, ATG3 like an E2 enzyme and the ATG12-ATG5 complex like an E3 ligase.

The lipidation process is initiated by an ATG4-dependent post-translational cleavage of the last C-terminal amino acid residue of Atg8. After the cleavage, Atg8 exposes a C-terminal glycine residue (Gly 116) to which PE can then be coupled during the following steps. In the first step, the Gly116 residue of Atg8 binds to a cysteine residue of ATG7 via a thioester bond in an ATP-dependent manner. During the second step, Atg8 is transferred to Atg3 assuming the same type of thioester bond. Finally, Atg8 is detached from Atg3 and coupled to the amine head group of PE via an amide bond. This final step was found to be facilitated and stimulated by the ATG5-ATG12 complex.[17]

Both proteins, Atg5 and Atg12 were originally identified as part of another Ubl conjugating system that promotes conjugation of ATG12 to ATG5 via ATG7 and Atg10. This implies, that the ATG12 and the Atg8 conjugation system are actually interdependent.

Mammalian homologues

In higher eukaryotes Atg8 is not encoded by a single gene as in yeast, but derived from a multigene family. Four of its homologues have already been identified in mammalian cells.

One of them is LC3 (MAP1LC3A), a light chain of the microtubule-associated protein 1[18] Like Atg8, LC3 needs to be proteolytically cleaved and lipidated to be turned into its active form which can localize to the autophagosomal membrane. Similar to the situation in yeast, the activation process of LC3 is triggered by nutrient depletion, as well as in response to hormones.[11]

Mammalian LC3 isoforms contain a conserved Ser/Thr12, which is phosphorylated by protein kinase A to suppress participation in autophagy/mitophagy.[19]

Other homologues are the transport factor GATE-16 (Golgi-associated ATPase enhancer of 16 kDa) [20] which plays an important role in intra-golgi vesicular transport by stimulating NSF (N-ethylmaleimide-sensitive factor) ATPase activity and interacting with the Golgi v-SNARE GOS-28, and GABARAP (γ-aminobutyric acid type A receptor associated protein)[21][22] which facilitates clustering of GABAA receptors in combination with microtubules.

All three proteins are characterized by proteolytic activation processes upon which they get lipidated and localized to the plasma membrane. However, for GATE-16 and GABARAP membrane association seems to be possible even for the non-lipidated forms. Apart from LC3, GABARAP and GATE-16 the most recently but less well characterized mammalian homologue is ATGL8. Little is known about its actual activation process except for its interaction with one of the mammalian ATG4 homologues, hATG4A.[23]

See also

References

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External links

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