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Major facilitator superfamily

From Wikipedia, the free encyclopedia

Major Facilitator Superfamily
Crystal Structure of Lactose Permease LacY.
Identifiers
SymbolMFS
Pfam clanCL0015
TCDB2.A.1
OPM superfamily15
CDDcd06174

The major facilitator superfamily (MFS) is a superfamily of membrane transport proteins that facilitate movement of small solutes across cell membranes in response to chemiosmotic gradients.[1][2]

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  • Structural and Mechanistic Studies of ABC Transporters: Nature's Favorite Pump
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  • Neurotransmitter sodium symporter (NSS), LeuT transporter (with sound)
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Transcription

CAPTIONS START IN A FEW MINUTES SHE IS ALSO A PEER SCHOLAR FOR MEDICAL SCIENCES. SHE'S AN EXPERT IN -- RESEARCH OF ABC TRANPORTERS WHICH ARE UBIQUITOUS AT EXPORT A VARIETY OF MOLECULES ACROSS THE CEREBRAL MEMBRANE. THESE ARE CRITICAL SURVIVAL FACTORS BACTERIUM E. COLI FOR EXAMPLE HAVE 80 DIFFERENT ABC TRANSPORTERS ON BOARD. HUMANS HAVE 48 DIFFERENT ABC TRANSPORTERS -- GENETIC DISEASES HAVE BEEN LINKED TO THE DEFECTS IN THESE TRANSPORTERS. ABC TRANSPORTERS ARE ALSO CENTRAL TO MULTIDRUG RESISTANCE IN BACTERIA, FUNGI AND -- TRANSPORTERS ARE A COMPELLING CLASS OF PROTEIN -- AND FOR BASIC MEMBRANE BIOLOGY. DR. CHEN USED THE MODEL TRANSPORT FROM E. COLI AS A MODEL SYSTEM TO UNDERSTAND ABC TRANSPORTERS FOR MORE THAN 30 DECADES SCIENTISTS HAD STACKED UP DATA THAT GIVE THEM AN EXCELLENT IDEA OF WHAT THE MODEL ABC TRANSPORTERS SHOULD BE DOING YET IT'S DR. CHEN'S WORK THAT PRODUCED DETAILED PICTURES OF TRANSPORTERS IN ACTION. WITH HER SUCCESS IN MODEL TRANSPORTERS EXTENDING HER INVESTIGATION INTO ABC EXPORTERS OF WHICH LESS IS KNOWN ABOUT THEIR MECHANISM OF FUNCTION SUCH AS SUBSTRATES -- TO SUBSTRATE TRANSLOCATION.MORE RECENT HER LAB DETERMIN ED THE STRUCTURE OF THE MULTIDRUG TRANSPORTER -- MULTIDRUG RESISTENT IN CANCER CELLS. THEY AFFECT ABSORPTION, DISTRIBUTION AND DRUGS FOUND RELATED TO CANCERS AND -- TODAY WE ARE IN FOR A TREAT NATURE'S MORE INTRICATE MACHINE IN ACTION. DR. CHEN WE APPRECIATE YOUR TAKING THE TIME TO COME HERE TO DELIVER THE LECTURE. THE TITLE TALK IS STRUCTURAL AND MECHANISTIC STUDIES OF ABC TRANSPORTERS, NATURE'S FAVORITE -- PLEASE WELCOME OUR SPEAKER, DR. CHEN.->> THANK YOU FOR THE IN VITATION, THANK YOU FOR THE WONDERFUL INTRODUCTION.IT'S REALLY MY HONOR TO BE HE RE TO GIVE THIS LECTURE. SO THE VERY NICE INTRODUCTION WAS ABOUT ABC TRANS PORTERS. I WOULD LIKE TO POINT OUT NOWADAYS WE HAVE PROBABLY MORE THAN 2000 DIFFERENT ABC TRANSPORTERS IDENTIFIED -- ALL THE WAY TO HUMANS. THE FIELD ACTUALLY STARTED IN THE EARLY 80'S BY THE REALIZATION THAT TWO PROKARYOTIC TRANSPORTERS -- SHARE SIMILARITIES TO A HUMAN MULTI-- WHICH IS FIRST -- HERE AT NIH IN MICHAEL --'S LAB. SO THE REALIZATION THOSE GROUP OF PROTEINS HAVE SPECIAL SEQUENCE THAT'S ABLE TO BIND AND HYDROLYZE ATP -- ATP BINDING. SO NOW WE KNOW ALL ABC TRANSPORTERS INCLUDING EXPORTERS AND IMPORTERS ARE COMPOSED OF TWO TRANSMEMBRANE DOMAINS. THEY CAN BE HOMO DIMERS -- THEY FORM THE PATHWAY FOR DIFFERENT SUBSTRATES AND ALSO HAVE TWO COPIES OF INTRACELLULAR OR CYTOPLASMIC ATP BINDING AND THIS AGAIN CAN BE HOMO DIMERS OR HETERODIMERS.-SO ALL THE MEMBERS OF THE FA MILY SHOW THIS ARCHITECTURE. SO THIS IS FOR HISTORICAL REASONS -- HAS BEEN STARTED FOR MORE THAN 50 YEARS NOW AS A MODEL TO UNDERSTAND ABC-TRANSPORTERS.SO TH IS IS A PICTURE TAKEN IN 1981 ALL THE PEOPLE FROM MORE THAN 70 PEOPLE FROM ALL OVER THE WORLD COME TOGETHER TO TALK ABOUT THIS ONE TRANSPORTER.-SO WE CAN FIND A PICTURE FOR P GLYCOPROTEIN, THIS PICK SURE WOULD BE EVEN MORE CROWDED. SO WHAT IS THE TRANSPORTERS ---INTO THE CE LLS TO SUPPORT THE BACTERIA GROWTH. IN THE PARAPLASMIC SPACE IT HAS A BINDING PROTEIN -- BINDING PROTEIN WILL INTERACT WITH SUBSTRATE WITH HIGH AFFINITY AND ON THE CONFIRMATION CHANGE FROM OPEN TO THE CLOSE CONFIRMATION. AND IN THE PARAPLASM MEMBRANE, IT HAS TWO TRANSMEMBRANE CALLED 9 MILD S AND MILD G TOGETHER WITH ATP SUBUNIT CALLED THE MILD K. SO THERE ARE TWO MAJOR EVENTS HAPPENING IN THE ATP TRANSPORTER-CYCLE.-ON E OF THEM IS THE CHEMICAL EVENT OF ATP -- THE OTHER IS A MECHANICAL EVENT OF CONFIRMATION OR CHANGE. SO TRANSPORTERS WORK BY WHAT WE CALL THE OPERATING ACCESS MODEL WHICH WAS ORIGINALLY PROPOSED IN 1966.THIS IS THE PICTURE FROM VERY SHORT NATURE. THIS WILL BRING ACROSS THE CHEMICAL GRADIENT. THE INTERNAL BINDING SITES WERE ONE SIDE OF THE MEMBRANE AND ONE SIDE OF THE MEMBRANE ONLY. ARGUMENTING BETWEEN THOSE TWO CONFIRMATIONS THE -- ALTERING BETWEEN THOSE TWO CONFIRMATIONS -- THE MOSTINTERESTING QUEST ION OF COURSE FOR THE FAMILY IS HOW DOES THE TWO EVENTS, CHEMICAL EVENT OF ATP HYDRAULIC AND THE MECHANICAL EVENT OF CONFIRMATION. THERE IS BIO CHEMICAL EVENT I HAVE TO TALK ABOUT FIRST -- WHEN SHE FIRST RESUBSTITUTE THE MODEL TRANSPORT INTO -- SO THIS THE TRANSPORTER HAS A VERY LOW -- THE TITRATING IN THE -- REALLY DIDN'T DO MUCH.OR YOU JUST ADD IN THE BIND ING PROTEIN WITHOUT THE SUBSTRATE YOU HAVE VERY LOW LEVEL STIMULATION.-SO ONLY WHEN SHE ADD BINDING PROTEINS TOGETHER WITH THE MODELS, SHE CAN SEE THE STIMULATION IS ATP ACTIVITY. SO THIS IS A VERY IMPORTANT RESULT BECAUSE IT SHOWS THE INTERACTIONS OF THE BINDING PROTEIN IN THE PARAPLASMA SIDE OF THE MEMBRANE WILL REGULATE THE ATP ACTIVITY OF THE TRANSPORTER ON THE OTHER SIDE OF THE MEMBRANE.SO IT HAS TO BE TRANSFUSED ACROSS THE MEMBRANE TO REGULATE ATP ACTIVITY. NOWADAYS IT'S A COMMON OBSERVATION NOW ATP ACTIVITY OF ABC OFTEN REGULATE AT THE PRESENCE OF SUBVAFT -- SUBSTRATE AND THIS IS A WAY -- IF THE SUBSTRATE WAS ABSENT.-WHEN I IF YOU ARE ST ARTED TO STUDY THE TRANSPORTER IT'S-THINKING MAYBE WE SHOULD STABILIZE THE TRANSPORTER IN ONE PARTICULAR CONFIRMATION FOR CRYSTALLIZATION -- IS A KNOWN INHIBITOR OF ABC TRANSPORTERS. SO INDEED WHEN THE TEST -- ON THE MODEL TRANSPORTER IT INHIBITS THE ATP HYDROLYSIS AND THE MOUSE TRANSPORTER. BUT ALSO THERE'S SOMETHING VERY INTERESTING I OBSERVED. SO WHEN WE, THIS IS A SIMPLE EXPERIMENT -- TO THE C TERMINAL OF MILD K I CAN PULL DOWN ALL THREE COMPONENTS OF THE TRANS PORTER.-SO THIS IS TWO COPIES OF MILD K, THE ATP COMPONENT AND MILD S IS ONE OF THE TRANSMEMBRANE COMPONENTS AND THE MILD G SO OTHER TRANSMEMBRANE COMPONENTS. SO THE COMPLEX WITH ATP, SOMETHING VERY STRANGE HAPPENED. THOSE ADDITIONAL TURNED OUT TO BE -- I CAN NEVER GET RID OF. SO WHAT THIS TELLS US IS THAT THE TRANSPORTER IN WHAT IS CALLED THE TRANSLATION STATE FOR HYDROLYSIS, THE TRANSPORTER CHANGES TO THE BINDING PROTEIN.-IT BECOME A VERY HIGH AFFINITY COMPLEX, ALL FOUR COMPONENTS FORM A VERY STABLE COMPACT. SO I THOUGHT THIS WOULD BE A GOOD WAY TO CRYSTALLIZE IT. SO HOW DO WE -- CATALYTIC COMPOUND. THIS IS THE MECHANISM FOR ATP HYDROLYSIS WHEN THE -- ATP WILL BIND CATALYTIC BASE WILL POLARIZE THE WATER AND FORM THE COVALENT -- UNDER THESE CONDITIONS ATP WILL BE HYDROLYZED -- INTERMEDIATE THERE ARE SEVERAL WAYS WE CAN DO. ONE IS WE CAN MAKE A MUTATION AND A FORM OF THIS BASE. SO WITH THIS MUTATION ATP WILL BIND WITH HIGH AFFINITY BUT NOT BEING ABLE TO HYDROLYZE IT -- WILL MIMIC THE COVALENT COMPLEX OF THE ATP DOING HYDROLYSIS AND ATTRACTS THE COMPLEX. SO THE MULTIPLE WAYS AND -- TO CAP THE TRANSITION STATE AT LEAST ONE STRUCTURE WHICH IS SHOWN HERE. SO HERE IS THE MEMBRANE COMPONENT OF THE TRANSPORTER BLUE AND YELLOW ARE THE TWO TRANSMEMBRANE SUBUNITS MILD S AND THE MILD G. PURPLE HERE IS THE BINDING PROTEIN AND ON THE OTHER SIDE OF THE MEMBRANE THE GREEN AND THE RED ARE THE TWO ATP COMPONENT OF MILD K. AND MOST INTERESTING THING WE WANT TO FOCUS ON ABOUT THIS COMPLEX IS THE TRANSPORTER SUBSTRAIGHT AND LIGAND ATP. SO FIRST LET'S LOOK AT THE ATP. SO IN THIS COMPLEX, TWO ATP'S ARE TRAPPED AT AN INTERFACE BETWEEN THE TWO MILD K SUBUNITS SO WE CALL THIS A CLOSED MILD K. A CLOSED DIMER WITH TWO ATP'S RIGHT AT INTERFACE SIMULTANEOUSLY INTERACTING WITH THE BOTH SUBUNITS. SO A DETAILED MAP VIEW OF THIS CONFIRMATION ATP IS A SANDWICH WHEN THE WALKER A WALKER B MOTIF OF ONE SUBUNIT AND -- FOR THE SIGNATURE MOTIF FOR ABC TRANSPORTER SINCE THEY ARE HIGHLY CONSERVING ABC TRANSPORTERS. SO ATP SIMULTANEOUSLY, THEY BIN INTO BOTH SIDES OF THE DIMER AND THE PURPOSE IS FOR HYDROLYSIS. SO IN THIS CONVERSATION ATP IS READY TO BE HYDROLYZED. WHERE IS THE SUBSTRATE. IT'S SUPPOSED TO BE DELIVERED BY THE MOUSE'S BINDING PROTEIN AND THROUGH THE WORK OF -- MY POST DOC MENTOR WE KNOW THAT MILD BINDING HAS TWO MAJOR CONFIRMATIONS. THEY FORM A CLOSE CONFIRMATION WHERE MODEL IS BUBBLE BETWEEN THE TWO LOBES OF MBP. IN THE ABSENCE OF THE SUBSTRATE THE TWO LOBES ARE IN THE MORE OPEN CONFIRMATION. SO WE'LL CALL THIS THE OPEN CONFIRMATION AND THE BINDING WITH THE SUBSTRATE WILL BE THE CLOSE CONFIRMATION. SO IN THESE COMPLEX THE BINDING PROTEIN -- IS TRAPPED IN THE OPEN CONFIRMATION AND WHERE IS THE SUBSTRATE. THE SUBSTRATE NO LONGER BOUND WITH MPT. INSTEAD IT'S DELIVERED INTO THE TRANSMEMBRANE SUBUNIT AND HERE'S THE DENSITY FOR THE MODEL TOGETHER WITH SEVERAL WATER MOLECULES MEDIATING INTERACTION-BETWEEN TH E SUBSTRATE AND THE TRANSMEMBRANE PROTEIN. AND HERE ALSO A POCKET FORMED INTERFACE WHEN MILD S MILD G AND THE BINDING PROTEIN. SO THIS IS LARGE ENOUGH -- GLUCOSE AND IT IS OCCLUDED FROM THE MEMBRANE AND FROM THE PARAPLASMA SPACE SO MOUSE WILL NOT BE ABLE TO ESCAPE BACK. BY THIS WAY IN THIS CONFIRMATION BASICALLY THE PROTEIN HALF OF THE SUBSTRATE INSIDE THE MEMBRANE IT HAS NO WHERE TO GO BACK. AND WE THINK OF THIS IS IMPORTANT TO MAKE SURE MOUSE WILL GO TRANSPORTED IN ONE DIRECTION INSTEAD OF ESCAPING BACK TO THE PARAPLASMA SPACE. SO WHERE DOES THIS STRUCTURE REPRESENT IN THE CONTEXT OF ACCESS MODEL. THIS IS THE FLAT VIEW. WE JUST TAKE -- ACROSS THE PROTEIN AND NOW YOU CAN CLEARLY SEE THE BINDING POCKET. THIS POCKET IS OPEN TO THE PARAPLASMIC SIDE BY THE BINDING PROTEIN. SO WE INFILTRATED THIS STRUCTURE OUTWARD FACING CONFIRMATION WHERE THE SUBSTRATE IS BINDING SITE IS FACING OUTSIDE FACING THE PARAPLASMA SPACE. SO HERE INSTEAD OF OPEN TO THE PARAPLASMIC SPACE IS ACTUALLY CAPPED BY THE BINDING PROTEIN. AND THIS BY THE BINDING PROTEIN IS IMPORTANT BECAUSE WE KNOW THE AFFINITY OF THE BINDING SITE IS QUITE LOW.SO THIS WILL BE IMPORTANT TO MAKE SURE THE SUBSTRATE WILL NOT ESCAPE BACK. SO THE ORDER CONFIRMATION, THE INWARD FACING CONFIRMATION WE WERE ABLE TO OBTAIN THE CRYSTALS IN THE ABSENCE OF BINDING PROTEINS AND ANY NUCLEOTIDE.SO THIS IS THE LOW RESOLUTION STRUCTURE BUT NEVERTHELESS YOU CAN SEE THE BASIC ARCHITECTURE. THE MOUSE BINDING SITE NOW IS FACING INSIDE THE CELL CORRECTED TO THE CYTOPLASM AND THE TWO MILD K SUBUNITS NO LONGER CONTACT EACH OTHER SO IT FORMS WHAT WE CALL THE OPEN DIMER. SO WHEN WE PUT THOSE TWO STRUCTURES NEXT TO EACH OTHER, WE CAN BASICALLY CAPTURE THE TWO BASIC CONFIRMATIONS IN A TRANSPORTER CYCLE. INWARD FACING CONFIRMATION WITH THE TWO NUCLEOTIDE BINDING DOMAINS OPEN, SEPARATED FROMEACH OTHER AND THE BINDING SITE IS FACING INSIDE THE CELL. AND OUR FACING CONFIRMATION WHERE THE MOUSE BINDING SITE IS FACING MBP AND THE TWO ATP SANDWICH WHAT WE CALL THE CLOSE DIMER OF MILD K. IT TURNS OUT THE TRANSITION BETWEEN THE INWARD FACING CONFIRMATION TO THE OUTWARD FACING CONFIRMATION REQUIRES NOT ONLY ATP BUT ALSO THE BINDING PROTEIN. SO THIS IS -- AMY DAVIS' LAB WHEN SHE WANTS TO UNDERSTAND WHAT DOES THE BINDING PROTEIN REALLY DO TO STIMULATE ATP HYDROLYSIS. WHAT SHE HAS DONE, SHE PUT A STIMULATOR AT THE TWO MBD'S INSIDE THE CELL ON MILD K AND -- INTERACTIONS OF THOSE TWO -- SHE CAN DISTINGUISH INWARD FACING OPEN DIMER WITH THE OUTWARD FACING CLOSER DIMER.BASICALLY WHAT HER DAT A SHOWS IS IF YOU TAKE THE -- INWARD FACING TRANSPORTER ADDING ATP, IT DOES NOT CAUSE ANY CONFIRMATIONAL-CHANGE. ONLY IN THE PRESENCE WHEN BOTH BINDING PROTEIN AND ATP INFORMED OUTWARD FACING CONFIRMATION -- WITH THE TRANSPORTER IS GOING TO DO SOMETHING WITH THE TRANSPORTER.WE TRY TO UNDERSTAND BY BASICALLY DETERMINE THE STRUCTURE OF WHAT WE CALL THE PRETRANSLOCATION STATE. SO THIS STRUCTURE IS IN THE PRESENCE OF BINDING PROTEIN WITH HIGH CONCENTRATIONS OF SUGAR AND ALSO IN THE ABSENCE OF A NUCLEOTIDE NO ATP OR ADP. SO WE CALL THIS THE PRETRANSLOCATION STATE.YOU CAN SEE THE BIE BLEDDING PROTEIN IN THE CLOSER CONFIRMATION WITH THE SUBSTRATE STILL BINDS TO IT. AND WE CAN ALSO SEE THE BINDING SITE INSIDE THE MEMBRANE BECAUSE WE HAD HIGH CONCENTRATIONS OF -- SO WE SEE BOUND HERE. THIS STRUCTURE REPRESENTS THE PRETRANSLOCATION BEFORE -- HASBEEN DELIVER ED TO THIS SITE. BECAUSE THIS BINDING SITE HAS MUCH HIGHER AFFINITY IN COMPARISON TO THE TRANSMEMBRANE BINDING SITE. SO WITH ALL THESE STRUCTURES, WHAT CAN WE LEARN ABOUT THE SYSTEM. WHAT KIND OF MECHANISTIC QUESTIONS CAN WE ADDRESS. SO FIRST WE'D LIKE TO SEE THE STRUCTURED DETAILS OF ALTERNATING ACCESS MODELS. HERE WE PRESENT THE THREE STRUCTURES. INWARD FACING STRUCTURE, WE ALSO BELIEVE IT REPRESENTS WHAT WE CALL THE RESTING STATE BECAUSE IT HAS VERY LOW ATP ACTIVITY AND THE SUBSTRAIGHT IS ABSENT. NOW WE ALSO PRESENT OUTWARD FACING STRUCTURE CONFIRMATION WHERE MILD MOUSE IS ALREADY DELIVERED FROM THE BINDING SITE FROM MDP INTO THE MEMBRANE AND THE TWO ATP'S ARE BEING POSITIONED AT THE DIMER INTERFACE READY TO BE HYDROLYZED.AND PRESENT AN INTERMEDIATE BETWEEN THE INWARD FACING AND OUTWARD FACING STATE WE CALL THE PRETRANSLOCATION STATE WHICH REPRESENTS THE INITIAL CONTACT OF THE BINDING PROTEIN WITH THE TRANSPORT ARE. WHEN WE ANALYZE THE STRUCK CHOOSH BETWEEN THOSE CONFIRMATIONS THEY ARE SMALL LOCAL CONFIRMATIONAL CHANGES. THE CONFIRMATIONAL CHANGE CAN DESCRIBE AS RIGID BODY LOCATIONS OF THE TWO TRANSMEMBRANE DOMAINS AND THE TWO NUCLEOTIDE BINDING DOMAINS.I SHOULD POINT OUT MILD K IS -- EACH HAS TWO SUBDOMAINS -- NUCLEOTIDE BINDING DOMAIN WILL HYDROLYZE ATM AND THE C TERMINAL REGULAR TO THE DOMAIN INTERACTING WITH OTHER REGULATORY PROTEINS. SO IN DOING THIS TRANSITION, THE TWO NUCLEOTIDE BINDING DOMAINS WILL ROTATE INWARDS TO EACH OTHER AND THE TWO MBD'S, THE TWO TRANSMEMBRANES WILL ALSO ROTATE. SO THIS IS THE TRANSITION BETWEEN THE INWARD FACING REST STATE -- INDUCE THE BINDING PROTEIN. AND THIS IS THE TRANSITION BETWEEN THE PRETRANSLOCATION STATE -- BIND HERE TOWARDS THE OUTWARD FACING STATE WHERE IT IS DELIVERED INTO THE MEMBRANE.-THEN YOU CAN SEE THE TWO LOBES OF MDP OPEN UP TO RELEASE MODELS AND THE TWO TRANSMEMBRANE DOMAINS WILL ROTATE TO RECEIVE THE MODEL AND THE TWO MBP WILL ROTATE INWARD SO THEY CAN BIND AND HYDROLYZE ATP. WHEN YOU LOOK AT THIS MOVIE PRETTY MUCH ALL PROTEIN PROTEIN INTERFACE ARE CHANGING EXCEPT FOR TWO PLACES. ONE PLACE IS AT THE C TERMINAL. THE REGULATORY DOMAIN INTERFACE OF MILD K DIMER IS MAINTAINED IN THIS TRANSITION. AND THE OTHER INTERFACE IS ACROSS WHAT WE CALL THE PG. THIS IS THE LARGE PARAPLASMIC LOOP FROM THE MILD S SUBUNIT WITH MBP. SO THIS INTERFACE IS MAINTAINED AND THIS INTERFACE IS MAINTAINED. WE LIKE TO TEST WHETHER THIS GRAPHIC OBSERVED CONFIRMATION CHANGE IS -- DURING A TRANSPORTER CYCLE.AGAIN THIS IS A WORK FRO M AMY DAVIDSON.-WHAT SHE DID IS SHE DECIDED TO CROSS LINK THE REGULATORY DOMAIN WHICH WE KNOW WILL MAINTAIN ITS INTERFACE DURING THE TRANSPORTER CYCLE BY 215. SO UNDER OXIDATION CONDITIONS-THE DIMER IS ALMOST 100% OF MILD K FORM OF DIMERS. SO THOSE TWO DOMAIN ARE CROSS LINKED AND THE CROSS LINK TRANSPORTER WORKS JUST FINE. SO THIS MEANS IN THE TRANSPORTER CYCLE -- THE TWO REGULATORY DOMAINS DO NOT NEED TO DEASSOCIATE JUST AS WE SEE IN THE CRYSTAL STRUCTURES. WE ALSO -- THE INTERFACE BETWEEN THE P2 DOMAIN AND THE MBP WHICH IS IN THE PARAPLASMIC SPACE. BY DOING ALSO CROSS LINKING WE CAN CROSS LINK MDP WITH MILD S A HUNDRED PERCENT. THIS CROSS LINK TRANSPORTER BETWEEN FUNCTION JUST FINE. SO IN CONTRAST THE CROSS LINK AT THE PROTEAN PROTEIN INTERFACE THAT'S SUPPOSED TO CHANGE. WE SEE SOMETHING TOTALLY DIFFERENT. SO ONE EXAMPLE IS YOU CAN SEE 230 -- COMING TOGETHER FOR WHAT WE BELIEVE FORM THE PARAPLALS MA IN ASMA IN THE INWARD FACING CONFIRMATION. AND WE CAN CROSS LINK THIS TRANSPORTER WILL SPONTANEOUSLY CROSS LINK THE MILD S AND THE MILD G WILL BECOME ONE BEND BE CROSS LINK. SO THE CROSS LINK STANDS FOR THE K NO LONGER FUNCTION BECAUSE THE TRANSITION FROM THE INWARD FACING STRUCTURE TO THE PRETRANSLOCATION STRUCTURE THEN FURTHER TOWARDS THE OUTWARD FATING STRUCTURE WILL REQUIRE THE TWO SMALL MOLECULES THE TWO AMINO ACIDS TO BE SEPARATED SO THEY OPEN UP THE -- SO THE MOUSE CAN DELIVER HERE. SO UNDER OXIDATION CONDITIONS,THE CROSS L INK TRANSPORTER NO LONGER FUNCTIONS AND PUTS THE -- BIOCHEMICAL OR EXPERIMENT WAS DONE TO VALIDATE THE CONFIRMATIONAL CHANGES WE OBSERVE IN THE CRYSTAL STRUCTURE. THE NEXT QUESTION I HAVE TO ADDRESS I MENTIONED FOR ATP TRANSPORTERS IT'S VERY COMMONTHAT THE PRES ENCE OF THE SUBSTRATE WILL TURN ON THE ATP'S ACTIVITY. AND WHEN THE BINDING PROTEIN DEPENDS SUCH AS TRANSPORTER IT'S THE PRESENCE OF THE MOUSE BINDING PROTEIN TOGETHER WITH THE MODEL WILL STIMULATE ATP'S ACTIVITY. SO -- BY COMPARING THE STRUCTURE OF THE RESTING STATE THE TRANSPORTER IN THE ABSENCE OF ANY SUBSTRATE AND TOGETHER WITH THE TRANSPORTER THAT'S BEEN STABILIZED BY THE BINDING PROTEIN WE CAN SEE THE INTERACTION OF THE BINDING PROTEIN WILL CROSS GLOBAL CONFIRMATIONAL CHANGE OFF OF THE TRANSPORTER. YOU NEED THIS PQ DOMAIN WHICH IS ABSENT IN THE INWARD FACING STRUCTURE BECOME ORGANIZED AND INTERACT WITH THE BINDING PROTEIN. WE BELIEVE IN THIS CONFIRMATION THE P2 DOMAIN IS QUITE FLEXIBLE. IT'S MOVING AROUND LIKE A RECEPTOR. ONCE THE BINDING PROTEIN WILL-HELP TO BRIN G THE BINDING PROTEIN TOWARDS THE TRANSPORTER TO FORM THIS INITIAL COMPLEX. THE MORE IMPORTANTLY THE INTERACTION OF THE BINDING PROTEIN WITH THE TRANSPORTERWILL CROSS ROT ATION OF THE TRANSMEMBRANE DOMAIN. AND YOU CAN SEE THAT BY COMPARING THE TRANSMEMBRANE BINDING SITE IN THE INWARD FACING STRUCTURE WITHOUT THE BIN BINDING PROTEIN NOW WE CHANGE FROM INWARD FACING BINDING -- SO THE TWO SUBUNITS ROTATED RELATIVELY TOWARD EACH OTHER AND CLOSE THESE ENDS. THESE ROTATIONS WILL BRING THE TO BINDING DOMAINS ON TO THOSE TWO SUBUNITS CLOSE TO EACH OTHER. AND IT WILL BE CLOSE ENOUGH. NOW ATP BINDING WILL COMPLETE THE TRANSITION TO THE OUTWARD FACING STATE. SO THIS IS A CLOSE UP VIEW OF THE CONFIRMATION REGARDING THE ATP BINDING SITE. SO THIS IS THE WALKER A MOTIF AND 192 THAT'S WE KNOW IN FACT WAS ATP. SO IN THE ABSENCE OF ANY BINDING PROTEINS IN THE OPEN DIMER CONFIRMATION OF MILD K, THE WALKER A MOTIF AND ATP BINDING MOTIF IS NOT IN CONTACT WITH ANY RESIDUE FROM THE OTHER SIDE OF THE, IN THE OTHER SUBUNITS SO THEY ARE SEPARATE FROM EACH OTHER.-BUT THE INTERACTION OF THE BINDING PROTEIN WITH THE TRANSPORTER WILL CAUSE THE MBD TO ROTATE INWARD. WITH THOSE CONFIGURATION THOSE RUSE DUES IS MAKING HYDROGEN BONDING WITH THE SECOND MBD. SO NOW THE TWO MBD START TO COMMUNICATE WITH EACH OTHER. AND IN THIS CONFIGURATION ATP COMES OVER WILL FURTHER CAUSE CLOSURE OF THIS MILD K INTERFACE.-NOW WE FORM THE CLOSE MILD K WHERE ATP'S POSITION AND SIMULTANEOUSLY INTERACTING WITHTHE SUBUNIT . SO IN THIS CLOSE CONFIRMATIONATP AS I MENT IONED BEFORE NOW IS THE POSITION ALL THE CAT POLITICAL RESIDUES ARE IN THE RIGHT PLACE TO HYDROLYZE ATP.-ONLY IN THE CLOSE THE CONFIRMATION ATP IS HYDROLYZED. SO FOR THIS OUTWARD FACING STATE THE MOLECULES THE TWO THINGS -- FROM THE BINDING PROTEIN INTO THE MEMBRANE THE SECOND THE THING IS IT WILL PLACE ATP IN A POSITION TO BE HYDROLYZED. SO THE REASON ONLY THE CLOSER DIMER CAN HYDROLYZE ATP ANALOGY TO WHAT WE KNOW -- DISCOVERED IN MANY OTHER ATP. THIS IS AN EXAMPLE FOR THE S1 ATPASE .ú THIS IS THE WALKER A MOTIF OF ONE SUBUNIT THAT WILL BIND ATP AND IT HAS ALL THE CAT POLITICAL RHESUS DOOTZ ABLE TO HYDROLYZE ATP.HOWEVER IT IS NOT ABLE TO HYDROLYZE ATP IN THE ABSENCE OF -- WHICH WILL BE SUPPLIED BY ANOTHER SUBUNIT.-SO THE FUNCTION OF THE AR GININE FINGER IS TO POSITION THE PHOSPHATE SO IT WILL BE ABLE TO DEHYDROLYZE.-SO HERE IN THE MODEL TRANSPORTER -- CAN BE REPLACED-WHAT WE CAL L THE SIGNATURE PHASE OF THE ATP TRANSPORTERS -- IT-DOES EXACTLY THE SAME THING AS AVERAGE MEAN FINGER. IT POSITIONS THE PHOSPHATE TO BE HYDROLYZED.AND AFTER THIS HYPOTHESES BY EXPERIMENT KIND OF -- MORE OR LESS FOR ACCIDENTS. WE TOOK ADVANTAGE OF WE INFORMED THE PRETRANSLOCATION STAGE BY TWO METHODS. ONE WAY IS CO-CRYSTALLIZE BINDING PROTEIN WILD TYPE BINDING PROTEIN WITH HIGH CONCENTRATIONS OF MODEL. ANOTHER WAY WE TOOK APPROACH IS WE PUT -- CROSS LINK AND STABILIZE THE BINDING PROTEIN IN THE CONFIRMATION.-SO THEY CAN UNLOCK THE TRANSPORTER IN THISPRETRANSLOCATION STAGE WHERE THE TWO MBD'S ARE SEPARATED FROM EACH OTHER. SO WE SAY OKAY LET'S NOW ATP AND SEE IF THERE'S ONLY LOCAL CONFIRMATION OF CHANGE ACROSS THE ATP BINDING.THAT WAS THE ORIGINAL DOSE FOR THIS EXPERIMENT. SO THE RESULTS CAME OUT -- SO IN THE CROSS LINK MBP ONE WOULD PREVENT MBP FROM OPENING. THIS IS A HYDROLYZABLE ATP ANALOGUE.-WHAT WE SEE IS WE CAN SEE THE CRYSTAL STAY IN THE SAME CONFIRMATION AND WE CAN SEE BINDING TO THE NUCLEAR BINDING SITE.BUT EQUALLY USED THE WILD TYPE MBP -- WE WERE VERY SURPRISED TO SEE THE -- OPENED UP AND THE WHOLE TRANSPORTER TRANSITION TO THE OUTWARD FACING CONFIRMATION. AND THE FIRST THING WITH FIRST TIME WE DID THIS WAS -- SO WE RADIATED THREE TIMES -- EXPERIMENT AND AGAIN EVERY TIME SINGLE TIME WAS TO HAVING THOSE OUTWARD FACING CONFIRMATIONS. SO WE HAD A VERY SPECIAL ARRANGEMENT IN OUR CRYSTALS AND THIS CONFIRMATIONAL SOMEHOW DESTROY IT. BUT WE ALSO SEE SOMETHING VERY INTERESTING. SO IN THIS OUTWARD FACING CONFIRMATION WE CAN SEE THE -- SO THIS EXPERIMENT TELLS US, IN THIS EXPERIMENT -- DO NOT GET HYDROLYZED. BUT WE LOOK AT THE DENSITIES FOR THE OPEN WHEN THE MBP'S ARE OPERATED FROM EACH OTHER. WE CAN ONLY SEE A -- WHEN WE LOOK AT THIS STRUCTURE WE SAY UH-HUH.THE REASON WE DON'T SEE THE -- GAMMA PHOSPHATE IS BECAUSE THE GAMMA PHOSPHATE IS NOT IN ONE PLACE IT'S PROBABLY MOVINGAROUND.-THAT'S W HY IT HAPPENS NO DENSITY.-AND THE REASON THE GAMMA PHOSPHATE IS MOVING AROUND IS BECAUSE -- IS NOT IN PLACE TO POSITION IT.AND WE WENT TO THE LITERATURE TO COMPARE.THERE ARE MANY HIGH RESOLUTION STRUCTURES THAT WAS ISOLATED MBD WITH ATP BOUND.SO WE TOOK A POSITION THOSE STRUCTURES THE POSITION FOR ACP IS VERY WELL BUT THE POSITION FOR THE GAMMA PHOSPHATE IS VERY DIFFERENT CRISES IN SOME STRUCTURES.SO THIS ACTUALLY IN FORCE ONLY IN THE CLOSE CONFIRMATION, CLOSE DIEMPLE CONFIRMATIONS THE PRESENCE OF -- WILL POSITION THE GAMMA PHOSPHATES FOR HYDROLYSIS. SO THIS AGAIN EXPLAINS WHY THE OPEN MBD DIMER HAS VERY LOW ATPACTIVITY. DURING ATP HYDROLYSIS THE CONFIRMATION OF ATP ACTUALLY CHANGES. SO IN THE GRAND STATE THE GOT MA PHOSPHATE FORMS THE -- CONFIRMATION AND -- WHAT WE CALL THE -- BASICALLY THOSE FOUR ATOMS PHOSPHATE AND THE THREE -- FROM ONE PLANE.-ON EACH SIDE WE HAVE OXYGE N. ONE IS THE OXYGEN FROM ADP. THE OTHER ONE IS ATTACKING THE OXYGENS ON THE ATTACKING WATER. THIS IS A VERY SPECIAL STRUCTURE AND THE TRANSITION STATE FOR ATP HYDROLYSIS. SO IN THE FIELD PEOPLE WONDER WHETHER THE TRANSITION FROM THE TETRAHEDRAL CONFIRMATION TO THE TRANSITION STATE WILL CROSS ANY GLOBAL CONFIRMATION CHANGE FOR THE PROTEIN. SO HERE WE ADDRESS THAT QUESTION BY BASICALLY CRYSTALLIZE DETERMINE THE HIGH RESOLUTION STRUCTURE OF THE TRANSPORTER IN CONTRAST WITH THE NUCLEOTIDES -- OR THE TRANSITION STATE. SO HERE IS THE DENSITY FOR THE GROUND STATE, THIS IS DETERMINED BY THE AMP -- YOU CAN SEE THE NICE TETRAHEDRAL STRUCTURE OF THE GAMMA PHOSPHATE IN THIS CONFIRMATION. WHEN WE HAVE THE TRANSITION STATE WITH ALUMINUM FLUORIDE -- WE CAN SEE THE CONFIRMATION. IT'S A GLOBAL CONFIRMATION FOR THE STRUCTURE DIDN'T CHANGE AND BUT NOW YOU CAN SEE THE NICE -- FOR THE GAMMA PHOSPHATE AND THE POSITION TO ATTACK A PHOSPHATE. SO THIS IS BASICALLY TELLS US FOR ABC TRANSPORTERS THE FORMATION OF THE TRANSITION STATE OF THE HYDROLYSIS DID NOT CROSS ANY GLOBAL CONFIRMATION OR CHANGE FOR THE PROTEIN. IT'S AN AREA CHEMICAL FORHYDROLYSIS. SO THE NEXT QUESTION WE LIKE TO AWE DRESS IS HOW THE ATP HYDROLYSIS ENABLES SUBSTRATE TRANSPORTER. SO MOST OF COURSE THE STRAIGHTFORWARD WAYS WOULD LIKE TO DETERMINE THE STRUCTURE OF THE POST HYDROLYSIS STATE TO SEE WHAT HAPPENS TO -- AFTER HYDROLYSIS WHICH WE WERE NOT SUCCESSFUL.AND I BELIEVE THERE'S A REASON. THE REASON IS IF YOU LOOK AT THE STRUCTURE OF THE OUTWARD FACING STATE, THE DIMER, THE OPEN CLOSED DIMER IS BASICALLY LINKED TOGETHER FOR THE GAMMA PHOSPHATE.-AND SO YOU CAN IMAGINE AFTER AT P HYDROLYSIS, THIS BOND IS GOING TO BREAK AND THEN AFTER RELEASE OF THE INORGANIC PHOSPHATES, THIS DIMER IS NO LONGER TO BE STABLE. SO IT WILL OPEN UP -- PROBABLY WILL BE VERY SIMILAR TO THE PRETRANSLOCATION STAGE.-WHEN YOU OPENED UP THE MBD ARE DIMER YOU WILL CROSS ROTATION OF THE TRANSMEMBRANE DOMAIN. BUT THERE YOU WERE FORCE THE MDB'S TO CLOSE. BUT THIS TIME THE SUBSTRATE MODEL IS ALREADY DELIVERED TO THE MEMBRANE SITE. SO MBP WILL HAVE TO CLOSE IN THE ABSENCE OF THE SUBSTRATE WHICH WE KNOW IS VERY IS UNFAVORABLE. SO IN THIS CASE I THINK OF THIS COMPLEX WILL QUICKLY RELAX INTO THE INWARD FACING CONFIRMATION MBT WILL DEASSOCIATE AND FIND ANOTHER MOUSE TO INTERACT WITH. AND FROM STUDIES OF EPR AND ISOLATED MBD WE KNOW AFTER ATP HYDROLYSIS THE TWO MBD'S WILL OPEN UP.BASED ON THOSE EVIDENCE WE PROPOSE THIS IS THE BASIC HYDROLYSIS CYCLE. THE ATP BINDING WILL INDUCE OUTWARD FACING STAGE. DELIVER INTO THE MEMBRANE AND ATP WILL BE READY TO DEHYDROLYZE. THEN THE ENERGY FROM ATP HYDROLYSIS WILL COMPLETE THE CYCLE ALL THE WAY BACK TO THE INWARD FACING STATE OR THE SUBSTRATE WILL BE DEASSOCIATED INTO THE MEMBRANE INSIDE THECELL. SO THIS IS OUR UNDERSTANDING OF THE TRANSPORTER CYCLE.-AND SO ONCE WE KNOW HOW THE ABC TRANSPORTER WORKS THE NATURAL QUESTION IS CAN WE REGULATE THESE ACTIVITIES. IT TURNS OUT THAT NATURE HAS ALREADY COME UP WITH A SOLUTIONFOR THE E. COLI MOUSE TRANSPORTER. SO THIS IS RELATED TO WHAT WE KNOW AS CARBON CATABOLIC REPRESSION.IT TURNS OUT -- IS NOT E. COLI FAVORITE SUGAR. SO FROM THE ENERGETIC POINT OF VIEW, THERE ARE CERTAIN CARBOHYDRATES WERE PREFERRED BY E. COLI BECAUSE IT WILL BE QUICKLY METABOLIZED. SO IN THE PRESENCE OF THOSE CARBOHYDRATES WHAT E. COLI WILL DO IS PRESS EXPRESSION AND THE TRANSPORTER ACTIVITIES OF ALL OTHER CARBOHYDRATES.-AND THIS IS A NOMINAL NOW REGULATED ABOUT FIVE TO TEN PERCENT OCCUR LIE GENES. THIS REGULATION IS BEING ACHIEVED THROUGH ONE PROTEIN CALLED QA. THE ENZYMES HERE OF THE GLUCOSE TRANSPORTER PART OF THE PTS SYSTEM WHICH IS STARTED HERE AT NIH. SO IN THE ABSENCE OF A PREFERRED SUGAR AS GLUCOSE, ETA WILL MOSTLY IN THE PHOSPHORYLATED STATE. THE TOAST FORELATED EQA WILL TURN AROUND CYCLIC A AND P SYNTHESIS WHICH IN TURN WILL TURN AROUND. A LOT -- WHICH I'LL ENCODE -- OTHER CARBON SOURCE. WHEN GLUCOSE IS PRESENT, IT WILL BE TRANSPORTED INTO THE SYSTEM THROUGH THE PTS SYSTEM AND PHOSPHORYLATED AND IT ORIGINATED FROM PEP THROUGH A CAST INDICATED OF REACTIONS. AND THE INTERMEDIATE OF THIS REACTION NOW E6789 TA WILL BE SHIFTED UPON THE PHOSPHORYLATED TO DEPHOSPHORYLATED STATE. NOW THE DEPHOSPHORYLATED ETA WILL GO AHEAD AND THE BLOCK OF ACTIVITIES OFF A NUMBER OF SUGAR TRANSPORTERS. WHICH INCLUDES THE LACK OF Y TRANSPORTER WILL PICK UP LACTOSE -- BY INTERACTING WITH -- SO THE QUESTION IS HOW DOES E2A DO IT. OKAY.-ONE MORE THING I WANT TO POINT OUT. PHYSICALLY BLOCKING THE ACTIVITIES OF THOSETRANSPORTERS, ACTUALLY THEY ARE TWO THINGS. ONE IS PREVENT IMMEDIATE UPTAKE OFF THESE SUGARS. ANOTHER THING IS ACTUALLY WILL DOWN REGULATE THE EXPRESSION OF ALL THE GENES THAT WILL ENABLE TRANSPORTER METABOLISM OF THOSE SUGAR.BOAST THOSE CARBOHYDRATES TURNSOUT T O BE THE INDUCERS OF THIS. IT'S BEST TO STUDY THE SYSTEM WE ALL LEARN IT'S THE LACTOSE, THE LACK OF IN THE ABSENCE OF ANY LACTOSE E COLI DOES NOT WASTE ENERGY TO MAKE ENZYME THAT WILL BREAK DOWN LACTOSE.-SO WHAT HAPPENS THERE' S A REPRESSER WILL BIND TO THE OPERATOR WILL PREVENT-EXPRESSION -- WILL B E TRANSPORTED INTO THE CELL.IS ICE FOAFERL O F LACTOSE WILL INTERACT WITH THE REPRESSER AND THIS INTERACTION WILL BLOCK THE BINDING OF REPRESSER TO THE OPERATOR.-NOW POLYMERASE WILL BIND AND. GO AHEAD AND MAKE A GENE WILL ENABLE LACTOSE UP TAKE AND THE BREAK DOWN. SO MILD -- ACTIVATOR WE'LL CALLED THE MILD T. SO ACTIVATION OF THE MILD -- ALL THE GENE THAT WILL ENABLE TRANSPORT AND BREAK DOWN IS UNDER REGULATION OF MILD T BUT ALSO REQUIRED THE PRESENCE OF -- SO WHEN ETA PREVENTS TRANSPORTER IT WILL ALSO DOWN REGULATE THE EXPRESSION OF ALL THE MILD -- SO E2A IS AN EVENTUAL MOLECULE IN THE SYSTEM HAS BEEN STARTED FORMANY YEARS THROUGH MANY LABORATORIES.THROUGH THE WORK WE KNOW E2A IS A MOLECULE WITH 168 MOLECULES -- FLEXIBLE AGENTS AND MAJOR STRUCTURE WHICH LOOKS LIKE THIS. SO WE KNOW PHOSPHORYLATION OR INTERACTIONS WITH OTHER MOLECULES WILL CHANGE THE CONFIRMATION OF E2A. THE STRUCTURE OF E2A WAS DOWN STREAM -- AS WELL AS KINASE DETERMINE AND THEY SHOW ACTUALLY E2A USE A COMMON SOURCES INTERACTING WITH ALL OF THE MOLECULES.AND THE ONE -- WHICH IS YELLOW HERE. ALL OF THE INTERFACE INVOLVES HISTIDINE 90 WHICH IS KNOWN AS PHOSPHORYLATION SIDE FOR E2A. SO WE LIKE TO KNOW HOW E2A IN THE DEPHOSPHORYLATED FORM WILL INHIBIT MILD ACTIVITY OF THE MOUSE TRANSPORTER. AND WE APPROACH THIS BY DETERMINING THE STRUCTURE OF THE TRANSPORTER TOGETHER WITH E2A.AND THIS IS WHAT IT LOOKS LIKE. SO THIS IS THE COMPLEX. AND MOUSE'S TRANSPORTER IS IN THE INWARD FACING STATE AND WE SEE TWO E2A MOLECULES WHICH ARE SHOWN IN PURPLE HERE BIND TO THE MILD K SUBUNITS. AND BEFORE OUR STRUCTURE, ACTUALLY THERE WERE MANY -- HAS ALREADY IDENTIFIED MUTATIONS IN THE MODEL TRANSPORTER WILL ESCAPE E2A INTERACTION. AND WE LOOK WHERE THE LOCATIONS THOSE MUTATIONS WHICHARE SHOWN I N GREEN AND YELLOW HERE WERE ALL LOCATED AS INTERFACE WITH E2A. SO THIS GIVES US CONFIDENCE ABOUT THE ACCURACY OF THISCOMPLEX. ALSO, THE SITE OF PHOSPHORYLATION IS AGAIN RIGHT AT THE INTERFACE. IT ACTUALLY FORMS A HYDROGEN BOND WITH THE MILD K SUBUNIT. SO THIS GIVES, THIS EXPLAINS WHY PHOSPHORYLATION OF THIS HISTIDINE WILL BECOME, WILL DEASSOCIATE, WILL MAKE THIS COMPLEX UNSTABLE SO THIS INTERFACE IS NOT COMPATIBLE WITH PHOSPHORYLATED E2A. SO ONLY IN THE DEPHOSPHORYLATION FORM E2A WILL BIND THE TRANSPORTER AND INHIBIT ITS-FUNCTION. SO HOW DOES E2A INHIBIT MOUSE TRANSPORTER.WE REVIEW WHAT THE TRANSPORTER HAS TO DO TO ENABLE -- BASIC THE RIDGED BODY ROTATION INVOLVES THE TRANSMEMBRANE DOMAIN AND THE MBD. NOW WE HAVE TWO E2A MONITORS COME AND BIND TO THE MILD K SUBUNITS. AND EVERY E2A SIMULTANEOUSLY INTERACTING WITH THE REGULATORY DOMAIN OF ONE SUBUNIT AND THE MBD DOMAIN OF OTHER SUBUNITS. THEY BASICALLY LOCK THE TRANSPORTER IN THIS INWARD FACING STATE. NOW THE MBD CAN NO LONGER ROTATE IN TO FORM THE OUTWARD FACING STATE. SO BASICALLY -- INHIBITOR IT PREVENTS MILD UPTAKE AND ATP HYDROLYSIS BY PREVENTING THE CONFIRMATION CHANGE.THIS TRANSPORT HAS TO GO THROUGH TO DO THESE THINGS. SO ANOTHER INTERESTING THING ABOUT E2A IS ACTUALLY BY OBSERVATIONS NATURALLY IT HAS THIS TWO FORMS. THE FULL LENGTH E2A. THE OTHER LINE IS TRUNCATED E2A -- WHEN PEOPLE STUDY HOW E2A FUNCTION WE NOTICE THE DIVERSION OF E2A HAS NO PROBLEM WITH INTERACTING WITH THE SOLUBLE PARTNER. HOWEVER THIS DEFICIENT IN INTERACTING WITH TRANSMEMBRANE SUBUNITS.SO IN OUR CRYSTAL STRUCTURE, WE HAVE E6789 2A BUT ONLY SEE RESIDUES FROM 19 -- SO WHEN YOU LOOK AT THE POSITION OF THE FIRST RESIDUE WE SEE THEY ARE POINTING RIGHT TOWARDS THE MEMBRANE. AND ACTUALLY WAS -- MANY YEARS AGO HAS PROPOSED THIS IDEA. MAYBE THIS TERMINAL REGION ALTHOUGH MOST PEOPLE DON'T SEE IN STRUCTURE HAS AN IMPORTANT FUNCTION.THEY MAY FUNCTION AS A MEMBRANE ANCHOR TO BRING E2A TO THE MEMBRANE SURFACE TO ENABLE TO AN HANCE THE INTERACTION WITH TRANSPORTERS.MORE STRUCTURES DETERMINE OF THE PEPTIDE AT THE END TERMINAL REGION SHOWS IT FORMS A HELIX WITH ALL THE HYDROPHOBIC LINING ON ONE SURFACE OF THE HELIX. SO ALSO SUGGESTS THIS MIGHT BE THE FUNCTIONS OF THE END TERMINAL REGION. SO WE HAVE THIS HYPOTHESES BY A VERY SINGLE EXPERIMENT. SO WHAT WOULD BE WE RECONSTITUTE OUR TRANSPORTER INTO WHAT WE CALL THE NANO DISK LIKE A MEMBRANE DISK WITH THE TRANSPORTER IMBEDDED TO THAT. THEN WE CAN ADD MDP AND THE MOUSE FROM ONE SIDE AND -- ON THE OTHER SIDE THEN WE MONITOR THE ABILITY OF THE E2A INHIBIT EPA HYDROLYSIS. WE CAN ACHIEVE ABOUT 90% INHIBITION COEFFICIENT ABOUT 1.5. SO THIS IS A CONSISTENT WITH WE NEED TWO E2A'S TO BIND TO THE TRANSPORTER.-WITH THE TRUNCATED VERSION OF E2A WE ALSO CAN INCLUDE IT BUT IT TAKES A LOT MORE PROTEIN. SO NOW THE -- IS ALMOST 100 MICRO MOLARS IN COMPARISON TO 1.6. THE ONLY DIFFERENCE BETWEEN THE TWO EXPERIMENTS IS THE TERMINAL REGIONS.THIS SUPPORTS THE IDEA THAT THE TERMINAL REGION OF THE E2A FUNCTIONS THE MEMBRANE ANCHOR. SO WITH THAT I'M GOING TO SUMMARIZE WHAT WE HAVE LEARNED ABOUT THIS SYSTEM. SO THE TRANSPORTER FUNCTION THROUGH ALTERNATING ACCESSMECHANISM. SO IN THE A SUBJECT OF ANY SUBSTRATE THE TRANSPORTERRESTING IN THE IN WARD FACING CONFIRMATION WITH TWO MBD SEPARATE FROM EACH OTHER. THEY WILL NOT AWAIT ATP. THE PRESENCE OF THE BINDING SUBSTRATE WILL STABILIZE THE BINDING PROTEIN IN THE CLOSE CONFIRMATION AND THE CLOSE CONFIRMATION BINDING PROTEIN WILL INTERACT WITH THE TRANSPORTER BRING THE TWO MBDS CLOSE TO EACH OTHER, CLOSE ENOUGH. NOW ATP BINDING WILL CONVERT THE -- TO OUTWARD FACING STATE WHERE MALTOSE IS DELIVERED INTO THE MEMBRANE AND READY TO HYDROLYZE.ATP HIGH DRUG SIST -- TO THE INWARD FACING STATE TO THE SAME TIME RELEASING THE MOUSE INTO THE CELL. WHEN THE PREFERRED SUGAR SUFFICIENT AS GLUCOSE IS PRESENT IN THE MEDIA, IT WILL BE TRANSPORTED THROUGH THE PTS SYSTEM -- OF THE GLUCOSE WILL BECOME DEPHOSPHORYLATED AND DEPHOSPHORYLATED E2A WILL INTERACT WITH THE TRANSPORTER STABILIZE IT IN THE INWARD FACING STATE. NOW BINDING PROTEIN AND ATP CAN NO LONGER -- THE TRANSPORTER CYCLE.I SHOULD ALSO POINT OUT IN E. COLI ONLY THE GLUCOSE SPECIFIC E2A WILL VIEW THE REGULATION FOR THE CARBON CATABOLIC REPRESSION. HOWEVER, ANY PTS SUGARS THERE ARE PROBABLY ABOUT 20 OF THEM. ANY UPTAKE OF THE PTA SUGAR WILL CONSUME THE PHOSPHATE FROM THE SAME P -- SO BY DOING THAT YOU CHANGE THE BALANCE BETWEEN THE PHOSPHORYLATE AND DEPHOSPHORYLATE FORM OF THIS GLUCOSE SPECIFIC E2A. SO THE PRESENCE OF ANY -- SUGAR WILL ENABLE INDUCE [INDISCERNIBLE]-SO WITH THAT I NEED TO THA NK PEOPLE WHO DID THE WORK. MIKE -- A PERMANENT SCIENTIST IN MY LAB. HE DETERMINED THE TWO CRYSTAL STRUCTURES. THOSE ARE THE OUTWARD FACING STATE AND THE PRETRANSLOCATION STATE -- IS A GRADUATE STUDENT IN MY LAB WHO JUST COMPLETED THE STRUCTURE OF THE E2A INHIBITOR TRANSPORTER -- IS MY FIRST POST DOC WHO DETERMINED THE INWARD FACING STRUCTURE.AND THIS HAS BEEN A LONG TERM COLLABORATION WITH -- CONTINUOUS FUNDING FROM NIH WAS EXTREMELY IMPORTANT FOR THIS PROJECT AS WELL AS LATER FUNDING FROM -- HHMI.-THANK YOU.-[APPLAUSE] >> I'M SURE SHE WILL BE HAPPY TO ANSWER SOME OF YOUR QUESTIONS. >> REALLY BEAUTIFUL WORK.->> THANK YOU. >> THE QUESTION IS REALLY SPECIFICITY OF THE PERI PLASMIC -- SYSTEM. NOW THE MD -- HOWEVER THERE ARE A LOT OF BIEBLEDDING PROTEINS IN THE PARAPLASMIC. SO HOW IS SPECIFICITY ENFORCED. PREDICTION IS THE ATP BINDING ACTUALLY STRENGTHENS, HAS A ROLE NOT JUST HOPING OR CLOSING INWARD OUTWARD PLAYING A ROLE IN SPECIFICITY.>> SPECIFICITY YOU MEAN FOR TH E TRANSPORTER SUBSTRATE.->> EXACTLY. >> YES. SO FOR THE MALTOSE SYSTEM WE ACTUALLY KNOW PRECISELY I DIDN'T HAVE TIME TO TALK ABOUT IT. WHAT'S KNOWN IS THE SPECIFICITY OF MALTOSE TRANSPORTER IS BY THE BINDING PROTEIN. SO THIS TRANSPORT -- LOOK THE GLUCOSE FROM TWO GLUCOSE TO-SEVEN GLUCOSE -- SO IT'S VERY SPECIFIC. SO MALTOSE BINDING PROTEINS SELECTIVELY BINDS THOSE SUGARS. WE ALSO KNOW SOME CHOORGZ -- CANNOT BE TRANSPORTED. SO MY WORK I DIDN'T HAVE TIME TO TALK ABOUT.WE NOW WHAT HAPPENS IS THE SUGA R HAS A POLARITY IT HAS A REDUCED END AND A NON-REDUCING END.MALTOSE BINDING PROTEIN WILL BIND THE SUGAR AT THE EITHER REDUCING END BIND THE SUGAR FROM THE -- BUT BASICALLY THE SUGAR -- FROM THE BINDING PROTEIN INTO THE MEMBRANE AND BOTH SIDES ARE RESTRICTED. SO THE SUBSTRATE SPECIFICITY FOR THE MALTOSE SYSTEM IS VERY -- THE BINDING PROTEIN AND THE TRANSMEMBRANE SUBUNIT.>> THAT'S VERY NICE. HOWEVER DOES ATP PLAY A ROLE IN SELECTIVITY.>> ATP LAYS NO ROLE, THAT'S CLEAR.-IT'S LIKE THE -- DRIVING THE SYSTEM.>> IF THAT'S THE CASE THE QUESTION'S ALSO THAT THE INTERFACE BETWEEN -- THE TRANSMEMBRANE PORTION. FROM YOUR DIAGRAM THE INTERFACE CHANGE AT DIFFERENT STATES. BUT IT'S NOT JUST A -- MECHANICAL MOTION IT'S MORE -- >> YES. SO SHE ASKED ABOUT WHAT ABOUT INTERFACE BETWEEN THE TRANSMEMBRANE SUBUNITS AND THE MBD. SO WHAT WE SEE IS THE MBD HAVE A PRETTY HYDROPHOBIC CLEAVE ON THE SURFACE AND -- HAS A HELIX COMING OUT.INSIDE THIS. WE CALL THIS -- SO DOING DIFFERENT CONFIRMATIONAL CHANGES-ESPECIALL Y WITH THIS BALL FROM THE TRANSMEMBRANE DOMAIN WILL ROTATE INSIDE CLIFF.-ONE SIDE OF THE CLIFF IS QUITE FLEXIBLE.YOU CAN ADJUST ITS SIZE. SO BY DOING IT IT WILL ENABLE DIFFERENT CONFIRMATIONAL CHANGES BUT IT MAINTAINS A CLOSE CONTACT. AND -- AT PRESENT POSITIONS IS ALSO CRITICAL SO THERE'S A CERTAIN -- AND THEN CERTAIN FLEXIBILITIES BY DOING THAT IT'S ABLE TO MAINTAIN HIGH AFFINITIES BUT ALSO ALLOW RELATIVE MOTION IN DIFFERENT CONFIRMATIONS. >> THANK YOU. >> THANK YOU, AN INTERESTING TALK -- THROUGH THE WHOLE TRANSPORT CYCLE.I HAVE A QUESTION REGARDIN G THE INWARD CONFIRMATION AND OUTWARD CONFIRMATION.IF I UNDERSTAND YOU CORRECTLY , IF YOU HAVE ATP HYDROLYZED ATP BINDING POCKET, THAT DOESN'T -- CONFIRMATION CHANGE WHICH WILL BE INWARD FROM OUTWARD -- OUTWARD TO INWARD. >> THAT'S CORRECT.->> SO YOU NEED TO HAVE BOTH THE SUBSTRATE AND THE ATP AT THE SAME TIME.->> PRECISELY.>> WHAT WOULD BE T HE NEXT STEP AFTER THIS? HOW WILL THE SEQUENCE OF EVEN THE ATP -- AFFINITY OF THE TRANSPORTER.-I'M ASKING THIS QUESTION IN REGARDS TO THE EXPORT WHERE YOU HAVE -- BUT WHAT WILL BRING A CHANGE IN THE AFFINITY TO THE BINDING SITE.>> I DON'T QUITE UNDERSTAND T HE QUESTION.YOU MEAN WHAT WILL HAPPEN AFTER ATP IS BOUND IN THE -- >> YES. >> SO WE KNOW ATP WILL BE HYDROLYZED. WE ALREADY SEE THE FORMATION OF THE TRANSITION STATE OF HYDROLYSIS.%THEN SO THE BOND BETWEEN ATP A ND THE PHOSPHATE WILL BE BROKEN. THEN WHAT HAPPENS IS PRETTY MUCH WE KNOW FOR SURE ORGANIC PHOSPHATE WILL BE RELEASED. THEN, THEN WHETHER IT'S THE RELEASE OF THE INORGANIC PHOSPHATE ALONE OR THE RELEASE OF THE INORGANIC PHOSPHATE PLUS ADP TO OPEN UP THE DIMER WE STILL DON'T KNOW THAT DETAIL. >> TWO DIFFERENT CONFIRMATIONS YOU BASICALLY NEED BOTH ATP AND THE SUBSTRATE OR YOU DON'T HAVE ANY OF THEM AND YOU CHANGE -- FROM OUTWARD TO INWARD BASICALLY.>> THERE ARE TWO BASIC CONFIRMATIONS.-INWARD AND OUTWARD. THERE'S AN ENERGY BARRIER IN BETWEEN. IN THE FORWARD CYCLE THE ENERGY BARRIER IS OVERCOME BY THE BINDING ENERGY FROM BOTH THE SUBSTRATES AND ATP. SO YOU NEED THE SUBSTRATES TO BIND AND ATP BIND NOW YOU CAN GO TO THE OUTWARD FACING STATE. ONCE WE REACH OUTWARD FACING STATE IT HAS NO CHOICE BUT TO HYDROLYZE ATP BECAUSE -- THEN THE HIGH HYDROLYSIS -- SO THE INWARD FACING STATE. THIS REVERSE CYCLE BUT NOW BY REVERSING THE CYCLE WE NOW EXPOSE THE SUBSTRATE INTO THE CYTOPLASM NOW AND THE BINDING SITE HAS VERY LOW AFFINITY FOR THE SUBSTRATE.THIS IS SECTED TO BE INTO TH E CELL AND WILL BE DIFFUSED OUT AND DEMETABOLIZED.->> THANK YOU. >> BEFORE I ASK THE LAST QUESTION I WANT AN ANNOUNCEMENT. THERE'S A RECEPTION AFTER THE Q&A.-PLEASE COME AND JOIN US. SO MY QUESTION IS YOU MENTIONED THE LIQUID [INDISCERNIBLE] ARE THEY COMING FROM THAT. >> YES. SO FUNCTIONALLIZE MODEL TRANSFERDOESN'T SE EM TO CARE WHERE THE LIPIDS, THEY ALL WANT LIPID PRESENCE.-IT'S REALLY WELL -- BUT THE STRUCTURALLY REDUCE THE ONE -- FORWARD BOUND TO A CERTAIN POSITION ON THE PERIPHERAL OFTHE TRANSPORT ER. YOU PHASE INTO A SURFACE DEPRESSION BETWEEN TWO TRANSMEMBRANE HELIXES AND BECAME PART OF THE STRUCTURE. BUT IN DIFFERENT CONFER MAKES WE ALL SEE THE SAME LIPIDS. SO YOU CAN IMAGINE THIS BECOMES PART OF THE STRUCTURE SO MAYBE STABILIZE THE TRANSPORT BEING THE CULTURE -->> THANK YOU AGAIN

Function

The major facilitator superfamily (MFS) are membrane proteins which are expressed ubiquitously in all kingdoms of life for the import or export of target substrates. The MFS family was originally believed to function primarily in the uptake of sugars but subsequent studies revealed that drugs, metabolites, oligosaccharides, amino acids and oxyanions were all transported by MFS family members.[3] These proteins energetically drive transport utilizing the electrochemical gradient of the target substrate (uniporter), or act as a cotransporter where transport is coupled to the movement of a second substrate.

Fold

The basic fold of the MFS transporter is built around 12,[4] or in some cases, 14 transmembrane helices[5] (TMH), with two 6- (or 7- ) helix bundles formed by the N and C terminal homologous domains[6] of the transporter which are connected by an extended cytoplasmic loop. The two halves of the protein pack against each other in a clam-shell fashion, sealing via interactions at the ends of the transmembrane helices and extracellular loops.[7][8] This forms a large aqueous cavity at the center of the membrane, which is alternatively open to the cytoplasm or periplasm/extracellular space. Lining this aqueous cavity are the amino-acids which bind the substrates and define transporter specificity.[9][10] Many MFS transporters are thought to be dimers through in vitro and in vivo methods, with some evidence to suggest a functional role for this oligomerization.[11]

Mechanism

The alternating-access mechanism thought to underlie the transport of most MFS transport is classically described as the "rocker-switch" mechanism.[7][8] In this model, the transporter opens to either the extracellular space or cytoplasm and simultaneously seals the opposing face of the transporter, preventing a continuous pathway across the membrane. For example, in the best studied MFS transporter, LacY, lactose and protons typically bind from the periplasm to specific sites within the aqueous cleft. This drives closure of the extracellular face, and opening of the cytoplasmic side, allowing substrate into the cell. Upon substrate release, the transporter recycles to the periplasmic facing orientation.

Structure of LacY open to the periplasm (left) or cytoplasm (right). Sugar analogs are shown bound in the cleft of both structures.

Exporters and antiporters of the MFS family follow a similar reaction cycle, though exporters bind substrate in the cytoplasm and extrude it to the extracellular or periplasmic space, while antiporters bind substrate in both states to drive each conformational change. While most MFS structures suggest large, rigid body structural changes with substrate binding, the movements may be small in the cases of small substrates, such as the nitrate transporter NarK.[12]

Transport

The generalized transport reactions catalyzed by MFS porters are:

  1. Uniport: S (out) ⇌ S (in)
  2. Symport: S (out) + [H+ or Na+] (out) ⇌ S (in) + [H+ or Na+] (in)
  3. Antiport: S1 (out) + S2 (in) ⇌ S1 (in) + S2 (out) (S1 may be H+ or a solute)

Substrate specificity

Though initially identified as sugar transporters, a function conserved from prokaryotes[10] to mammals,[13] the MFS family is notable for the great diversity of substrates transported by the superfamily. These range from small oxyanions[14][15][16] to large peptide fragments.[17] Other MFS transporters are notable for a lack of selectivity, extruding broad classes of drugs and xenobiotics.[18][19][20] This substrate specificity is largely determined by specific side chains which line the aqueous pocket at the center of the membrane.[9][10] While one substrate of particular biological importance is often used to name the transporter or family, there may also be co-transported or leaked ions or molecules. These include water molecules[21][22] or the coupling ions which energetically drive transport.

Structures

Crystal structure of GlpT in the inward facing state, with helical N and C domains colored purple and blue respectively. Loops colored green.

The crystal structures of a number of MFS transporters have been characterized. The first structures were of the glycerol 3-phosphate/phosphate exchanger GlpT[8] and the lactose-proton symporter LacY,[7] which served to elucidate the overall structure of the protein family and provided initial models for understanding the MFS transport mechanism. Since these initial structures other MFS structures have been solved which illustrate substrate specificity or states within the reaction cycle.[23][24] While the initial MFS structures solved were of bacterial transporters, recently structures of the first eukaryotic structures have been published. These include a fungal phosphate transporter PiPT,[16] plant nitrate transporter NRT1.1,[11][25] and the human glucose transporter GLUT1.[26]

Evolution

The origin of the basic MFS transporter fold is currently under heavy debate. All currently recognized MFS permeases have the two six-TMH domains within a single polypeptide chain, although in some MFS families an additional two TMHs are present. Evidence suggests that the MFS permeases arose by a tandem intragenic duplication event in the early prokaryotes. This event generated the 12 transmembrane helix topology from a (presumed) primordial 6-helix dimer. Moreover, the well-conserved MFS specific motif between TMS2 and TMS3 and the related but less well conserved motif between TMS8 and TMS9 prove to be a characteristic of virtually all of the more than 300 MFS proteins identified.[27] However, the origin of the primordial 6-helix domain is under heavy debate. While some functional and structural evidence suggests that this domain arose out of a simpler 3-helix domain,[28][29] bioinformatic or phylogenetic evidence supporting this hypothesis is lacking.[30][31]

Medical significance

MFS family members are central to human physiology and play an important role in a number of diseases, through aberrant action, drug transport, or drug resistance. The OAT1 transporter transports a number of nucleoside analogs central to antiviral therapy.[32] Resistance to antibiotics is frequently the result of action of MFS resistance genes.[33] Mutations in MFS transporters have also been found to be cause neurodegerative disease,[34] vascular disorders of the brain,[35] and glucose storage diseases.[36]

Disease mutations

Disease associated mutations have been found in a number of human MFS transporters; those annotated in Uniprot are listed below.

Human MFS proteins

There are several MFS proteins in humans, where they are known as solute carriers (SLCs) and Atypical SLCs.[62] There are today 52 SLC families,[63] of which 16 families include MFS proteins; SLC2, 15 16, 17, 18, 19, SLCO (SLC21), 22, 29, 33, 37, 40, 43, 45, 46 and 49.[62] Atypical SLCs are MFS proteins, sharing sequence similarities and evolutionary origin with SLCs,[62][64][65][66] but they are not named according to the SLC root system, which originates from the hugo gene nomenclature system (HGNC).[67] All atypical SLCs are listed in detail in,[62] but they are: MFSD1,[66] MFSD2A,[68] MFSD2B, MFSD3,[66] MFSD4A,[69] MFSD4B,[70] MFSD5,[64] MFSD6,[65] MFSD6L, MFSD8,[71] MFSD9,[65][69] MFSD10,[65][72] MFSD11,[64] MFSD12, MFSD13A, MFSD14A,[65][73] MFSD14B,[65][73] UNC93A,[74][75][76] UNC93B1,[77] SV2A, SV2B, SV2C, SVOP, SVOPL, SPNS1,[78] SPNS2, SPNS3 and CLN3.[79] As there is high sequence identity and phylogenetic resemblance between the atypical SLCs of MFS type, they can be divided into 15 AMTFs (Atypical MFS Transporter Families), suggesting there are at least 64 different families including SLC proteins of MFS type.[80]

References

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