Protein fold class

Transcription

So why is it so important to learn about protein structure? Well, let's take the example of Alzheimer's disease, which affects the brain. So in certain people as they age, proteins and their neurons start to become misfolded and then form aggregates outside of the neurons, and this is called amyloid. So amyloid is really just clumps of misfolded proteins that look a bit like this. And as you can see, as this amyloid builds up, it starts to interfere with the neuron's ability to send messages, and this leads to dementia and memory loss. So if we can understand how these proteins become misfolded in the first place, then we might be able to find a cure for this debilitating disease. And to understand how proteins become misfolded, we must first understand how they become properly folded. So before we begin, I just want to do a quick review of terms. You can have one amino acid, so I'll just write AA for amino acid. And then you can have two amino acids that are linked together by a peptide bond. So this is a peptide bond. And as you add more and more amino acids to this chain of amino acids, you start to get what is called a polypeptide, or many peptide, bonds. And each amino acid within this polypeptide is then termed a residue. And then proteins consist of one or more polypeptides. And so I will use the terms polypeptide and protein interchangeably. So at the most basic level, you have primary structure. And primary structure just describes the linear sequence of amino acids, and it is determined by the peptide bond linking each amino acid. So if I were to take my amyloid example from Alzheimer's disease and I stretch out that protein all the way, then this linear sequence is just the primary structure. So then, moving on, we have secondary structure. And secondary structure just refers to the way that the linear sequence of amino acids folds upon itself. This is determined by backbone interactions. And this is determined primarily by hydrogen bonds. There are two motifs or patterns that you should be familiar with, the first of which is called an alpha helix. And if you were to take this polypeptide and wrap it around itself into a coil-like structure, just like so, then you'd have the alpha helix. And the hydrogen bonds just run up and down, stabilizing this coiled structure. And another motif or pattern that you can be familiar with is with a beta sheet, and that just looks like this. It kind of looks more like a zigzag pattern. And the beta sheet is stabilized by hydrogen bonds, just like so. And if you have the amino ends and the carboxyl ends line up, like so, then this sheet is called a parallel beta sheet. And then conversely, if you have a single polypeptide that is then wrapping up upon itself just like this, and you have the hydrogen bond stabilizing like so, then you have the amino end coming around and lining up with the carboxyl end, and you have an anti-parallel configuration. There is a third level of protein structure called tertiary structure, and tertiary structure just refers to a higher order of folding within a polypeptide chain. And so you can kind of think of it as the many different folds within a polypeptide, which then fold upon each other again. And so this depends on distant group interaction, so distant interactions. And just like secondary structure, it is stabilized by hydrogen bonds, but you also have some other interactions that come into play, such as van der Waals interactions. You also have hydrophobic packing, and also disulfide bridge formation. So if we explore hydrophobic packing just a little bit more over here-- say we have a folded up polypeptide or protein. And this protein is found within the watery polar environment of the interior of a cell. So if we have water on the exterior of this protein, then we will find all of the polar groups on the exterior interacting with this water. And then on the interior, you would find the nonpolar or hydrophobic groups hiding from the water. Disulfide bridges, on the other hand, describe an interaction that happens only between cystines. So cystines are a type of amino acid that have a special thiol group as part of its side-chain. And this thiol group has a sulfur atom that can become oxidized, and when this oxidation occurs, you get the formation of a covalent bond between the sulfur groups. The formation of a disulfide bridge happens on the exterior of a cell, and you tend to see the formation of separated thiol groups on the interior of a cell. And that is because the interior of the cell has antioxidants, which generate a reducing environment. And since the exterior of a cell lacks these antioxidants, you get an oxidizing environment. So if I were to ask you which environment favors the formation of disulfide bridges, you would say the extracellular space does. Then there is one final level of protein structure, and that is called quaternary structure. And quaternary structure describes the bonding between multiple polypeptides. The same interactions that determine tertiary structure play a role in quaternary structure. And so let's say I have one folded up polypeptide, two folded up polypeptides, and a third and a fourth. The quaternary structure is described by the interactions between these four polypeptides. And within the completed protein structure, each individual polypeptide is termed a subunit. Since this protein has four subunits, it is called a tetramer. And so if I were to have two subunits, it would be called a dimer, three would be called a trimer, and then anything above four is called a multimer. So the term for a completely properly folded up protein is called the proper confirmation of a protein. And to achieve the proper confirmation, you must have the correct primary structure, secondary structure, tertiary structure, and quaternary structure. And if any of these levels of protein structure were to break down, then you start to have misfolding, which can then contribute to any of a number of disease states.