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Four levels of protein structure

The four levels of protein structure are primary, secondary, tertiary, and quaternary. It is helpful to understand the nature and function of each level of protein structure in order to fully understand how a protein works.  By Tracy Kovach. Created by Tracy Kim Kovach.

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  • ohnoes default style avatar for user seb
    at 1.24 tracy mentions "each a.a is turn into an residue"
    What does a.a residue means?
    (15 votes)
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  • leaf blue style avatar for user Viraj Bhatt
    Secondary structure is ONLY stabilized by H bonds correct? No covalent bonding whatsoever?
    (10 votes)
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    • piceratops ultimate style avatar for user Brian Doss
      Correct.

      Primary structure is determined by covalent peptide bonds.
      Secondary structure is determined by Hydrogen bonds between the backbone of the chain.
      Tertiary structure is determined by all electrostatic interactions (e.g. H-bond, Van der Waals) as well as disulfide bridges.
      Quaternary structure is determined by the subunits and the attractions between the different subunits.
      (28 votes)
  • blobby green style avatar for user Moez Sumar
    Near the end of the video you suggested that we can cure/ fight certain diseases if we understand where the conformation breaks down which leads to the mis-folding of a protein. Is this the case for Alzheimer's Disease? If so, have we been able to identify which level of protein structure that is mis-folding?
    (7 votes)
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    • male robot hal style avatar for user Bryce Manchester
      I'm not too confident about this mercury statement concerning Alzheimer's (AD). Alzheimer's is a very complex disorder that we're only just beginning to understand. What is known is that Amyloid Precursor Protein (APP) is synthesized in the presynaptic terminal and is released into the synaptic cleft. Occasionally, it is cleaved at 40-42 oligomers long and those are the most common peptide lengths that misfold and become plaques.

      The reason for their misfolding is still yet to be elucidated as far as I can tell. Some promising studies are looking at excess copper levels in the cleft as it has been shown that when copper binds to any one of 3 binding sites in the 42 oligomer long peptides, the peptide misfolds. In the presence of a copper chelator (takes all the copper out of the misfolded protein), the protein will return to its natural state and the plaques will dissolve.

      (See http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1241263/)

      Alzheimer's also has a genetic component as evidenced by early onset of AD in Trisomy 21 individuals (Down's Syndrome). The gene responsible for synthesis on chromosome 21, and individuals with three copies of chromosome 21 frequently develop early onset AD, possibly as a result of over-production of APP.
      (10 votes)
  • blobby green style avatar for user jkshah29
    How does antibodies made the interior of the cell a reducing agent?
    (1 vote)
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    • leaf red style avatar for user Jennifer Ness
      She was referring to antioxidants not antibodies.
      There is a great article that explains free radicals and antioxidants here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3249911/
      Specifically, "An antioxidant is a molecule stable enough to donate an electron to a rampaging free radical and neutralize it, thus reducing its capacity to damage."

      In other words, it is called an antioxidant because it works AGAINST oxidation. It's sort of like if there were a pyramid of oranges in a grocery store. If a small child were to come along and remove an orange from the bottom of the pile (the process of oxidation), the pile would be destabilized. If someone were to bump into it at this point the orange pile may even knock over the apple pile next to it - causing complete chaos (in our bodies this could even lead to cancer)! If however, an observant store clerk were to notice the missing orange and replace it with another one before someone knocked into it (reduction) - he would be a hero by circumventing the chaos that may have ensued.
      Here:
      The entire pyramid is our protagonist molecule.
      The single orange = an electron.
      The process of removing the electron (oxidation) turns the pyramid into a free radical...a molecule that threatens to cause havoc by it's unpredictable nature.
      Finally, our hero grocery clerk is the antioxidant...he gives the free radical his own electron restabilizing the pile. (reducing the free radical back to a normal molecule)

      When Ms Kovach is referring to a disulphide bridge being formed, it does so because the atoms are losing electrons. There are antioxidants inside the cell to help prevent this from occurring. There are no (or fewer?) antioxidants outside of the cell. That is why you will see these bridges more on the outside of the cell than on the inside of the cell.

      Good luck with this concept. It's easy to find yourself going in circles with it. ...I think I might have done so above! ....Ill re-check tomorrow when Im thinking straight again.
      (25 votes)
  • blobby green style avatar for user Ian McAmmond
    What does she say at ? ".. each polypeptide is termed ___' thanks!
    (5 votes)
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  • old spice man green style avatar for user Jonathan Ziesmer
    What does "peptide" (as in peptide bonds) mean, and where does it come from?
    (5 votes)
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    • leafers ultimate style avatar for user Peterson Wagner
      Peptides are molecules composed of amino acid monomers joined together by peptide bonds (covalent bonds between the carboxyl group of one amino acid and the amino acid group of another). The word "peptide" comes from a Greek word meaning "to digest"; I have no clue how digesting relates to peptides, but there you go! Many peptides joined in a sequence form molecules known as "polypeptides". I hope that answers your question!
      (8 votes)
  • piceratops tree style avatar for user custer.eremy
    What about the ionic bonds that are also produced from the positively and negatively charged r groups( side chains) that are acidic/basic?
    (5 votes)
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  • old spice man green style avatar for user maham malik
    the bond between two amino acids is called peptide bond or dipeptide bond??
    (4 votes)
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    • purple pi purple style avatar for user Hamad Sagheer
      A peptide bond is a bond between a carboxyl group of one molecule with the amino group of an other molecule. A dipeptide bond has a bit of an ambiguous meaning but is generally understood as the bond between two amino acids. So to answer your question, a bond between two amino acids would be a dipeptide!
      (2 votes)
  • blobby green style avatar for user Tyler Cohen
    Does a residue refer to the entire amino acid or just the R group on it? I believe in an earlier video she termed just the R group as a residue
    (3 votes)
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  • piceratops ultimate style avatar for user Liam
    Is methionine also able to form disulfide bridges, or is it only cysteine?
    (2 votes)
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    • piceratops ultimate style avatar for user Iman Baharmand
      Hey Liam, I had the same question before getting clarification from my biochem prof.

      Quick Answer: Only cysteine residues can form disulfide bridges.

      Rationale: Although methionine also has sulfur, it has a methyl (-CH3) group attached to it [as opposed to just a hydrogen in cystein]. The presence of this methyl makes methionine hydrophobic/nonpolar, and sterically hindered ... ultimately less reactive in the formation of a disulfide bond
      (3 votes)

Video transcript

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 conformation 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.