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167 Cards in this Set

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  • Back
What are 4 reasons amino acid sequence is dynamic?
It is dynamic due to splicing, post-translational modifications, proteolytic processing, and covalent cross-bridging
What does amino acid sequence in a protein determine for the protein?
It determines the protein's physiological function
All amino acid sequences in the human genome are due to what?
The Human Genome Project
What is a mechanism to find the functional encoding gene in a protein?
Experimentally, specific functional isolated proteins are isolated and analyzed by spectormetric methods
What does allelic variation account for?
It accounts for differences in amino acid sequence between individuals
Do these allelic variations produce diseases, and if they do, what is an example of such a thing?
They can produce molecular disease, and an example is the change in the alpha and beta chains of hemoglobin, which causes hemoglobin apathies
How can peptides be reproduced biologically?
They can be produced by inserting an amino acid sequence into a plasmid to produce a recombinant protein in large amounts, which can be tagged for testing
How are peptides reproduced chemically?
Via solidphase peptide synthesis
Who developed this?
Merrifield in the 1960s
What happens during this method?
The desired peptide chain is created by protecting the N (at alpha amino group) and C (at the alpha carboxyl group) termini, and then selecting removing the protecting group from the alpha-amino group to add an amino acid in a cyclical fashion until the desired polypeptide is formed
What does it mean if during this method the polypeptide chains are considered to be pure?
The C-terminus of the desired polypeptide chain is attached to a polymer resin bead and all bi-products of the reaction remain in solution
What do quaternary structures come together to form?
They come together to form even higher complexes to make structures like organelles (ribosomes, etc)
Why are peptide bonds polar?
The nitrogen takes on a partially positive charge in the resonance form, and the oxygen takes on a partially negative charge in the resonance form
Why are peptide bonds polar?
The resonance form of the bond is lower in energy than its extremes, so its atoms resonate
Why are peptide bonds planar?
The resonance form of the bond is lower in energy than its extremes, so its atoms resonante
What is necessary for the atoms of the peptide bonds to be in order for resonation to occur?
They have to be in the same plane in order for resonation to be possible
What is the ratio of charge : uncharged forms?
Are peptide bonds in trans or cis configuration?
They are in trans configuration
Why do they like trans over cis?
Steric interactions between the N termial and C terminal substituents of the peptide bond prohibit the cis configuration
Which has lower energy, cis or trans?
If peptide bonds are planar, how can the chain fold?
Through rotation about two bonds
What rotates in a phi bond?
The alpha carbon to nitrogen
What rotates in psi bond?
The alpha carbon to carbonyl bond
What is defined by the phi and psi angles of each individual amino acid?
The complete structure of the polypeptide
Does folding of peptide bonds assume any particular confirmation usually?
It assumes the conformation of lowest energy
In an alpha helix, where do hydrogen bonds form?
They form between the carbonyl oxygens and hydrogens within the same polypeptide chain
Which axis do the hydrogen bonds align on?
They align on the long axis
What does aligning along the long axis allow?
It allows the packing of amino acids over a short distance
Is there a hole in the middle of the alpha helix?
No, there is no hole
Where do polar side chains exist in an alpha helix?
They exist on the side chain in contact with the aqueous environment
Where do nonpolar side chains exist on the alpha helix?
They exist on the side chain in contact with proteins
Are alpha helices amphipathic in nature as a result?
Yes, they are
What is a beta sheet characterized by?
It is characterized by polypeptide chains running in opposite directions attached by hydrogen bonds between different polypeptide molecules
Does the beta sheet appear 3-dimensional when viewed at an edge?
No, largely it appears flat when viewed on edge
How do polar and nonpolar sidechains orient themselves on different sides of the Beta sheet, and does this relate to an alpha helix style of orientation?
Polar and nonpolar side chains are on different sides of the beta sheet, and yes, this is just like the alpha helix
Are beta sheets amphipathic by nature?
Yes, they are
What do beta-turns encompass?
They encompass three residues and stabilization by hydrogen bonding
What do beta-turns do?
They reverse the direction of the polypeptide chain
When looking at tertiary structure of proteins, is there continuity between folding patterns from protein to protein?
Yes. Similar folding patterns are seen in proteins that are not homologous in sequence
What can be used to predict folding patterns to some extent?
Patterns can be better predicted by what?
The nature of amino acid residues
Where do hydrophobic residues lie?
They lie in the center of the protein
Where do hydrophilic residues lie?
They lie on the exterior
Can uncharged residues be found on the exterior? What about charged on the interior?
Uncharged residues can be found on the exterior, but charged residues are not found on the interior
Are secondary structures closely packed or far packed?
They are closely packed to maximize the surface area to volume ratio
What are aggregated secondary structures known as?
They are known as super-secondary structures
Are super-secondary structures common?
What are 3 examples of super-secondary structures?
Beta-Beta, Alpha-Alpha, and Beta-Alpha-Beta
What are Beta-Beta?
They are a beta-turn connecting two inverted beta sheets
What are alpha-alphas?
They are two alpha helices coupled by a turn
What are beta-alpha-betas?
They are characterized by parallel Beta sheets coupled by an alpha helix
What do these structures come together to form?
Tertiary structures
What are 4 examples of tertiary structures?
Saddle-shaped type
What are saddle shaped?
They are parallel beta sheets that configure into a spiral shape in 3d space
What are two examples of saddle-shaped?
Flavodoxin and Carboxypeptidase
What are beta barrel type?
They are parallel beta sheets folded over on themselves to form a barrel structure
What are 2 examples of beta barrel type?
Triose phosphate isomerase, and pyruvate kinase domain I
What are anti-parallel beta sheets?
Beta sheets come together to make a sandwich
Can the anti-parallel beta sheet be seen anywhere of note?
They can be seen in antibodies
What are the beta sheets in anti-parallel beta sheet structures held together by?
They are held together by a disulfide bridge
Four alpha-helix motif structures are what?
They are alpha-alpha structures that comes together to form bundles
Where is four alpha-helix motif seen?
It is seen in cytochromes and some virus proteins
If we have 2 alpha helices and another 2 alpha helices coming togehter, do we still call them alpha alpha?
Yes. The way it folds up is that two alpha structures come together to form a cylinder
What are integral membrane proteins?
They span the membrane with hydrophobic properties on the interior
What do integral membrane proteins require to solubilize?
What are membrane assisted proteins?
They interact with lipid head groups or integral membrane proteins
What does it take to solubilize membrane associated proteins?
It requires an increased salt concentration
What are 2 examples of membrane proteins?
What are bacteriorhodopsin proteins?
They are light harvesting and embedded in the membrane by a set of parallel polypeptide chains in alpha helical conformation
Where do bacteriorhodopsins have charged residues?
They have charged residues ont he interior
What are bacteriorhodopsins embedded in the membrane by?
A set of paralle polypeptide chains in alpha-helical conformation
Why are there no charged residues on the interior of the membrane?
This is because of hydrophibicity
What is a bacterial porin?
It forms a pore in the membrane
The pore of a bacterial porin is filled with what?
What is the pore delineated by?
Beta sheets build its perimeter
Does each arrow show a single row of a beta sheet?
What is something post-translationally to insert a membrane protein into the membrane?
They can have hydrocarbon additions
Historically, what was 3d structure determined by?
It was determined by single crystal x-ray crystallography
What does this technique give?
It gives precise information about the 3d structure of protein
Is it high resolution or low resolution?
High resolution
Does it give a dynamic or static picture of a 3d protein?
It gives a static picture of 3d protein
Why are proteins not really static though?
They arent static because structures are, to some degree, always dynamic
Does a polypeptide appear on an electron density map?
No, because it is moving around so much and has no defined structure
Why must proteins fold during their lifetimes?
They must fold so that they can be functional
Can proteins have more than one defined 3d structure shape?
Yes. They can flip between 2 or more structure
Why is it important that proteins can assume more than one shape?
It is important because it allows cooperativity of proteins
What is an example of structural changes like this?
Hemoglobin relies on conformational chages and flips from a high affinity for oxygen to form a low affinity for oxygen form
Do some proteins have entirely or largely disordered structures?
What are these proteins called?
Intrinsically unstructured proteins
What does computation suggest about the number of this kind of protein?
One-third of proteins may be this kind
Where do intrinsically structured proteins have polypeptides exposed to?
They have polypeptides exposed to solvent
How are the amino acid compositions in these disordered proteins?
They are very rich in positively / negatively charged residues
Are these proteins hydrophic or hydrophilic?
They are very hydrophilic
What is an example of an intrinsically structured protein?
p-27 protein is one
The cell cycle is regulated by what?
It is regulated by cyclin protein, which is the master timekeeper of the cell cycle
What does cyclin protein determine?
It determines when the cell changes from each stage in the cell cycle
What does cyclin combine with?
It combines with kinase called cyclin-dependent kinase
What does this form?
A dimeric protein with two subunits (cyclin and kinase)
Does this activate or inactivate the kinase?
It activates the kinase, which is an enzyme that phosphorylates other proteins, which are then responsible for the remodeling that takes place when a cell divides
These kinases also trigger something else in the cell cycle, what is this?
They trigger DNA synthesis
The whole cycle is then regulated by couplings of what two things?
Cyclin and cyclin-dependent kinases
Is this process self-limited, or must it be stopped by something else?
It must be stopped by something else
So how does p-27 enter into this?
It is a cyclin-dependent kinase inhibitor, which binds to this pair of subunits and stops them from working
When looking at a molecular graphic simulation of p-27, what is notable about the N and C terminals of the structure?
THey are floppy pieces of polypeptide linked together by an alpha helix
Which domain of p-27 binds to Cyclin A?
Domain 1
Where does p-27 bind to?
It binds to the cyclin at terminus
What does this do?
It causes conformational changes
What is this finally followed by?
It is followed by a folding of domain 2 to adopy a correct conformation to interact with cyclin dependent kinase
What does this boil down to, when considering unstructures proteins?
A protein that starts out without a structure assumes a structure when binding to another protein.
Do many proteins interact this way?
The folding pathway is analogous to what?
A metabolic pathway with a defined sequence of events that take place in order to get from a fully unstructured protein to a correct structural one
Does more occur during this process than just rotation of phi and psi angles?
What happens when a protein is folding up, and its structural stabilization by disulfide bridges is wrong?
If it locks into this position, it is dead, so protein disulfide isomerase fix it.
How do they work specifically?
They shuffle disulfide bridges to give dead proteins another change to fold to the correct conformation
What is the amino acid that is not in the trans configuration?
So does this mean peptide bonds can be formed in the cis configuration?
Some proline forms do form cis configuration peptide bonds
How does this happen?
During the folding, they shift from trans to cis
What is the enzyme that allows them to do this?
Peptidyl proline isomerase
Is there anything to catalyze the folding process in the lab?
They have folding machines
When newly unfolded polypeptide chains are made, what is the danger for them?
Hydrophobic-hydrophobic interactions will cause them to aggregate and become dead junk
What is the goal then to prevent this?
The goal is to sequester unfolded proteins away from interactions with other unfolded proteins
What does this?
How does it work?
Unfolded proteins can bind to chaperones, and they can fold up on their arms without having destructive interactions with other proteins
What else can chaperone proteins assist in?
They also assist in shock responses like heat shock
What is a histone?
Histones are responsible for the organization of chromatin
Does the introduction of chaperones fix prion disease?
Its unrealistic from a therapeutic standpoint
Is there any evidence that proteins fold while being translated?
There is evidence of this
Polypeptides are so long that they have what that fold into globular structures?
They have subregions that fold in globular regions
So, when the polypeptide is finished, what does it look like?
It looks like beads on a string
What are these beads on a string called?
They are called domains
What are domains?
They are independently folding subsections of a single polypeptide strand
What does a characteristic domain structure of an antibody protein look like?
It is composed of 4 chains, with 2 light chains and 2 heavy chains
Light chains are like 2 balls, and each ball is what?
A domain
Are these domains usually genetically related to one another?
They usually are related to one another
What do these domains arise from?
They arose by duplication of mutational divergence of a primordial immunoglobulin folding gene
What is a primordial immunoglobulin fold gene?
It's a gene that encodes the protein and adopts the 3d structure of an immunoglobulin domain
How much heavier is the heavy chain than the light chain?
It is about twice as long
How many domains does a heavy chain have?
It has 4 domains
What is the structure held together by?
It is held together by disulfide bridges between second domain of light chain and second domain of heavy chain, and between the two heavy chains in the hinge region
What is the hinge region?
It allows two arms to rotate relative to one another
What are the ends of the structure?
They are the antigen-combining site of the antibody molecule, which the infectious agent recognizes as foreign and interacts with
Immunoglobulin G has how many polypeptide chains hooked together?
It has 4 polypeptide chains hooked together by disulfide bridges
What is the result functionally of some protein aggregates having a very low affinity?
They are too transitory to be isolated
What is an example of this?
Enzymes of the Kreb's cycle
How so?
The enzyme sof the Kreb's cycle in the test tube are too slow in reacting
The enzymes of Kreb's cycle in mitochondria are faster or slower than in a test tube?
Must faster
Why is this?
Proteins collect into 2-3 big complexes
What is an example of this, and how does it work?
Metablomes are like this, and they are where the substrate on one enzyme is the transformed product of the prior reaction.
Diseases of 3d structural proteins arise from?
Misfolding / abnormal reactions between proteins
What happens in cystic fibrosis?
There is a deficiency of chloride ion conductance channel on the cell surface
What causes this?
Amino acid substitution causes the protein to flow more slowly than it should
What does this lead to?
What happens to this aggregation?
The ER tries to get rid of protein, which diminishes the number of active proteins
What about sickel cell anemia?
The deoxygenated form of hemoglobin is normally completely soluble, but a hydrophobic patch on hemoglobin due to amino acid substitution interacts with its neighbors, so hemoglobin precipitates
Does aggregation happen in Huntington Disease, Parkinsons Disease, and Alzheimer's Disease?
Yes, due to the abnormal interactions between proteins
When thinking about protein-protein interaction, how does it relate to insulin taking diabetics and glucose in the blood?
It takes some time for the insulin to build up to a point where it will prevent destabilization of glucose in the blood
Why is this?
Injected insulin is a 6 protein aggregate, but it needs to dissociate into a dimer and then a monomer to be active
How does this relate to pharmacology?
The rate at which a medicine is effective is limited by the rate the complexes dissociate from one another
What is Lispro?
It is a fast acting insulin that stops aggregation from taking place and helps facilitate dissociation to form more active monomers
In botulism shots for cosmetic reasons, why is it necessary for the protein to be monomer?
If it aggregates or dimers form, the medicines efficacy vastly increases, which can be lethal
Quality control of medicine to nail down aggregate state is important or not important then?
Extremely important
Review classical saturation binding curve, in Section V, Figure 1
Kd increases when?
When there is a large amount of dissociation
Kd decreases when?
When a small amount is dissocated
What does r refer to in the saturation binding equations?
It refers tot he fraction of protein molecules bound to ligand
What does [A] refer to?
Unbound ligand at equilibrium
Kd is effective in large amounts?
No. It's more effective in smaller amounts.