Protein tertiary Structure formation

Protein tertiary Structure formation

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As we know that coils and loops are evolutionary variable regions where mutations,deletions, and insertions frequently occur. So does it mean that they don't have much role in the structure of protein? If it so then what are the factors for the protein core structure formation?

Firstly, is important to remember that protein structures are dynamic due to the torsion angles between the N-terminal and C-terminal bonds. There are different conformations to expose different sequences to the outside of the protein to react/catalyze. So there is no one perfect conformation for a protein in a biological system.

The best models we have are taken through x-ray crystallography of the crystalized protein structure. This static portrayal of the protein may be inaccurate, because the biological system will expose the protein to different hydrophobic/hydrophilic interactions than the affect of the protein to itself.

Anfinsen's experiments were able to definitively prove the a proteins structure is coded by its amino acid sequence. To answer your question, this sequence is primarily responsible for a protein's core structure formation.

It is still incredibly difficult to predict the structure of a protein using its amino acid sequence. The tertiary structure is a product of salt bridges, hydrogen bonds, hydrophobic forces and polar attractive forces within the molecule (disregarding a proteins possible quaternary structure ). Scientists (from what I believe is Yale, but I may be incorrect), have been trying to find a pattern using computing software for years. As of right now, we cannot purely use amino acid sequence to determine a protein's dynamic structure.

Loops and coils on the outside of proteins because they tend to compose of polar or charged amino acids. Hydrophobic amino acids tend to get pushed towards the center of the protein structure. This occurs because polar residues do not affect affect the entropy of water molecules as much as the nonpolar residues (in the system).

Many deletions/insertions occur during specific transition states that the protein is in. Enzymes actually target specific conformations of a protein that best produces the P product. See image:

Solving the 3D structure of a protein is complex problem. There are multiple layer of informations that come into play.

The first level of organization comes from secondary structure, which is in turn dictated by the AminoAcid sequence. There are common secondary structure motifs such as alpha-elices and beta-sheets. The combination of several 2nd structure motifs will give rise to more complex motifs and eventually to a local 3d structure. This local 3D structure is called a "domain" and is a minimal independent functional unit of a protein, which means it can often be cut out from the rest and retain its function.

Given this overview, the first layer of selection comes from creating 2nd structures which depends on the charge and size of amino acidic residues.

Mutations that destroy the creation of these secondary structure motifs will ultimately have an effect on the final 3d structure.

Loops in a way connect these more rigid motifs and therefore they are less likely to be subjected to evolutionary selection.

However in the end it all ties down to function. If you have a loop within a catalytic site inside a protein, the sequence in the loop will be greatly preserved because size and charge will strongly dictate its interaction with substrates.

Hope this helps.

Protein tertiary structure

Protein tertiary structure is the three dimensional shape of a protein. The tertiary structure will have a single polypeptide chain "backbone" with one or more protein secondary structures, the protein domains. Amino acid side chains may interact and bond in a number of ways. The interactions and bonds of side chains within a particular protein determine its tertiary structure. The protein tertiary structure is defined by its atomic coordinates. These coordinates may refer either to a protein domain or to the entire tertiary structure. [1] [2] A number of tertiary structures may fold into a quaternary structure. [3]

Structural Classes of Proteins

Proteins can be divided into 3 classes of protein, depending on their characteristic secondary structure. See the dynamics models below for each class.

Alpha proteins - consist of predominately alpha helix.

Example: myoglobin P562 (4mbn)

Alpha/Beta proteins - consist of a common of alpha and beta structure.

These are the most common class. Example: Triose phosphate Isomerase

Beta proteins - consist of predominately beta structure.

Example: Superoxide Dismutase (2sod).

Here are some resources about protein structure

Here are some 3D structures resources, accessible through a sequence or ID-based search. and collated in Nature's Structural Biology Knowledge Base.

Protein Structure

As discussed earlier, the shape of a protein is critical to its function. For example, an enzyme can bind to a specific substrate at a site known as the active site. If this active site is altered because of local changes or changes in overall protein structure, the enzyme may be unable to bind to the substrate. To understand how the protein gets its final shape or conformation, we need to understand the four levels of protein structure: primary, secondary, tertiary, and quaternary.

Figure 2

Figure 2. Results for (AAQAA)15. (a) ΔS(E). (b) Radius of gyration Rg(E). (c) Rates of H-bond and side-chain energies dEhb/dE and dEsc/dE. Horizontal arrows indicate where most of the secondary structure forms and where non-native tertiary contacts dissolve. The vertical line marks the transition point.

While of similar length, the 73 amino acid de novo three-helix bundle α3D (PDB entry 2A3D)(15) does show a discontinuous transition (Figure 3a). Representative conformations sampled in the two coexisting ensembles stand as good proxies of the ground and unfolded states, unlike the case of the downhill-folding transition of (AAQAA)15. The radius of gyration again shows a minimum above the transition (Figure 3b), and folding once more starts from maximally compact non-native states. Notably, secondary structure formation and the loss of non-native tertiary contacts (Figure 3c) are sharp and predominantly localized within the coexistence region. The three helices form inside the same energetic interval because of the interhelical cooperativity imprinted in the sequence.(16) Chain compaction is due to strong side chain−side chain interactions.


Structure of Chemokines

Tertiary structures of chemokines are similar because of the conserved disulfide bonds. Structural analysis of chemokines reveals a flexible N-terminal region, an N-terminal loop, three antiparallel beta sheets, and a C-terminal alpha helix ( Figure 1 ). Chemokines are believed to interact with their receptors through two domains. 19 The N-region loop of chemokines interacts with the receptor N-domain residues (receptor Site-I), and the N-terminal flexible region of the chemokine associates with the extracellular loops and/or transmembrane residues of the receptor (receptor Site-II).

Although homodimers and aggregation of chemokines are often observed in structural studies, functional analysis of chemokines by in vitro assays (calcium flux, chemotaxis, internalization of receptor) shows that at least some chemokines can function as monomers to activate their receptors. 5 Nonetheless, it has been reported that oligomerization is required for binding glycosaminoglycans (GAGs), which is in turn required for recruiting leukocytes in vivo. GAGs such as heparan sulfate are highly expressed on cell surfaces and extracellular matrix, and by binding to GAGs, chemokines can form high local concentrations. Site-directed mutagenesis in CCL2, CCL3, and CCL5 showed that mutants incapable of binding GAGs or incapable of forming oligomers could not recruit leukocytes into the peritoneum of mice. 2

Quaternary Structure

In nature, some proteins are formed from several polypeptides, also known as subunits, and the interaction of these subunits forms the quaternary structure. Weak interactions between the subunits help to stabilize the overall structure. For example, insulin (a globular protein) has a combination of hydrogen bonds and disulfide bonds that cause it to be mostly clumped into a ball shape.

Insulin starts out as a single polypeptide and loses some internal sequences in the presence of post-translational modification after the formation of the disulfide linkages that hold the remaining chains together. Silk (a fibrous protein), however, has a β-pleated sheet structure that is the result of hydrogen bonding between different chains.

The illustration below shows the four levels of protein structure (primary, secondary, tertiary, and quaternary).

You can observe the four levels of protein structure in these illustrations. Image Attribution: modification of work by National Human Genome Research Institute

Figure 1

Figure 1. Results for (AAQAA)3. (a) ΔS(E) error bars reflect the variance of the data points (1σ interval). (b) Inverse temperatures from canonical [Tcan −1 (⟨Ecan), blue] and microcanonical [Tμc −1 (E) = ∂S/∂E, red] analyses, where ⟨Ecan is the canonical average energy. (c) Radius of gyration Rg(E) with the error of the mean. (d) Rates of H-bond and side-chain energies dEhb/dE and dEsc/dE. Vertical lines delimit the transition region, whose width corresponds to the microcanonical latent heat ΔQ.

Elongating the sequence to (AAQAA)15 led to a qualitative change in the folding mechanism. The ground state again forms a single α-helix, but the transition is now continuous: as shown in Figure 2a and Figure S2 in the Supporting Information, there is a single transition point, and the latent heat is zero. The radius of gyration (Figure 2b) features a sharp minimum above the transition point, indicative of chain collapse into “maximally compact non-native states”.(13) Upon a further decrease in the energy, the chain reorganizes from such non-native states into the helical state. In doing so, the rate of tertiary contact formation dEsc/dE dips below zero (Figure 2c), so there is an energetic penalty associated with tertiary rearrangements. Hydrogen-bond formation occurs over a large energetic interval, as indicated by the broad maximum in dEhb/dE. The absence of any two-state signal is consistent with theoretical models of the helix−coil transition:(14) the energetic cost of breaking a hydrogen bond is outweighed by the conformational entropy gained. Further analysis indicates two helices on average at the transition point.

How is the Tertiary Structure of Proteins Formed?

The tertiary structure of proteins is such that it is suited to the function of the protein. Proteins function in different environments, and thus each protein has different requirements.

For example, if a protein works in a water-based environment, then it is not appropriate to have hydrophobic amino acids in the section of the protein which is in contact with the water. To avoid this, hydrophobic amino acids are tucked away inside of the protein. So here, hydrophobic interactions would be keeping these hydrophobic amino acids together, while the &ldquowater-liking&rdquo (hydrophilic) amino acids on the outside of the proteins will form hydrogen bonds with the water.

The cell membrane is a hydrophobic environment, so the parts of proteins which will be within the cell membrane is usually made up of hydrophobic amino acids. These proteins can also have regions which poke out of the membrane, and these outer regions are usually made up of hydrophilic amino acids.

The protein α-keratin is found in hair, skin and nails. The polypeptides which make up α-keratin is shaped as a helix, and four of these coil together to form a protofibril. The protofibrils then become coiled into larger microfibrils, which are coiled again to form macrofibrils. In the microfibrils, disulfide bonds can be formed, and the number of disulfide bonds changes the hardness of α-keratin there are more disulfide bonds in the α-keratin found in nails, compared to the α-keratin found in skin and hair. This ensures that the nails are tough, while skin and hair are given enough structure while maintaining more movement.


The exit tunnel of the ribosome is commonly considered to be sufficiently narrow that co-translational folding can begin only when specific segments of nascent chains are fully extruded from the tunnel. Here we show, on the basis of molecular simulations and comparison with experiment, that the long-range contacts essential for initiating protein folding can form within a nascent chain when it reaches the last 20 Å of the exit tunnel. We further show that, in this “exit port”, a significant proportion of native and non-native tertiary structure can form without steric overlap with the ribosome itself, and provide a library of structural elements that our simulations predict can form in the exit tunnel and is amenable to experimental testing. Our results show that these elements of folded tertiary structure form only transiently and are at their midpoints of stability at the boundary region between the inside and the outside of the tunnel. These findings provide a framework for interpreting a range of recent experimental studies of ribosome nascent chain complexes and for understanding key aspects of the nature of co-translational folding.


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