(10 points) Some proteins of biological interest lack defined structure. These p
ID: 180600 • Letter: #
Question
(10 points) Some proteins of biological interest lack defined structure. These proteins are known as natively unfolded proteins. Structural biologists are interested in whether there are particular features of amino acid sequences that are responsible for the lack of ordered structure in natively unfolded proteins. In a recent bioinformatics analysis, it was found that compared to structured proteins, non-folding proteins are significantly depleted in isoleucine, valine, leucine, cysteine, tryptophan, tyrosine, and phenylalanine. Offer an explanation, as to why a depletion of these amino acids would favor an unfolded state for proteins. Your explanation should include a brief discussion on the free energy of folding, interactions that contribute to folding, and how the lack of these residues effect the free energy of folding.
Explanation / Answer
Proteins conformation and folding plays a major role in its function failing which can lead to many diseases. The consequences of misfolding are protein aggregation, loss of function and gain of toxic function. However, some proteins which naturally lack a defined structure, i.e., natively unfolded proteins differ from structured globular proteins and domains in many attributes which include amino acid composition, sequence complexity, hydrophobicity, charge, flexibility, and type and rate of amino acid substitutions over evolutionary time. Folded globular proteins have hydrophobic core, which natively unfolded proteins lack/ or are depleted eg., Ile, Leu, and Val as well as aromatic amino acid residues such as Trp, Tyr, and Phe. On the contrary, natively unfolded proteins were shown to substantially enriched with polar, disorder-promoting, amino acids: Ala, Arg, Gly, Gln, Ser, Pro, Glu, and Lys. Disordered regions are often found as flexible linkers or loops connecting domains which allow the connecting domains to freely twist and rotate to recruit their binding partners. Quiet often, the post-translational modifications such as phosphorylation tune the affinity of individual linear motifs for specific interactions. Many unstructured proteins undergo transitions to more ordered states upon binding to their targets and retain their conformational freedom even after binding.Natively unfolded proteins typically contain numerous uncompensated charged groups, resulting in a large net charge at neutral pH and a low content of hydrophobic amino acid residues. Thus they lack the formation of favorable structures stabilized by hydrophobic interactions clumping, hydrogen bonding and Van der Waals forces between amino acids. The free energy of protein folding is measured by reversible chemical denaturation.Their are a vatiety of physical forces/entropic considerations play an important role in protein folding, viz Gibbs free energy. The entropy of the protein decreases when it is folded because the chain is arranged in a more orderly fashion. In natively unfolded proteins, since the basic hydriphobic residues are missing the basic entropic changes for folding cannot take place.
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