In class, we talked about protein structure and the fact that the primary sequen

Question

In class, we talked about protein structure and the fact that the primary sequence of the protein dictates the specific structure based on amino acid
interactions and conformations of these amino acids into secondary structure. However, what we learned in class is not the complete story. It is now
becoming increasingly recognized that many proteins have some degree of “nonstructure”, or disorder, which likely plays an important role in their
function. Below is a series of questions designed to inform you of this new area of research. To answer these questions, I’ve provided 2 review articles on
this topic: Chouard, Nature, 2011 and Babu et al., Current Opinion in Structural Biology, 2011. With these reviews, you will be able to effectively answer
each of the questions below. Although you do not need to cite the 2 articles used, you must answer clearly and in your own words.

https://www.nature.com/news/2011/110309/full/471151a.html

https://www.sciencedirect.com/science/article/pii/S0959440X11000637?via%3Dihub

1A) In class, we talked about the “lock and key” model of protein-substrate interaction. Explain the "lock and key" model and how intrinsically disordered
proteins (IDPs) fail to conform to this model. (4 pts)

1B) A common hypothesis for how IDPs recognize and bind their targets involves the protein molding itself into the shape of the target (i.e., fold as you
bind). This folding pattern is thought to lead to protein-target interactions that are high in specificity and low in affinity. What is one advantage of this
mechanism in regard to signaling? (3 pts)

1C) Opponents of the disordered protein hypotheses argue that proteins must stay folded in the cell to avoid protein aggregation. What would you predict
to be the composition of IDPs in terms of amino acid characteristics? How would this prevent protein aggregation? (3 pts)

1D) Because of the many potential binding interactions of IDPs and their targets, the availability of IDPs in the cell needs to be tightly regulated to ensure
that only appropriate binding occurs and that it occurs at appropriate levels. List 2 means by which IDP levels in the cell are controlled. (4 pts)

1E) There are many very cool proteins known to have a level of structural disorder within the cell. Choose one IDP and describe how the structural
disorder contributes to the function of that protein. Include in your description a general discussion of the nature of the disorder and the effects of the
disorder on the protein’s secondary and/or tertiary structure. Keep your description short, no more than a page double-spaced. Please do not use CREB,
Sic1, or p53 as examples since they have already been described so beautifully in the Chouard paper. Cite any and all references (even 1 reference will
suffice if it addresses the question). Please note, simply restating an abstract or section of an article or review is not acceptable. The discussion /
description that you submit must be your own. (12 pts)

Explanation / Answer

1(A). The basic mechanism by which enzymes catalyze chemical reactions begins with the binding of the substrate to the active site on the enzyme. The active site is the specific region of the enzyme which combines with the substrate. The active site has a unique geometric shape that is complementary to the geometric shape of a substrate molecule. The specific action of an enzyme with a single substrate can be explained using a Lock and Key analogy first postulated in 1894 by Emil Fischer. In this analogy, the lock is the enzyme and the key is the substrate. Only the correctly sized key (substrate) fits into the key hole (active site) of the lock (enzyme).The binding of the substrate to the enzyme causes changes in the distribution of electrons in the chemical bonds of the substrate and ultimately causes the reactions that lead to the formation of products.

Since intrinsically disordered proteins do not fold spontaneously into a unique three-dimensional (geometric) shape they fail to conform to this model.

1(B). The advantage of this mechanism in regard to signalling is that it helps a helping a signalling protein to recognize and react to a protein partner. It also allows a regulatory protein to interact with multiple targets. Such flexibility can prove to be an essential part of the assembly process

1(C).Disordered proteins contain only few hydrophobic amino acids, which tend to stick together and are rich in 'polar' amino acids that are happy swimming in water. Natural selection against aggregation may have given disordered proteins this particular amino-acid composition.

1(D). Most IDPs are tightly regulated. Dosage-sensitive genes are involved in encoding the IDPs. Tight regulation of IDPs minimises non-functional interactions. Hence, contributing to signalling reliability, this ensures that IDPs are available in appropriate amounts and duration.

1(E).

Tau protein is classified as intrinsically disordered protein (IDP). It is the major constituent of neurofibrillary tangles in Alzheimer's disease (AD) and related tauopathies. In tauopathies, highly soluble disordered tau protein acquires rigid fold and forms highly insoluble filaments. (Skrabana R et al 2006).

Studies reveal that (1) dynamically ordered conformations with close lysine–cysteine distances essential for tau self-acetylation and (2) high ?-sheet content and large hydrophobic surface exposure for the two critical hexapeptides (275VQIINK280 and 306VQIVYK311), crucial for tau aggregation. This indicates that tau’s disordered state can fullfil both roles.(Yin luo et al 2014)

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