# Structural Biochemistry/Intrinsically Disordered Proteins: 10-year recap/Functional modes of disordered proteins
## Functional Modes

This section deals with the physiological function and functional mode of intrinsically disordered proteins and intrinsically disordered regions of proteins. Experimental observations and advances in “comparative evolutionary and experimental structure-function studies, it is now lear that structural disorder provides multiple functional advantages, and intrinsically disordered protein functions either directly stem from their disorder (entropic chains) or from molecular recognition, when they undergo induced folding (disorder-to-order transition) upon binding to a partner molecule”. Some of their functional properties and characteristics, such as their affinity in binding, high functional density, weak but specific binding, and frequent regulation by post-translational modification, have been analyzed. The properties of the inducted folding concept led to the development of research and led to many discoveries in the field of short motifs. Research has shown that many types of protein-protein interactions and enzymatic modifications are determined by short sequence proteins, which “gave way to the much broader concept of short linear motifs (SLIMs) or eukaryotic linear motifs (ELMs)”. SLIMs are short stretches of protein sequence that mediate protein-protein interaction. The sequences of various proteins contain short conserved, motifs that are involved in recognition and targeting activities, often independent from the other functional properties described on the protein. Motifs are mainly linear and the 3-dimensional structure is not required to bring distant segments of the protein together to make the recognizable unit. Short linear motifs show “extreme evolutionary agility, represent extremely versatile short recognition modules, and are usually bound by recognition domains of the partner molecule”. Scientists have discovered that most motifs are located in intrinsically disordered regions of proteins. Structurally, the concepts of preformed structural elements and molecular features are “suggested to be short disordered regions that sample structured states within the conformational ensemble, and become fully ordered upon binding to the partner”. Binding of motifs to molecules are usually weak, fast, and possibly of limited specificity, which “can be made stronger and/or more specific by cooperating with flanking regions, combining several motifs, or utilizing longer disordered domains”.
A question to raise is whether folding occurs before or after the binding of the motif to its molecule. This issue shows strong correlation with the question of the mechanism used to fold proteins. Research on intrinsically disordered protein binding showed that folding can occur both before and after binding. For example, “NMR 15N relaxation dispersion studies of the binding of the phosphorylated kinase-inducible domain (pKID) of cyclic AMP response element-binding protein (CREB) to the KID-interaction domain (KIX) of CREB-binding protein (CBP) shows that binding proceeds through an ensemble of disordered encounter complexes dominated by nonspecific hydrophobic contacts, only to complete folding in the final bound state”.
Other concepts have formed from the binding-folding paradigm. The first is the surprising observation that two intrinsically disordered proteins or intrinsically disordered regions of proteins can bind to each other through mutual folding. The second is that recognition of the both disordered proteins or regions of disorder can proceed even in the lack of folding in the final bound state.
Intrinsically disordered proteins or intrinsically disordered regions of proteins have the ability capture greater radius than a globular protein and “can bind at a relatively larger distance followed by reeling on to the partner, potentially enhancing the rate of binding by a ‘fly-casting’ mechanism”. The mechanism is likely to occur in the assembly of large multiprotein complexes, such as”in nonsense-mediated decay (NMD) , for example, which is triggered by the productive interaction of UPF proteins. The interaction is initiated by the long-disordered C-terminal domain of UPF2 initially binding UPF1 and bringing various parts of the complex in proximity”.

## Reference

* 1 2 3 4 5 6 7 8 Tompa, Peter. "Intrinsically Disordered Proteins: A 10-year Recap." Science Direct. N.p., n.d. Web. 6 Dec. 2012. doi:10.1016/j.tibs.2012.08.004.