Understanding the functional significance of intrinsically disordered regions in proteins using computational methods

Abstract

The main aim of structural biology has been to understand how a protein functions based on its structure. This approach has been remarkably successful but with a side-effect that proteins or regions in proteins which do not have a well defined three dimensional structure (also called as disordered regions/proteins) have been ignored. The limitations of experimental methods in studying these regions have also not helped. But these proteins/regions can no longer be ignored not only because they are exciting to study but also because they are surprisingly common in eukaryotes. Computational methods to predict disordered regions in proteins have advanced rapidly. Concurrently, genome wide functional data, particularly for yeast has become available. I took advantage of these resources to find associations between predicted disorder and various functional data to increase our understanding of the functional roles of disordered regions/proteins. newline I find significant association between protein disorder and PEST regions in proteins, which are involved in rapid degradation of proteins, suggesting that PEST regions mediate rapid degradation of proteins due to their disorderedness. I also find that hubs in the protein interaction networks, which interact with their partners in transient manner, tend to be more disordered. This finding in protein-protein interaction networks is extended to transcriptional regulatory networks, wherein I find that transcription factor hubs tend to be more disordered than non-hub transcription factors. Further, I find that expression levels and aggregation propensity of proteins also influence their disorderness. newline Overall these results suggest that structural disorder in proteins does not mean functional disorderness, but that disorder regions/proteins are crucial in the functioning of biological systems, particularly eukaryotic organisms.