Nagarajaram, H. A. | bioRxiv Science

bioRxiv2021

Effect of Disease Causing Missense Mutations on Intrinsically Disordered Regions in Proteins

It is well known that disease-causing missense mutations (DCMMs) reduce the structural stability/integrity of the proteins with well-defined 3D structures thereby impacting their molecular functions. However, it is not known in what way DCMMs affect the intrinsically disordered proteins (IDPs) that do not adopt well defined stable 3D structures. In order to investigate how DCMMs may impact intrinsically disordered regions (IDRs) in proteins we undertook Molecular Dynamics (MD) based studies on three different examples of functionally important IDRs with known DCMMs. Our studies revealed that the functional impact of DCMMs is in reducing the conformational heterogeneity of IDRs which is intrinsic and quintessential for their multi-faceted cellular roles. These results are reinforced by energy landscapes of the wildtype and mutant IDRs where the former is characterized by many local minima separated by low barriers whereas the latter are characterized by one global minimum and several local minima separated by high energy barriers. Our MD based studies also indicate that DCMMs stabilize a very few structural possibilities of IDRs either by the newly formed interactions induced by the substituted side chains or by means of restricted or increased flexibilities of the backbone conformations at the mutation sites. Furthermore, the structural possibilities stabilized by DCMMs do not support the native functional roles of the IDRs thereby leading to disease conditions.

bioinformatics↗

bioRxiv2021

Comparative analysis of Pure Hubs and Pure Bottlenecks in Human Protein-protein Interaction Networks

Bottlenecks and hubs form a set of topologically important nodes in a network. In this communication, we have made a detailed investigation on hubs and bottlenecks in human protein-protein interaction networks. We find that, three distinct groups exist which we refer to as: a) pure hubs (PHs, nodes having high degree but low betweenness values), b) mix proteins (MXs, nodes having both high degree and high betweenness values) and c) pure bottlenecks (PBs, nodes having high betweenness values but low degree values). Our investigations have revealed that pure hubs, as compared with MXs and PBs, (i) are more disordered, (ii) have higher potential to bind to multiple partners, (iii) are enriched with essential proteins as well as enriched with a higher number of splice variants. The MX proteins, as compared with PHs and PBs, (i) show slower evolutionary patterns, (ii) are involved in multiple pathways, (iii) enriched with the products of genes associated with various diseases and (iv) are more often targeted by bacteria, viruses, protozoa, and fungi pathogens. PBs, as compared with the PHs and MXs, (i) are associated with cancer genes and (ii) are the targets or the nearest neighbors of the targets of most of the approved drugs. Furthermore, our study revealed that these three categories of proteins are involved in distinct functional roles; PHs are involved in housekeeping processes such as transcription and replication; MXs proteins are involved in core signaling pathways whereas PBs are involved in signal transduction processes. Our work, therefore, has identified the distinct characteristics features associated with pure hubs, mix proteins and pure bottlenecks and thus helps in prioritizing proteins based on their degree and betweenness centrality values.

systems biology↗