Influence of Disease-Causing Mutations on Protein Structural Networks.

Vasam Manjveekar Prabantu,Nagarajan Naveenkumar,Narayanaswamy Srinivasan

doi:10.3389/fmolb.2020.620554

Abstract

The interactions between residues in a protein tertiary structure can be studied effectively using the approach of protein structure network (PSN). A PSN is a node-edge representation of the structure with nodes representing residues and interactions between residues represented by edges. In this study, we have employed weighted PSNs to understand the influence of disease-causing mutations on proteins of known 3D structures. We have used manually curated information on disease mutations from UniProtKB/Swiss-Prot and their corresponding protein structures of wildtype and disease variant from the protein data bank. The PSNs of the wildtype and disease-causing mutant are compared to analyse variation of global and local dissimilarity in the overall network and at specific sites. We study how a mutation at a given site can affect the structural network at a distant site which may be involved in the function of the protein. We have discussed specific examples of the disease cases where the protein structure undergoes limited structural divergence in their backbone but have large dissimilarity in their all atom networks and vice versa, wherein large conformational alterations are observed while retaining overall network. We analyse the effect of variation of network parameters that characterize alteration of function or stability.

Highlights

The amino acid sequence determines the protein 3-D structure (Anfinsen, 1973) which is related to its function
We identified crystal structure variants corresponding to 74 disease cases and used those structures solved with the best resolution
We have identified edges and hubs that are unique to the wildtype structure that are lost in the mutant where new edges and hubs unique to the mutant structure are gained

Summary

Introduction

The amino acid sequence determines the protein 3-D structure (Anfinsen, 1973) which is related to its function. A mutation in the amino acid sequence may alter the structure of a protein but it does not necessarily alter its function, the mutation at specific sites such as conserved residues can bring about a change in the structure and function of the protein. SNPs could be non-synonymous which bring about a change in the amino acid sequence. Several such genetic variants are known to cause mutations in their gene product and their information is available in resources such as the SNPdb (Sherry et al, 2001) and 1000 Genomes project (Auton et al, 2015).

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Conclusion