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Protein & Peptide Letters

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Research Article

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

Author(s): Suryanarayana Seera and Hampapathalu A. Nagarajaram*

Volume 29, Issue 3, 2022

Published on: 03 March, 2022

Page: [254 - 267] Pages: 14

DOI: 10.2174/0929866528666211126161200

Price: $65

Abstract

Introduction: Disease causing missense mutations (DCMMs) destabilize protein structures. However it is not known how they impact the intrinsically disordered regions (IDRs) as these regions do not adopt stable 3D structures under physiological conditions. It is therefore imperative to investigate the effect of DCMMs on the functionally important IDRs.

Objective: To investigate impact of DCMMs on functionally important IDRs in human proteins.

Methods: We investigated the impact of the known DCMMs on three IDRs: a) an IDR with CRIB motif from WAS protein , b) a proline rich IDR of p22 protein and c) an IDR horboring TRM motif from SH3BP2 protein. Both the wild type and the mutant forms were subjected to detailed structural investigations using MD simulations for 100ns.

Results: MD studies revealed that the mutants adopt fewer conformational states as compared with their wild-type counterparts of which one or two form the dominant conformational states. This result was also corroborated by the free-energy landscapes of the mutants with a fewer minima as compared with the wild-types. It was also observed that the side chains of the mutated amino acid residues introduce new hydrogen bonding interactions that stabilize one or two of the dominant conformational states.

Conclusion: Our studies, thus, revealed that the disease causing missense mutations reduce the conformational heterogeneity of the intrinsically disordered proteins and furthermore, they are “locked” in one or two of those conformational states that presumably disfavour binding of the IDRs with their cognate interacting partners.

Keywords: Conformational heterogeneity, Intrinsically disordered protein, intrinsically disordered region, molecular dynamics, conformation, disease causing mutation, missense mutation, energy landscape.

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