Conformational Changes Induced by S34Y and R98C Variants in the Death Domain of Myd88.

Vijayakumar Gosu,Kyeonghye Won,Jae-Don Oh,Donghyun Shin

doi:10.3389/fmolb.2020.00027

Vijayakumar Gosu, Kyeonghye Won + Show 2 more

Open Access

https://doi.org/10.3389/fmolb.2020.00027

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Abstract

Myeloid differentiating factor 88 (Myd88) is a universal adaptor protein that plays a critical role in innate immunity by mediating TLR downstream signaling. Myd88 death domain (DD) forms an oligomeric complex by association with other DD-containing proteins such as IRAK4. Despite its universal role, polymorphisms in Myd88 can result in several diseases. Previous studies have suggested that, out of several non-synonymous single-nucleotide polymorphisms (nsSNPs), the variants S34Y and R98C in the DD of Myd88 disrupt the formation of the Myddosome complex. Therefore, we performed molecular dynamics (MD) simulations on wild-type (Myd88WT) and mutant (Myd88S34Y, Myd88R98C) DDs to evaluate the subtle conformational changes induced by these mutations. Our results suggest that the S34Y variant induces large structural transitions compared to the R98C variant as evidenced by residual flexibility at the variable loop regions, particularly in the H1–H2 loop, and variations in the collective modes of motion observed for wild-type and mutant Myd88 DDs. The residue interaction network strongly suggests a distortion in the interaction pattern at the location of the mutated residue between the wild type and mutants. Moreover, betweenness centrality values indicate that variations in the distribution of functionally important residues may be reflected by distinct residue signal transductions in both wild-type and mutant Myd88 DDs, which may influence the interaction with other DDs in TLR downstream signaling.

Highlights

Pattern recognition receptors (PRRs) play a crucial role in triggering the host innate immune response against harmful microbial organisms (Takeuchi and Akira, 2010; Thompson et al, 2011)
In this study, we performed molecular dynamics (MD) simulations on wildtype and mutant Myeloid differentiating factor 88 (Myd88) death domain (DD) to better understand the subtle conformational changes induced by the mutations in the DD of Myd88
Our results suggest that the high residue flexibility in the H1–H2 loop region at residues 39– 48 may affect Myddosome formation

Summary

Introduction

Pattern recognition receptors (PRRs) play a crucial role in triggering the host innate immune response against harmful microbial organisms (Takeuchi and Akira, 2010; Thompson et al, 2011). Toll-like receptors (TLRs) are an important class of PRRs that are activated when pathogenassociated molecular patterns (PAMPs) are sensed. When PAMPs are detected, TLRs trigger the signaling mediators and activate NF-κB, thereby inducing proinflammatory genes encoding cytokines and chemokines (Gosu et al, 2012; Liu et al, 2017). There are five adaptor proteins such as Myd, TRIF, Mal, TRAM, and SARM in TLR signaling (Troutman et al, 2012). Myd point mutations have been associated with several deadly bacterial infections (von Bernuth et al, 2008; Cervantes, 2017). The S34Y variant is inactive in all Myd88-dependent signaling (Nagpal et al, 2011)

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