| Literature DB >> 33972532 |
Max T B Clabbers1,2, Susannah Holmes3, Timothy W Muusse4, Parimala R Vajjhala4, Sara J Thygesen4, Alpeshkumar K Malde5, Dominic J B Hunter4,6,7, Tristan I Croll8, Leonie Flueckiger3, Jeffrey D Nanson4, Md Habibur Rahaman4, Andrew Aquila9, Mark S Hunter9, Mengning Liang9, Chun Hong Yoon9, Jingjing Zhao1, Nadia A Zatsepin3, Brian Abbey3, Emma Sierecki6, Yann Gambin6, Katryn J Stacey4,7,10, Connie Darmanin11, Bostjan Kobe12,13,14, Hongyi Xu15, Thomas Ve16.
Abstract
MyD88 and MAL are Toll-like receptor (TLR) adaptors that signal to induce pro-inflammatory cytokine production. We previously observed that the TIR domain of MAL (MALTIR) forms filaments in vitro and induces formation of crystalline higher-order assemblies of the MyD88 TIR domain (MyD88TIR). These crystals are too small for conventional X-ray crystallography, but are ideally suited to structure determination by microcrystal electron diffraction (MicroED) and serial femtosecond crystallography (SFX). Here, we present MicroED and SFX structures of the MyD88TIR assembly, which reveal a two-stranded higher-order assembly arrangement of TIR domains analogous to that seen previously for MALTIR. We demonstrate via mutagenesis that the MyD88TIR assembly interfaces are critical for TLR4 signaling in vivo, and we show that MAL promotes unidirectional assembly of MyD88TIR. Collectively, our studies provide structural and mechanistic insight into TLR signal transduction and allow a direct comparison of the MicroED and SFX techniques.Entities:
Year: 2021 PMID： 33972532 DOI： 10.1038/s41467-021-22590-6
Source DB: PubMed Journal: Nat Commun ISSN： 2041-1723 Impact factor: 14.919