MyD88 TIR domain higher-order assembly interactions revealed by microcrystal electron diffraction and serial femtosecond crystallography

Max T. B. Clabbers, Susannah Holmes, Timothy W. Muusse, Parimala R. Vajjhala, Sara J. Thygesen, Alpeshkumar K. Malde, Dominic J. B. Hunter, Tristan I. Croll, Leonie Flueckiger, Jeffrey D. Nanson, Md. Habibur Rahaman, Andrew Aquila, Mark S. Hunter, Mengning Liang, Chun Hong Yoon, Jingjing Zhao, Nadia A. Zatsepin, Brian Abbey, Emma Sierecki, Yann Gambin, Katryn J. Stacey, Connie Darmanin (), Bostjan Kobe (), Hongyi Xu () and Thomas Ve ()
Additional contact information
Max T. B. Clabbers: Stockholm University
Susannah Holmes: La Trobe University
Timothy W. Muusse: The University of Queensland
Parimala R. Vajjhala: The University of Queensland
Sara J. Thygesen: The University of Queensland
Alpeshkumar K. Malde: Griffith University
Dominic J. B. Hunter: The University of Queensland
Tristan I. Croll: University of Cambridge
Leonie Flueckiger: La Trobe University
Jeffrey D. Nanson: The University of Queensland
Md. Habibur Rahaman: The University of Queensland
Andrew Aquila: SLAC National Accelerator Laboratory
Mark S. Hunter: SLAC National Accelerator Laboratory
Mengning Liang: SLAC National Accelerator Laboratory
Chun Hong Yoon: SLAC National Accelerator Laboratory
Jingjing Zhao: Stockholm University
Nadia A. Zatsepin: La Trobe University
Brian Abbey: La Trobe University
Emma Sierecki: University of New South Wales
Yann Gambin: University of New South Wales
Katryn J. Stacey: The University of Queensland
Connie Darmanin: La Trobe University
Bostjan Kobe: The University of Queensland
Hongyi Xu: Stockholm University
Thomas Ve: Griffith University

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22590-6

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