Journal Article

PUBDB-2022-00632

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png MyD88 TIR domain higher-order assembly interactions revealed by microcrystal electron diffraction and serial femtosecond crystallography

Clabbers, M. T. B. ; Holmes, S. ; Muusse, T. W. ; Vajjhala, P. R. ; Thygesen, S. J. ; Malde, A. K. ; Hunter, D. J. B. ; Croll, T. I. ; Flueckiger, L.Extern* ; Nanson, J. D. ; Rahaman, M. H. ; Aquila, A.Extern* ; Hunter, M. S.XFEL.EU* ; Liang, M. ; Yoon, C. H.Extern* ; Zhao, J. ; Zatsepin, N. A.Extern*XFEL.EU* ; Abbey, B.Extern* ; Sierecki, E. ; Gambin, Y. ; Stacey, K. J. ; Darmanin, C. (Corresponding author) ; Kobe, B.Extern* ; Xu, H. (Corresponding author) ; Ve, T. (Corresponding author)Extern*

2021
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-021-22590-6  doi:10.3204/PUBDB-2022-00632

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 (MyD88$^{TIR}$). 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 MyD88$^{TIR}$ assembly, which reveal a two-stranded higher-order assembly arrangement of TIR domains analogous to that seen previously for MAL$^{TIR}$. We demonstrate via mutagenesis that the MyD88$^{TIR}$ assembly interfaces are critical for TLR4 signaling in vivo, and we show that MAL promotes unidirectional assembly of MyD88$^{TIR}$R. Collectively, our studies provide structural and mechanistic insight into TLR signal transduction and allow a direct comparison of the MicroED and SFX techniques.

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Contributing Institute(s):

1. DOOR-User (DOOR ; HAS-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)

Experiment(s):

1. PETRA Beamline P11 (PETRA III)

Appears in the scientific report 2021

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