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

Author

Listed:
  • Max T. B. Clabbers

    (Stockholm University
    University of California Los Angeles)

  • 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
    University of New South Wales
    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
    The University of Queensland
    The University of Queensland)

  • Connie Darmanin

    (La Trobe University)

  • Bostjan Kobe

    (The University of Queensland
    The University of Queensland
    The University of Queensland)

  • Hongyi Xu

    (Stockholm University)

  • Thomas Ve

    (Griffith University)

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.

Suggested Citation

  • 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. Nan, 2021. "MyD88 TIR domain higher-order assembly interactions revealed by microcrystal electron diffraction and serial femtosecond crystallography," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22590-6
    DOI: 10.1038/s41467-021-22590-6
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