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A conformation-specific nanobody targeting the nicotinamide mononucleotide-activated state of SARM1

Author

Listed:
  • Yun Nan Hou

    (Peking University Shenzhen Graduate School)

  • Yang Cai

    (Southern University of Science and Technology)

  • Wan Hua Li

    (Peking University Shenzhen Graduate School
    The Chinese University of Hong Kong)

  • Wei Ming He

    (Peking University Shenzhen Graduate School)

  • Zhi Ying Zhao

    (Peking University Shenzhen Graduate School)

  • Wen Jie Zhu

    (Peking University Shenzhen Graduate School)

  • Qiang Wang

    (Peking University Shenzhen Graduate School)

  • Xinyi Mai

    (The Chinese University of Hong Kong)

  • Jun Liu

    (Peking University Shenzhen Graduate School)

  • Hon Cheung Lee

    (Peking University Shenzhen Graduate School)

  • Goran Stjepanovic

    (The Chinese University of Hong Kong)

  • Hongmin Zhang

    (Southern University of Science and Technology)

  • Yong Juan Zhao

    (Peking University Shenzhen Graduate School
    The Chinese University of Hong Kong)

Abstract

Sterile alpha (SAM) and Toll/interleukin-1 receptor (TIR) motif containing 1 (SARM1) is an autoinhibitory NAD-consuming enzyme that is activated by the accumulation of nicotinamide mononucleotide (NMN) during axonal injury. Its activation mechanism is not fully understood. Here, we generate a nanobody, Nb-C6, that specifically recognizes NMN-activated SARM1. Nb-C6 stains only the activated SARM1 in cells stimulated with CZ-48, a permeant mimetic of NMN, and partially activates SARM1 in vitro and in cells. Cryo-EM of NMN/SARM1/Nb-C6 complex shows an octameric structure with ARM domains bending significantly inward and swinging out together with TIR domains. Nb-C6 binds to SAM domain of the activated SARM1 and stabilized its ARM domain. Mass spectrometry analyses indicate that the activated SARM1 in solution is highly dynamic and that the neighboring TIRs form transient dimers via the surface close to one BB loop. We show that Nb-C6 is a valuable tool for studies of SARM1 activation.

Suggested Citation

  • Yun Nan Hou & Yang Cai & Wan Hua Li & Wei Ming He & Zhi Ying Zhao & Wen Jie Zhu & Qiang Wang & Xinyi Mai & Jun Liu & Hon Cheung Lee & Goran Stjepanovic & Hongmin Zhang & Yong Juan Zhao, 2022. "A conformation-specific nanobody targeting the nicotinamide mononucleotide-activated state of SARM1," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35581-y
    DOI: 10.1038/s41467-022-35581-y
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