Dynamics of the SS Loop Regulates SARM1's Catalysis

  • ACS Chem Neurosci. 2026 May 6;17(9):1644-1657. doi: 10.1021/acschemneuro.5c00829.
Jian Yuan Yang  1 ,  Wei Ming He  2 ,  Wan Hua Li  1  2 ,  Qianwen Wang  2 ,  Tsz-Fung Wong  3 ,  Xiaowan Jin  1 ,  Dongjie Hu  1 ,  Jingxuan Gao  1 ,  Yilin Guo  1 ,  Zhongping Yao  3 ,  Deqiang Niu  4 ,  Hon Cheung Lee  1 ,  Ying-Chih Chiang  1  5  6 ,  Yong Juan Zhao  1  2
Affiliations
  • 1. School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China.
  • 2. State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
  • 3. State Key Laboratory of Chemical Biology and Drug Discovery, Research Institute for Future Food and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR 999077, China.
  • 4. Artivila (Shenzhen) Innovation Center, Ltd., Shenzhen 518172, China.
  • 5. Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China.
  • 6. School of Science and Engineering, The Chinese University of Hong Kong, Shenzhen 518172, China.
PMID: 42024581 DOI: 10.1021/acschemneuro.5c00829
Abstract

Axonal degeneration (AxD) is a defining feature of many neurodegenerative disorders, with SARM1 functioning as a key pro-degenerative NADase that becomes activated through conformational change. Here, we identify a critical regulatory mechanism mediated by the SARM1-specific (SS) loop within its TIR domain. Using mutagenesis, activity assays, and molecular dynamics simulations, we demonstrate that dynamic conformational transitions of the SS loop, particularly the flipping of His640, are essential for NAD recruitment and catalytic site assembly. Zinc ions inhibit SARM1 activity by coordinating with a conserved C2H2 motif in the SS loop, thereby restricting His640 flipping and preventing NAD engagement. Notably, chemical tethering of adjacent cysteine residues within the SS loop similarly suppresses its conformational dynamics, resulting in potent inhibition of catalysis. The essential role of SS loop dynamics uncovered here offers new mechanistic insight and establishes a foundation for developing therapeutic strategies targeting SARM1.

Keywords
ADP-ribosyl cyclase; PAO; PC6; SARM1; SS loop; cADPR; cysteine; zinc ion.
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