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Dynamics of the SS Loop Regulates SARM1's Catalysis
Jian Yuan Yang1, Wei Ming He2, Wan Hua Li1,2
1School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China.
ACS Chemical Neuroscience
|April 23, 2026
Summary
Researchers discovered that the SARM1-specific loop
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Axonal degeneration (AxD) is a hallmark of neurodegenerative diseases.
- SARM1 is a critical pro-degenerative enzyme (NADase) activated by conformational changes.
Purpose of the Study:
- To identify the regulatory mechanism of SARM1 activation.
- To elucidate the role of the SARM1-specific (SS) loop in SARM1's catalytic activity.
Main Methods:
- Site-directed mutagenesis
- Enzyme activity assays
- Molecular dynamics simulations
- Biochemical inhibition studies
Main Results:
- Dynamic conformational transitions of the SS loop, including His640 flipping, are crucial for SARM1 NAD recruitment and catalysis.
- Zinc ions inhibit SARM1 by binding to a C2H2 motif in the SS loop, restricting His640 movement.
- Chemical tethering of SS loop cysteines also inhibits SARM1 activity by limiting conformational dynamics.
Conclusions:
- SS loop dynamics are essential for SARM1 NADase activity.
- This finding provides mechanistic insight into SARM1 regulation.
- The study lays the groundwork for developing SARM1-targeted therapeutics for neurodegenerative disorders.
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