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TitleStepwise activation of SARM1 for cell death and axon degeneration revealed by a biosynthetic NMN mimic.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 122, Issue 8, Page e2424906122, Year 2025
Publish dateFeb 25, 2025
AuthorsYinpin Huang / Jun Zhang / Wenbin Zhang / Jie Chen / Sijia Chen / Qincui Wu / Sanduo Zheng / Xiaodong Wang /
PubMed AbstractAxon degeneration, driven by the NAD hydrolyzing enzyme SARM1, is an early pathological hallmark of numerous neurodegenerative diseases. SARM1 exists in an inactive form and is activated following ...Axon degeneration, driven by the NAD hydrolyzing enzyme SARM1, is an early pathological hallmark of numerous neurodegenerative diseases. SARM1 exists in an inactive form and is activated following nerve injury. However, the precise molecular mechanism underlying SARM1 activation remains to be fully elucidated. In this study, we report the identification of a potent proactivator of SARM1, G10, which is converted into a direct activator (M1) by the enzyme nicotinamide phosphoribosyltransferase. Cryoelectron microscopy structures of SARM1 bound to M1, as well as to M1 and a nonhydrolyzable NAD analog (1AD), captured two intermediate activation states and the fully active state, revealing a stepwise mechanism of SARM1 activation. Further, introducing a disulfide bond to prevent conformational transitions between the two intermediate states mediated by M1 stabilized SARM1 in its inactive form and blocked M1-induced cell death. Together, these findings propose a sequential, stepwise activation model for SARM1 and offer a framework for developing potential SARM1 inhibitors for the treatment of neurodegenerative diseases.
External linksProc Natl Acad Sci U S A / PubMed:39964720 / PubMed Central
MethodsEM (single particle)
Resolution2.46 - 3.55 Å
Structure data

62772

9l2d

EMDB-62772, PDB-9l2d:
Structure of SARM1 bound to M1 in the intermediate state 1
Method: EM (single particle) / Resolution: 2.83 Å

62773

9l2e

EMDB-62773, PDB-9l2e:
Structure of SARM1 bound to M1 in the intermediate state 2
Method: EM (single particle) / Resolution: 2.46 Å

62774

9l2f

EMDB-62774, PDB-9l2f:
Structure of SARM1 bound to M1 and 1AD in the active state
Method: EM (single particle) / Resolution: 3.55 Å

62775

9l2g

EMDB-62775, PDB-9l2g:
Structure of SARM1 2C-mutant bound to M1
Method: EM (single particle) / Resolution: 3.27 Å

Chemicals

PDB-1eiv:
Unknown entry

Source
  • homo sapiens (human)
KeywordsHYDROLASE / NAD(+) hydrolase / cell death / apoptosis

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