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Function
SARM1 or NAD(+) hydrolase or sterile alpha and TIR motif-containing protein 1 or NADase is a NAD-cleaving enzyme whose activation triggers axon destruction. SARM1 is a metabolic sensor responding to an increased NMN/NAD+ ratio by cleaving residual NAD+ and inducing axonal demise[1]. SARM1-induced axon destruction can be counteracted by increased NAD+ synthesis[2].
Disease
SARM1 mutations were found in ALS patients[3].
Structural highlights
The 3D structure of SARM1 shows the octamer structure with outer ring dimension of 200A, inner ring of 45A and thickness of 60A[4]. The 3 domains of SARM1 are ARM, SAM and TIR. The interaction of the ARM and TIR domains cause the autoinhibition of SARM1. NAD(+) binding pocket is at the concave side of the ARM domain.
3D structures of SARM1
SARM1 3D structures
- ↑ Figley MD, Gu W, Nanson JD, Shi Y, Sasaki Y, Cunnea K, Malde AK, Jia X, Luo Z, Saikot FK, Mosaiab T, Masic V, Holt S, Hartley-Tassell L, McGuinness HY, Manik MK, Bosanac T, Landsberg MJ, Kerry PS, Mobli M, Hughes RO, Milbrandt J, Kobe B, DiAntonio A, Ve T. SARM1 is a metabolic sensor activated by an increased NMN/NAD(+) ratio to trigger axon degeneration. Neuron. 2021 Mar 1. pii: S0896-6273(21)00083-0. doi:, 10.1016/j.neuron.2021.02.009. PMID:33657413 doi:https://dx.doi.org/10.1016/j.neuron.2021.02.009
- ↑ Gerdts J, Brace EJ, Sasaki Y, DiAntonio A, Milbrandt J. SARM1 activation triggers axon degeneration locally via NAD(+) destruction. Science. 2015 Apr 24;348(6233):453-7. doi: 10.1126/science.1258366. Epub 2015 Apr, 23. PMID:25908823 doi:https://dx.doi.org/10.1126/science.1258366
- ↑ Gilley J, Jackson O, Pipis M, Estiar MA, Al-Chalabi A, Danzi MC, van Eijk KR, Goutman SA, Harms MB, Houlden H, Iacoangeli A, Kaye J, Lima L, Ravits J, Rouleau GA, Schule R, Xu J, Zuchner S, Cooper-Knock J, Gan-Or Z, Reilly MM, Coleman MP. Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders. Elife. 2021 Nov 19;10. pii: 70905. doi: 10.7554/eLife.70905. PMID:34796871 doi:https://dx.doi.org/10.7554/eLife.70905
- ↑ Jiang Y, Liu T, Lee CH, Chang Q, Yang J, Zhang Z. The NAD(+)-mediated self-inhibition mechanism of pro-neurodegenerative Sarm1. Nature. 2020 Oct 14. pii: 10.1038/s41586-020-2862-z. doi:, 10.1038/s41586-020-2862-z. PMID:33053563 doi:https://dx.doi.org/10.1038/s41586-020-2862-z
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