| Structural highlights
Function
SARM1_HUMAN Negative regulator of MYD88- and TRIF-dependent toll-like receptor signaling pathway which plays a pivotal role in activating axonal degeneration following injury. Promotes Wallerian degeneration an injury-induced axonal death pathway which involves degeneration of an axon distal to the injury site. Can activate neuronal death in response to stress. Regulates dendritic arborization through the MAPK4-JNK pathway. Involved in innate immune response. Inhibits both TICAM1/TRIF- and MYD88-dependent activation of JUN/AP-1, TRIF-dependent activation of NF-kappa-B and IRF3, and the phosphorylation of MAPK14/p38.[1] [2] [3] [4]
Publication Abstract from PubMed
SARM1 regulates axonal degeneration through its NAD-metabolizing activity and is a drug target for neurodegenerative disorders. We designed and synthesized fluorescent conjugates of styryl derivative with pyridine to serve as substrates of SARM1, which exhibited large red-shifts after conversion. With the conjugates, SARM1 activation was visualized in live cells following elevation of endogenous NMN or treatment with a cell-permeant NMN-analog. In neurons, imaging documented mouse SARM1 activation preceded vincristine-induced axonal degeneration by hours. Library screening identified a derivative of nisoldipine as a covalent inhibitor of SARM1 that reacted with the cysteines, especially Cys311 in its ARM domain and blocked its NMN-activation, protecting axons from degeneration. The Cryo-EM structure showed that SARM1 was locked into an inactive conformation by the inhibitor, uncovering a potential neuroprotective mechanism of dihydropyridines.
Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate.,Li WH, Huang K, Cai Y, Wang QW, Zhu WJ, Hou YN, Wang S, Cao S, Zhao ZY, Xie XJ, Du Y, Lee CS, Lee HC, Zhang H, Zhao YJ Elife. 2021 May 4;10. pii: 67381. doi: 10.7554/eLife.67381. PMID:33944777[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Liberati NT, Fitzgerald KA, Kim DH, Feinbaum R, Golenbock DT, Ausubel FM. Requirement for a conserved Toll/interleukin-1 resistance domain protein in the Caenorhabditis elegans immune response. Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6593-8. PMID:15123841 doi:http://dx.doi.org/10.1073/pnas.0308625101
- ↑ Carty M, Goodbody R, Schroder M, Stack J, Moynagh PN, Bowie AG. The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling. Nat Immunol. 2006 Oct;7(10):1074-81. doi: 10.1038/ni1382. Epub 2006 Sep 10. PMID:16964262 doi:http://dx.doi.org/10.1038/ni1382
- ↑ O'Neill LA. DisSARMing Toll-like receptor signaling. Nat Immunol. 2006 Oct;7(10):1023-5. doi: 10.1038/ni1006-1023. PMID:16985498 doi:http://dx.doi.org/10.1038/ni1006-1023
- ↑ Peng J, Yuan Q, Lin B, Panneerselvam P, Wang X, Luan XL, Lim SK, Leung BP, Ho B, Ding JL. SARM inhibits both TRIF- and MyD88-mediated AP-1 activation. Eur J Immunol. 2010 Jun;40(6):1738-47. doi: 10.1002/eji.200940034. PMID:20306472 doi:http://dx.doi.org/10.1002/eji.200940034
- ↑ Li WH, Huang K, Cai Y, Wang QW, Zhu WJ, Hou YN, Wang S, Cao S, Zhao ZY, Xie XJ, Du Y, Lee CS, Lee HC, Zhang H, Zhao YJ. Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate. Elife. 2021 May 4;10:e67381. PMID:33944777 doi:10.7554/eLife.67381
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