| 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
The NADase SARM1 (sterile alpha and TIR motif containing 1) is a key executioner of axon degeneration and a therapeutic target for several neurodegenerative conditions. We show that a potent SARM1 inhibitor undergoes base exchange with the nicotinamide moiety of nicotinamide adenine dinucleotide (NAD(+)) to produce the bona fide inhibitor 1AD. We report structures of SARM1 in complex with 1AD, NAD(+) mimetics and the allosteric activator nicotinamide mononucleotide (NMN). NMN binding triggers reorientation of the armadillo repeat (ARM) domains, which disrupts ARM:TIR interactions and leads to formation of a two-stranded TIR domain assembly. The active site spans two molecules in these assemblies, explaining the requirement of TIR domain self-association for NADase activity and axon degeneration. Our results reveal the mechanisms of SARM1 activation and substrate binding, providing rational avenues for the design of new therapeutics targeting SARM1.
Structural basis of SARM1 activation, substrate recognition, and inhibition by small molecules.,Shi Y, Kerry PS, Nanson JD, Bosanac T, Sasaki Y, Krauss R, Saikot FK, Adams SE, Mosaiab T, Masic V, Mao X, Rose F, Vasquez E, Furrer M, Cunnea K, Brearley A, Gu W, Luo Z, Brillault L, Landsberg MJ, Di Antonio A, Kobe B, Milbrandt J, Hughes RO, Ve T Mol Cell. 2022 Mar 18. pii: S1097-2765(22)00216-7. doi:, 10.1016/j.molcel.2022.03.007. PMID:35334231[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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
- ↑ Shi Y, Kerry PS, Nanson JD, Bosanac T, Sasaki Y, Krauss R, Saikot FK, Adams SE, Mosaiab T, Masic V, Mao X, Rose F, Vasquez E, Furrer M, Cunnea K, Brearley A, Gu W, Luo Z, Brillault L, Landsberg MJ, Di Antonio A, Kobe B, Milbrandt J, Hughes RO, Ve T. Structural basis of SARM1 activation, substrate recognition, and inhibition by small molecules. Mol Cell. 2022 Mar 18. pii: S1097-2765(22)00216-7. doi:, 10.1016/j.molcel.2022.03.007. PMID:35334231 doi:http://dx.doi.org/10.1016/j.molcel.2022.03.007
|
