7cm5
From Proteopedia
Full-length Sarm1 in a self-inhibited state
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 PubMedPathological degeneration of axons disrupts neural circuits and represents one of the hallmarks of neurodegeneration(1-4). Sterile alpha and Toll/interleukin-1 receptor motif-containing protein 1 (Sarm1) is a central regulator of this neurodegenerative process(5-8), and its Toll/interleukin-1 receptor (TIR) domain exerts the pro-neurodegenerative action through the NADase activity(9,10). However, the mechanism underlying the stringent control of Sarm1 activation remains to be fully understood. Here, we report the cryo-EM structures of full-length Sarm1 proteins at 2.6- to 3.0-A resolution. We discovered NAD(+) as an unexpected ligand of the armadillo/heat repeat motifs (ARM) domain. This NAD(+) binding facilitated the ARM domain to inhibit the TIR-domain NADase through their domain interface. Disruption of the NAD(+)-binding site or the ARM-TIR interaction caused the constitutively-active Sarm1 leading to axonal degeneration. These findings have suggested the novel NAD(+)-mediated self-inhibition of this central pro-neurodegenerative protein. The NAD(+)-mediated self-inhibition mechanism of pro-neurodegenerative Sarm1.,Jiang Y, Liu T, Lee CH, Chang Q, Yang J, Zhang Z Nature. 2020 Oct 14. pii: 10.1038/s41586-020-2862-z. doi:, 10.1038/s41586-020-2862-z. PMID:33053563[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Human | Large Structures | Jiang, Y | Zhang, Z | Arm | Hydrolase | Nadase | Sam | Tir
