+Search query
-Structure paper
Title | Structure-function analysis of ceTIR-1/hSARM1 explains the lack of Wallerian axonal degeneration in C. elegans. |
---|---|
Journal, issue, pages | Cell Rep, Vol. 42, Issue 9, Page 113026, Year 2023 |
Publish date | Aug 26, 2023 |
Authors | Tami Khazma / Atira Grossman / Julia Guez-Haddad / Chengye Feng / Hadas Dabas / Radhika Sain / Michal Weitman / Ran Zalk / Michail N Isupov / Marc Hammarlund / Michael Hons / Yarden Opatowsky / |
PubMed Abstract | Wallerian axonal degeneration (WD) does not occur in the nematode C. elegans, in contrast to other model animals. However, WD depends on the NADase activity of SARM1, a protein that is also expressed ...Wallerian axonal degeneration (WD) does not occur in the nematode C. elegans, in contrast to other model animals. However, WD depends on the NADase activity of SARM1, a protein that is also expressed in C. elegans (ceSARM/ceTIR-1). We hypothesized that differences in SARM between species might exist and account for the divergence in WD. We first show that expression of the human (h)SARM1, but not ceTIR-1, in C. elegans neurons is sufficient to confer axon degeneration after nerve injury. Next, we determined the cryoelectron microscopy structure of ceTIR-1 and found that, unlike hSARM1, which exists as an auto-inhibited ring octamer, ceTIR-1 forms a readily active 9-mer. Enzymatically, the NADase activity of ceTIR-1 is substantially weaker (10-fold higher Km) than that of hSARM1, and even when fully active, it falls short of consuming all cellular NAD. Our experiments provide insight into the molecular mechanisms and evolution of SARM orthologs and WD across species. |
External links | Cell Rep / PubMed:37635352 / PubMed Central |
Methods | EM (single particle) |
Resolution | 2.68 - 3.82 Å |
Structure data | EMDB-17369, PDB-8p2l: EMDB-17370, PDB-8p2m: |
Chemicals | ChemComp-NAD: |
Source |
|
Keywords | HYDROLASE / SARM1; TIR-1; C. elegans; neurodegeneration; cryo-EM; structural biology; NAD+ metabolism; axon Wallerian degeneration |