8p2m

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C. elegans TIR-1 protein.C. elegans TIR-1 protein.

Structural highlights

8p2m is a 9 chain structure with sequence from Caenorhabditis elegans. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 3.82Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SARM1_CAEEL NAD(+) hydrolase, which plays a key role in non-apoptotic cell death by regulating NAD(+) metabolism (PubMed:27671644). In response to stress, homooligomerizes and catalyzes cleavage of NAD(+) into ADP-D-ribose (ADPR) and nicotinamide; NAD(+) cleavage promoting non-apoptotic neuronal cell death (PubMed:31439792). In males, involved in non-apoptotic death of the linker cell which guides gonad elongation during larval development (PubMed:22363008). Required for both innate immune response and specification of AWC(OFF) neuron (PubMed:15048112, PubMed:15123841, PubMed:15625192). During late embryogenesis, it acts downstream of CAMKII (unc-43) to regulate specification of asymmetric odorant receptors in AWC(OFF) neuron via the nsy-1/ASK1 pmk-1/p38 MAP kinase signaling cascade. Required to localize nsy-1 to postsynaptic regions of AWC neuron, suggesting that it may act by assembling a signaling complex that regulate odorant receptor expression (PubMed:15625192). Also plays a central role in resistance to infection to a broad range of bacterial and fungi pathogens, possibly by activating pmk-1, independently of the NF-kappa-B pathway. Required for expression of antimicrobial peptides nlp-29 and nlp-31 (PubMed:15048112, PubMed:15123841). Its role in immune response and neuron specification may be mediated by the same nsy-1/ASK1 pmk-1/p38 MAP kinase cascade signaling pathway (PubMed:15048112, PubMed:15123841, PubMed:15625192). Involved in the response to anoxic conditions probably by activating the p38 pathway composed of nsy-1/sek-1/pmk-1 (PubMed:21212236). Involved in regulation of the serotonergic response of ADF neurons to pathogenic food (PubMed:23505381). In addition, plays a role in the up-regulation of gcs-1 upon arsenite treatment, most likely through activation of pmk-1, to confer protection against toxicity induced by heavy metals (PubMed:25204677).[1] [2] [3] [4] [5] [6] [7] [8] [9] Regulates expression of antimicrobial peptide nlp-29 in response to fungal infection or physical injury.[10]

Publication Abstract from PubMed

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.

Structure-function analysis of ceTIR-1/hSARM1 explains the lack of Wallerian axonal degeneration in C. elegans.,Khazma T, Grossman A, Guez-Haddad J, Feng C, Dabas H, Sain R, Weitman M, Zalk R, Isupov MN, Hammarlund M, Hons M, Opatowsky Y Cell Rep. 2023 Aug 26;42(9):113026. doi: 10.1016/j.celrep.2023.113026. PMID:37635352[11]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Couillault C, Pujol N, Reboul J, Sabatier L, Guichou JF, Kohara Y, Ewbank JJ. TLR-independent control of innate immunity in Caenorhabditis elegans by the TIR domain adaptor protein TIR-1, an ortholog of human SARM. Nat Immunol. 2004 May;5(5):488-94. PMID:15048112 doi:10.1038/ni1060
  2. ↑ 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
  3. ↑ Chuang CF, Bargmann CI. A Toll-interleukin 1 repeat protein at the synapse specifies asymmetric odorant receptor expression via ASK1 MAPKKK signaling. Genes Dev. 2005 Jan 15;19(2):270-81. PMID:15625192 doi:10.1101/gad.1276505
  4. ↑ Hayakawa T, Kato K, Hayakawa R, Hisamoto N, Matsumoto K, Takeda K, Ichijo H. Regulation of anoxic death in Caenorhabditis elegans by mammalian apoptosis signal-regulating kinase (ASK) family proteins. Genetics. 2011 Mar;187(3):785-92. PMID:21212236 doi:10.1534/genetics.110.124883
  5. ↑ Blum ES, Abraham MC, Yoshimura S, Lu Y, Shaham S. Control of nonapoptotic developmental cell death in Caenorhabditis elegans by a polyglutamine-repeat protein. Science. 2012 Feb 24;335(6071):970-3. PMID:22363008 doi:10.1126/science.1215156
  6. ↑ Xie Y, Moussaif M, Choi S, Xu L, Sze JY. RFX transcription factor DAF-19 regulates 5-HT and innate immune responses to pathogenic bacteria in Caenorhabditis elegans. PLoS Genet. 2013;9(3):e1003324. PMID:23505381 doi:10.1371/journal.pgen.1003324
  7. ↑ Crook-McMahon HM, Oláhová M, Button EL, Winter JJ, Veal EA. Genome-wide screening identifies new genes required for stress-induced phase 2 detoxification gene expression in animals. BMC Biol. 2014 Aug 14;12:64. PMID:25204677 doi:10.1186/s12915-014-0064-6
  8. ↑ Summers DW, Gibson DA, DiAntonio A, Milbrandt J. SARM1-specific motifs in the TIR domain enable NAD+ loss and regulate injury-induced SARM1 activation. Proc Natl Acad Sci U S A. 2016 Oct 11;113(41):E6271-E6280. doi:, 10.1073/pnas.1601506113. Epub 2016 Sep 26. PMID:27671644 doi:http://dx.doi.org/10.1073/pnas.1601506113
  9. ↑ Horsefield S, Burdett H, Zhang X, Manik MK, Shi Y, Chen J, Qi T, Gilley J, Lai JS, Rank MX, Casey LW, Gu W, Ericsson DJ, Foley G, Hughes RO, Bosanac T, von Itzstein M, Rathjen JP, Nanson JD, Boden M, Dry IB, Williams SJ, Staskawicz BJ, Coleman MP, Ve T, Dodds PN, Kobe B. NAD(+) cleavage activity by animal and plant TIR domains in cell death pathways. Science. 2019 Aug 23;365(6455):793-799. doi: 10.1126/science.aax1911. PMID:31439792 doi:http://dx.doi.org/10.1126/science.aax1911
  10. ↑ Pujol N, Cypowyj S, Ziegler K, Millet A, Astrain A, Goncharov A, Jin Y, Chisholm AD, Ewbank JJ. Distinct innate immune responses to infection and wounding in the C. elegans epidermis. Curr Biol. 2008 Apr 8;18(7):481-9. PMID:18394898 doi:10.1016/j.cub.2008.02.079
  11. ↑ Khazma T, Grossman A, Guez-Haddad J, Feng C, Dabas H, Sain R, Weitman M, Zalk R, Isupov MN, Hammarlund M, Hons M, Opatowsky Y. Structure-function analysis of ceTIR-1/hSARM1 explains the lack of Wallerian axonal degeneration in C. elegans. Cell Rep. 2023 Aug 26;42(9):113026. PMID:37635352 doi:10.1016/j.celrep.2023.113026

8p2m, resolution 3.82Å

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