Proteopedia

SARM1


Function

SARM1 or NAD(+) hydrolase or sterile alpha and TIR motif-containing protein 1 or NADase is a NAD-cleaving enzyme[1] whose activation triggers Wallerian axon destruction after injury[2]. SARM1 is thought to be a metabolic sensor responding to an increased NMN/NAD+ ratio by cleaving residual NAD+ and inducing axonal demise[3]. SARM1-induced axon destruction can be counteracted by increased NAD+ synthesis[4].

Disease

SARM1 mutations were found in ALS patients[5]. SARM1 induces axonal degeneration after nerve injury[6] and in other neuropathological conditions, such as chemotherapy induced peripheral neuropathy (CIPN), a dose-restricting chemotherapy side effect[7],[8]. Consistent with its pro-degenerative function, genetic ablation of SARM1 protects against axonal and other types of neuronal degeneration, without inflicting any apparent impediments on the animal models[9]. Particularly, it was demonstrated that SARM1 ablation provides protection against CIPN induced by the widely used chemotherapy agents vincristine[10], cisplatin and paclitaxel[11].

Structural highlights

The 3D structure of SARM1 shows the with outer ring dimension of 200A, inner ring of 45A and thickness of 60A[12]. The 3 domains of SARM1 are . The the autoinhibition of SARM1. of the ARM domain. . The domain topology includes an N-terminal ARM domain, followed by two SAM and one TIR domain. NADase activity requires homo-oligomerization of TIR domains[13], which is naturally facilitated by the SAM domains through complementing electrostatic and hydrophobic interactions that assembles eight protomers into a closed ring structure[14],[15]. The ARM domain inhibits NADase activity in cultured cells and in axons[16]. In the auto-inhibitory conformation, a tightly packed arrangement of overlapping ARM domains surrounds the SAM core ring and supports TIR docking in a way that keeps them separated from each other to prevent their oligomerization and NADase activity. Accordingly, SARM1 activation involves a conformational re-arrangement that would allow nearing of the TIR domains, as demonstrated by the introduction of NMN or by gain-of-function point mutations that disturb ARM-TIR interactions[17],[18],[19],[20].

3D structures of SARM1

SARM1 3D structures

Human SARM1 complex with NAD(+) (PDB ID 7cm6).

Drag the structure with the mouse to rotate

ReferencesReferences

  1. ↑ Essuman K, Summers DW, Sasaki Y, Mao X, DiAntonio A, Milbrandt J. The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD(+) Cleavage Activity that Promotes Pathological Axonal Degeneration. Neuron. 2017 Mar 22;93(6):1334-1343.e5. doi: 10.1016/j.neuron.2017.02.022. PMID:28334607 doi:http://dx.doi.org/10.1016/j.neuron.2017.02.022
  2. ↑ Osterloh JM, Yang J, Rooney TM, Fox AN, Adalbert R, Powell EH, Sheehan AE, Avery MA, Hackett R, Logan MA, MacDonald JM, Ziegenfuss JS, Milde S, Hou YJ, Nathan C, Ding A, Brown RH Jr, Conforti L, Coleman M, Tessier-Lavigne M, Zuchner S, Freeman MR. dSarm/Sarm1 is required for activation of an injury-induced axon death pathway. Science. 2012 Jul 27;337(6093):481-4. doi: 10.1126/science.1223899. Epub 2012 Jun, 7. PMID:22678360 doi:http://dx.doi.org/10.1126/science.1223899
  3. ↑ Figley MD, Gu W, Nanson JD, Shi Y, Sasaki Y, Cunnea K, Malde AK, Jia X, Luo Z, Saikot FK, Mosaiab T, Masic V, Holt S, Hartley-Tassell L, McGuinness HY, Manik MK, Bosanac T, Landsberg MJ, Kerry PS, Mobli M, Hughes RO, Milbrandt J, Kobe B, DiAntonio A, Ve T. SARM1 is a metabolic sensor activated by an increased NMN/NAD(+) ratio to trigger axon degeneration. Neuron. 2021 Mar 1. pii: S0896-6273(21)00083-0. doi:, 10.1016/j.neuron.2021.02.009. PMID:33657413 doi:http://dx.doi.org/10.1016/j.neuron.2021.02.009
  4. ↑ Gerdts J, Brace EJ, Sasaki Y, DiAntonio A, Milbrandt J. SARM1 activation triggers axon degeneration locally via NAD(+) destruction. Science. 2015 Apr 24;348(6233):453-7. doi: 10.1126/science.1258366. Epub 2015 Apr, 23. PMID:25908823 doi:http://dx.doi.org/10.1126/science.1258366
  5. ↑ Gilley J, Jackson O, Pipis M, Estiar MA, Al-Chalabi A, Danzi MC, van Eijk KR, Goutman SA, Harms MB, Houlden H, Iacoangeli A, Kaye J, Lima L, Ravits J, Rouleau GA, Schule R, Xu J, Zuchner S, Cooper-Knock J, Gan-Or Z, Reilly MM, Coleman MP. Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders. Elife. 2021 Nov 19;10. pii: 70905. doi: 10.7554/eLife.70905. PMID:34796871 doi:http://dx.doi.org/10.7554/eLife.70905
  6. ↑ Gerdts J, Summers DW, Sasaki Y, DiAntonio A, Milbrandt J. Sarm1-mediated axon degeneration requires both SAM and TIR interactions. J Neurosci. 2013 Aug 14;33(33):13569-80. doi: 10.1523/JNEUROSCI.1197-13.2013. PMID:23946415 doi:http://dx.doi.org/10.1523/JNEUROSCI.1197-13.2013
  7. ↑ Geisler S, Doan RA, Strickland A, Huang X, Milbrandt J, DiAntonio A. Prevention of vincristine-induced peripheral neuropathy by genetic deletion of SARM1 in mice. Brain. 2016 Dec;139(Pt 12):3092-3108. doi: 10.1093/brain/aww251. Epub 2016 Oct, 25. PMID:27797810 doi:http://dx.doi.org/10.1093/brain/aww251
  8. ↑ Cetinkaya-Fisgin A, Luan X, Reed N, Jeong YE, Oh BC, Hoke A. Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation. Sci Rep. 2020 Dec 14;10(1):21889. doi: 10.1038/s41598-020-78896-w. PMID:33318563 doi:http://dx.doi.org/10.1038/s41598-020-78896-w
  9. ↑ Zhu C, Li B, Frontzek K, Liu Y, Aguzzi A. SARM1 deficiency up-regulates XAF1, promotes neuronal apoptosis, and accelerates prion disease. J Exp Med. 2019 Apr 1;216(4):743-756. doi: 10.1084/jem.20171885. Epub 2019 Mar 6. PMID:30842236 doi:http://dx.doi.org/10.1084/jem.20171885
  10. ↑ Geisler S, Doan RA, Cheng GC, Cetinkaya-Fisgin A, Huang SX, Hoke A, Milbrandt J, DiAntonio A. Vincristine and bortezomib use distinct upstream mechanisms to activate a common SARM1-dependent axon degeneration program. JCI Insight. 2019 Sep 5;4(17). pii: 129920. doi: 10.1172/jci.insight.129920. PMID:31484833 doi:http://dx.doi.org/10.1172/jci.insight.129920
  11. ↑ Bosanac T, Hughes RO, Engber T, Devraj R, Brearley A, Danker K, Young K, Kopatz J, Hermann M, Berthemy A, Boyce S, Bentley J, Krauss R. Pharmacological SARM1 inhibition protects axon structure and function in paclitaxel-induced peripheral neuropathy. Brain. 2021 Nov 29;144(10):3226-3238. doi: 10.1093/brain/awab184. PMID:33964142 doi:http://dx.doi.org/10.1093/brain/awab184
  12. ↑ Jiang Y, Liu T, Lee CH, Chang Q, Yang J, Zhang Z. The NAD(+)-mediated self-inhibition mechanism of pro-neurodegenerative Sarm1. Nature. 2020 Oct 14. pii: 10.1038/s41586-020-2862-z. doi:, 10.1038/s41586-020-2862-z. PMID:33053563 doi:http://dx.doi.org/10.1038/s41586-020-2862-z
  13. ↑ 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
  14. ↑ Sporny M, Guez-Haddad J, Lebendiker M, Ulisse V, Volf A, Mim C, Isupov MN, Opatowsky Y. Structural Evidence for an Octameric Ring Arrangement of SARM1. J Mol Biol. 2019 Jul 3. pii: S0022-2836(19)30419-X. doi:, 10.1016/j.jmb.2019.06.030. PMID:31278906 doi:http://dx.doi.org/10.1016/j.jmb.2019.06.030
  15. ↑ 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
  16. ↑ 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
  17. ↑ Sporny M, Guez-Haddad J, Khazma T, Yaron A, Dessau M, Shkolnisky Y, Mim C, Isupov MN, Zalk R, Hons M, Opatowsky Y. The structural basis for SARM1 inhibition and activation under energetic stress. Elife. 2020 Nov 13;9. pii: 62021. doi: 10.7554/eLife.62021. PMID:33185189 doi:http://dx.doi.org/10.7554/eLife.62021
  18. ↑ Bratkowski M, Xie T, Thayer DA, Lad S, Mathur P, Yang YS, Danko G, Burdett TC, Danao J, Cantor A, Kozak JA, Brown SP, Bai X, Sambashivan S. Structural and Mechanistic Regulation of the Pro-degenerative NAD Hydrolase SARM1. Cell Rep. 2020 Aug 4;32(5):107999. doi: 10.1016/j.celrep.2020.107999. PMID:32755591 doi:http://dx.doi.org/10.1016/j.celrep.2020.107999
  19. ↑ Shen C, Vohra M, Zhang P, Mao X, Figley MD, Zhu J, Sasaki Y, Wu H, DiAntonio A, Milbrandt J. Multiple domain interfaces mediate SARM1 autoinhibition. Proc Natl Acad Sci U S A. 2021 Jan 26;118(4). pii: 2023151118. doi:, 10.1073/pnas.2023151118. PMID:33468661 doi:http://dx.doi.org/10.1073/pnas.2023151118
  20. ↑ Jiang Y, Liu T, Lee CH, Chang Q, Yang J, Zhang Z. The NAD(+)-mediated self-inhibition mechanism of pro-neurodegenerative Sarm1. Nature. 2020 Oct 14. pii: 10.1038/s41586-020-2862-z. doi:, 10.1038/s41586-020-2862-z. PMID:33053563 doi:http://dx.doi.org/10.1038/s41586-020-2862-z

This page was mainly constructed by Yarden Opatowsky.

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Michal Harel, Alexander Berchansky
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