A duplex structure of SARM1 octamers stabilized by a new inhibitor

Abstract In recent years, there has been growing interest in SARM1 as a potential breakthrough drug target for treating various pathologies of axon degeneration. SARM1-mediated axon degeneration relies on its TIR domain NADase activity, but recent structural data suggest that the non-catalytic ARM domain could also serve as a pharmacological site as it has an allosteric inhibitory function. Here, we screened for synthetic small molecules that inhibit SARM1, and tested a selected set of these compounds in a DRG axon degeneration assay. Using cryo-EM, we found that one of the newly discovered inhibitors, a calmidazolium designated TK106, not only stabilizes the previously reported inhibited conformation of the octamer, but also a meta-stable structure: a duplex of octamers (16 protomers), which we have now determined to 4.0 Å resolution. In the duplex, each ARM domain protomer is engaged in lateral interactions with neighboring protomers, and is further stabilized by contralateral contacts with the opposing octamer ring. Mutagenesis of the duplex contact sites leads to a moderate increase in SARM1 activation in cultured cells. Based on our data we propose that the duplex assembly constitutes an additional auto-inhibition mechanism that tightly prevents pre-mature activation and axon degeneration..

Medienart:

E-Artikel

Erscheinungsjahr:

2022

Erschienen:

2022

Enthalten in:

Zur Gesamtaufnahme - volume:80

Enthalten in:

Cellular and molecular life sciences - 80(2022), 1 vom: 23. Dez.

Sprache:

Englisch

Beteiligte Personen:

Khazma, Tami [VerfasserIn]
Golan-Vaishenker, Yarden [VerfasserIn]
Guez-Haddad, Julia [VerfasserIn]
Grossman, Atira [VerfasserIn]
Sain, Radhika [VerfasserIn]
Weitman, Michal [VerfasserIn]
Plotnikov, Alexander [VerfasserIn]
Zalk, Ran [VerfasserIn]
Yaron, Avraham [VerfasserIn]
Hons, Michael [VerfasserIn]
Opatowsky, Yarden [VerfasserIn]

Links:

Volltext [lizenzpflichtig]

Themen:

Cryo-EM
Drug discovery
NAD + metabolism
Neurodegeneration
SARM1
Structural biology

Anmerkungen:

© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2022. corrected publication 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

doi:

10.1007/s00018-022-04641-3

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

OLC2133164243

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