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Structure paper

TitleStructural basis for SARM1 inhibition and activation under energetic stress.
Journal, issue, pagesElife, Vol. 9, Year 2020
Publish dateNov 13, 2020
AuthorsMichael Sporny / Julia Guez-Haddad / Tami Khazma / Avraham Yaron / Moshe Dessau / Yoel Shkolnisky / Carsten Mim / Michail N Isupov / Ran Zalk / Michael Hons / Yarden Opatowsky /
PubMed AbstractSARM1, an executor of axonal degeneration, displays NADase activity that depletes the key cellular metabolite, NAD+, in response to nerve injury. The basis of SARM1 inhibition and its activation ...SARM1, an executor of axonal degeneration, displays NADase activity that depletes the key cellular metabolite, NAD+, in response to nerve injury. The basis of SARM1 inhibition and its activation under stress conditions are still unknown. Here, we present cryo-EM maps of SARM1 at 2.9 and 2.7 Å resolutions. These indicate that SARM1 homo-octamer avoids premature activation by assuming a packed conformation, with ordered inner and peripheral rings, that prevents dimerization and activation of the catalytic domains. This inactive conformation is stabilized by binding of SARM1's own substrate NAD+ in an allosteric location, away from the catalytic sites. This model was validated by mutagenesis of the allosteric site, which led to constitutively active SARM1. We propose that the reduction of cellular NAD+ concentration contributes to the disassembly of SARM1's peripheral ring, which allows formation of active NADase domain dimers, thereby further depleting NAD+ to cause an energetic catastrophe and cell death.
External linksElife / PubMed:33185189 / PubMed Central
MethodsEM (single particle)
Resolution2.68 - 7.7 Å
Structure data

11187

6zfx

EMDB-11187, PDB-6zfx:
hSARM1 GraFix-ed
Method: EM (single particle) / Resolution: 2.88 Å

11190

6zg0

EMDB-11190, PDB-6zg0:
SARM1 SAM1-2 domains
Method: EM (single particle) / Resolution: 7.7 Å

11191

6zg1

EMDB-11191, PDB-6zg1:
SARM1 SAM1-2 domains
Method: EM (single particle) / Resolution: 3.77 Å

11834

7anw

EMDB-11834, PDB-7anw:
hSARM1 NAD+ complex
Method: EM (single particle) / Resolution: 2.68 Å

Chemicals

ChemComp-S1N:
(~{E})-4-methylnon-4-enedial

ChemComp-EDO:
1,2-ETHANEDIOL / Ethylene glycol

ChemComp-BME:
BETA-MERCAPTOETHANOL / 2-Mercaptoethanol

ChemComp-PEG:
DI(HYDROXYETHYL)ETHER / Diethylene glycol

ChemComp-PGE:
TRIETHYLENE GLYCOL / Polyethylene glycol

ChemComp-NAD:
NICOTINAMIDE-ADENINE-DINUCLEOTIDE / NAD*YM / Nicotinamide adenine dinucleotide

Source
  • homo sapiens (human)
KeywordsHYDROLASE / NADase / ARM domain / SAM domain / TIR domain / APOPTOSIS

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