Structural basis for SARM1 inhibition and activation under energetic stress

Sporny, MichaelBar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Ramat Gan, Israel. (författare)

QC 20210107
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 angstrom 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.

Guez-Haddad, JuliaBar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Ramat Gan, Israel. (författare)
Khazma, TamiBar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Ramat Gan, Israel. (författare)
Yaron, AvrahamWeizmann Inst Sci, Dept Biomol Sci, Rehovot, Israel. (författare)
Dessau, MosheBar Ilan Univ, Azrieli Fac Med, Safed, Israel. (författare)
Shkolnisky, YoelTel Aviv Univ, Sch Math Sci, Dept Appl Math, Tel Aviv, Israel. (författare)
Mim, CarstenKTH,Strukturell bioteknik(Swepub:kth)u1ce0qjf (författare)
Isupov, Michail N.Univ Exeter, Biosci, Exeter, Devon, England. (författare)
Zalk, RanBen Gurion Univ Negev, Natl Inst Biotechnol Negev, Beer Sheva, Israel. (författare)
Hons, MichaelEuropean Mol Biol Lab, Grenoble, France. (författare)
Opatowsky, YardenBar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Ramat Gan, Israel. (författare)
Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Ramat Gan, Israel.Weizmann Inst Sci, Dept Biomol Sci, Rehovot, Israel. (creator_code:org_t)

Av författaren/redakt...: Sporny, Michael; Guez-Haddad, Jul ...; Khazma, Tami; Yaron, Avraham; Dessau, Moshe; Shkolnisky, Yoel; visa fler...; Mim, Carsten; Isupov, Michail ...; Zalk, Ran; Hons, Michael; Opatowsky, Yarde ...; visa färre...

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