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SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration
DOI:
10.1016/j.neuron.2021.02.009
Authors:
Matthew D.
Figley
(University School of Medicine in Saint Louis)
,
Weixi
Gu
(University of Queensland)
,
Jeffrey D.
Nanson
(University of Queensland)
,
Yun
Shi
(Griffith University)
,
Yo
Sasaki
(University School of Medicine in Saint Louis)
,
Katie
Cunnea
(Evotec (UK) Ltd; Evotec SE)
,
Alpeshkumar K.
Malde
(Griffith University)
,
Xinying
Jia
(University of Queensland)
,
Zhenyao
Luo
(University of Queensland)
,
Forhad K.
Saikot
(University of Queensland)
,
Tamim
Mosaiab
(Griffith University)
,
Veronika
Masic
(Griffith University)
,
Stephanie
Holt
(Griffith University)
,
Lauren
Hartley-Tassell
(Griffith University)
,
Helen Y.
Mcguinness
(University of Queensland)
,
Mohammad K.
Manik
(University of Queensland)
,
Todd
Bosanac
(Disarm Therapeutics)
,
Michael J.
Landsberg
,
Philip S.
Kerry
(Evotec (UK) Ltd; Evotec SE)
,
Mehdi
Mobli
(University of Queensland)
,
Robert O.
Hughes
(Disarm Therapeutics)
,
Jeffrey
Milbrandt
(Washington University School of Medicine in Saint Louis)
,
Bostjan
Kobe
(University of Queensland)
,
Aaron
Diantonio
(Washington University School of Medicine)
,
Thomas
Ve
(Griffith University)
Co-authored by industrial partner:
Yes
Type:
Journal Paper
Journal:
Neuron
, VOL 109
, PAGES 1118 - 1136.e11
State:
Published (Approved)
Published:
April 2021
Diamond Proposal Number(s):
24981
Abstract: Axon degeneration is a central pathological feature of many neurodegenerative diseases. Sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) is a nicotinamide adenine dinucleotide (NAD+)-cleaving enzyme whose activation triggers axon destruction. Loss of the biosynthetic enzyme NMNAT2, which converts nicotinamide mononucleotide (NMN) to NAD+, activates SARM1 via an unknown mechanism. Using structural, biochemical, biophysical, and cellular assays, we demonstrate that SARM1 is activated by an increase in the ratio of NMN to NAD+ and show that both metabolites compete for binding to the auto-inhibitory N-terminal armadillo repeat (ARM) domain of SARM1. We report structures of the SARM1 ARM domain bound to NMN and of the homo-octameric SARM1 complex in the absence of ligands. We show that NMN influences the structure of SARM1 and demonstrate via mutagenesis that NMN binding is required for injury-induced SARM1 activation and axon destruction. Hence, SARM1 is a metabolic sensor responding to an increased NMN/NAD+ ratio by cleaving residual NAD+, thereby inducing feedforward metabolic catastrophe and axonal demise.
Journal Keywords: NADase; TIR domain; ARM domain; allostery; cryo-EM; X-ray crystallography; nicotinamide riboside
Diamond Keywords: Enzymes
Subject Areas:
Biology and Bio-materials,
Chemistry,
Medicine
Diamond Offline Facilities:
Electron Bio-Imaging Centre (eBIC)
Instruments:
Scios-Scios at Diamond
Added On:
09/06/2021 11:21
Discipline Tags:
Neurodegenerative Diseases
Non-Communicable Diseases
Health & Wellbeing
Biochemistry
Neurology
Chemistry
Structural biology
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Microscopy
Electron Microscopy (EM)
Cryo Electron Microscopy (Cryo EM)