The NAD+-mediated self-inhibition mechanism of pro-neurodegenerative SARM1

Jiang, Yuefeng; Liu, Tingting; Lee, Chia‐Hsueh; Chang, Qing; Yang, Jing; Zhang, Zhe

doi:10.1038/s41586-020-2862-z

Cited by 137 publications

(208 citation statements)

References 52 publications

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“…In conclusion, we found that hSARM1 inhibition requires ARM-TIR interaction through the ‘primary TIR docking site’. This conclusion is supported by other recently published reports ( Bratkowski et al, 2020 ; Jiang et al, 2020 ). We further calculated the surface conservation scores of SARM1 orthologs.…”

Section: Resultssupporting

confidence: 92%

“…Point mutations in this distal site promoted hSARM1 activity in cultured cells and demonstrates their key allosteric role for inhibition of the NADase activity. We also found that hSARM1 is inhibited in vitro by NAD+ for NADase activity, demonstrating a ‘substrate inhibition mechanism’, as was also reported by another recent study ( Jiang et al, 2020 ).…”

Section: Discussionsupporting

confidence: 89%

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Structural basis for SARM1 inhibition and activation under energetic stress

Sporny

Guez-Haddad

Khazma

et al. 2020

eLife

143

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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.

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Section: Resultssupporting

confidence: 92%

Section: Discussionsupporting

confidence: 89%

Structural basis for SARM1 inhibition and activation under energetic stress

Sporny

Guez-Haddad

Khazma

et al. 2020

eLife

143

View full text Add to dashboard Cite

show abstract

“…With Cryo-EM, we found that dHNN stabilized a similar inhibitory conformation of SARM1 as that induced by NAD (PDB: 7cm6)(Jiang et al, 2020). In 2D-classification of the untreated SARM1, most particles presented only the SAM octamer ring (Figure 5—figure supplement 3 A ).…”

Section: Resultsmentioning

confidence: 91%

“…5 E and Figure 5—figure supplement 3 D ). Structural superimposition with the NAD-bound SARM1 (PDB: 7cm6)(Jiang et al, 2020) showed RMSD values of 0.91 (Figure 5—figure supplement 3 E ), suggesting that dHNN constrains SARM1 in an inactive conformation similar to that induced by NAD. Extra electron density was only observed near residue Cys311 (Figure 5—figure supplement 4 A ), the dHNN-target (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…It is self-inhibitory and is activated by nicotinamide mononucleotide (NMN)(Zhao et al, 2019), resulting in depletion of the intracellular NAD-pool(Essuman et al, 2017, Zhao et al, 2019). However, a recent study suggests that NAD may be an inhibitor of SARM1 activation and the decrease of NAD actually may activate SARM1 (Jiang et al, 2020). In any case, no direct evidence of SARM1 activation in live cells is available and no potent inhibitor has been identified.…”

Section: Introductionmentioning

confidence: 99%

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Permeant Fluorescent Probes Visualize the Activation of SARM1 and Uncover an Anti-neurodegenerative Drug Candidate

Huang

Cai

et al. 2021

Preprint

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SARM1 regulates axonal degeneration through its NAD-metabolizing activity and is a drug target for neurodegenerative disorders. We designed and synthesized fluorescent conjugates of styryl derivative with pyridine to serve as substrates of SARM1, which exhibited large red-shifts after conversion. With the conjugates, SARM1 activation was visualized in live cells following elevation of endogenous NMN or treatment with a cellpermeant NMN-analog. In neurons, imaging documented SARM1 activation preceded vincristine-induced axonal degeneration by hours. Library screening identified a derivative of nisoldipine as a covalent inhibitor of SARM1 that reacted with Cys311 in its Armadillo-domain and blocked its NMN-activation, protecting axons from degeneration. CryoEM showed that SARM1 was locked into an inactive conformation by the inhibitor, uncovering an unsuspected neuroprotective mechanism of dihydropyridines.

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How enzyme‐centered approaches are advancing research on cyclic oligo‐nucleotides

Wenzl,

de Oliveira Mann

2024

FEBS Letters

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Cyclic nucleotides are the most diversified category of second messengers and are found in all organisms modulating diverse pathways. While cAMP and cGMP have been studied over 50 years, cyclic di‐nucleotide signaling in eukaryotes emerged only recently with the anti‐viral molecule 2´3´cGAMP. Recent breakthrough discoveries have revealed not only the astonishing chemical diversity of cyclic nucleotides but also surprisingly deep‐rooted evolutionary origins of cyclic oligo‐nucleotide signaling pathways and structural conservation of the proteins involved in their synthesis and signaling. Here we discuss how enzyme‐centered approaches have paved the way for the identification of several cyclic nucleotide signals, focusing on the advantages and challenges associated with deciphering the activation mechanisms of such enzymes.

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The NAD+-mediated self-inhibition mechanism of pro-neurodegenerative SARM1

Cited by 137 publications

References 52 publications

Structural basis for SARM1 inhibition and activation under energetic stress

Structural basis for SARM1 inhibition and activation under energetic stress

Permeant Fluorescent Probes Visualize the Activation of SARM1 and Uncover an Anti-neurodegenerative Drug Candidate

How enzyme‐centered approaches are advancing research on cyclic oligo‐nucleotides

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