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

Pathological degeneration of axons disrupts neural circuits and represents one of the hallmarks of neurodegeneration.sup.1-4. Sterile alpha and Toll/interleukin-1 receptor motif-containing protein 1 (SARM1) is a central regulator of this neurodegenerative process.sup.5-8, and its Toll/interleukin-1 receptor (TIR) domain exerts its pro-neurodegenerative action through NADase activity.sup.9,10. However, the mechanisms by which the activation of SARM1 is stringently controlled are unclear. Here we report the cryo-electron microscopy structures of full-length SARM1 proteins. We show that NAD.sup.+ is an unexpected ligand of the armadillo/heat repeat motifs (ARM) domain of SARM1. This binding of NAD.sup.+ to the ARM domain facilitated the inhibition of the TIR-domain NADase through the domain interface. Disruption of the NAD.sup.+-binding site or the ARM-TIR interaction caused constitutive activation of SARM1 and thereby led to axonal degeneration. These findings suggest that NAD.sup.+ mediates self-inhibition of this central pro-neurodegenerative protein. NAD.sup.+ is shown to be a ligand of the armadillo/heat repeat motifs (ARM) domain of SARM1, and it is suggested that this binding of NAD.sup.+ mediates self-inhibition of SARM1.
Author(s): Yuefeng Jiang [sup.1] , Tingting Liu [sup.1] , Chia-Hsueh Lee [sup.2] , Qing Chang [sup.3] , Jing Yang [sup.1] , Zhe Zhang [sup.1] Author Affiliations: (1) State Key Laboratory [...]