Discovering an apoptotic octamer SARM1 ring

This continuing project aims to discover the activation mechanism(s) of SARM1. Recently, we determined the 3D structure of the SARM1 ring octamer in an inhibitory conformation, and found that SARM1 is kept inactive through a ‘substrate inhibition’ mechanism, where NAD+ stabilizes the tightly packed, inhibited conformation of the protein. In this way, SARM1 activation is directly triggered by a decrease in the concentration of NAD+ (a hallmark of several stress conditions), and not necessarily only by the introduction of an activating factor. Very recently, we have also determined the cryo EM structure of SARM1 in a metastable duplex conformation, induced by a new inhibitor that we have discovered. These recent findings are now submitted for publication to eLife. The expected results will reveal how the structure and activity of SARM1 have evolved during evolution, and will contribute to our understanding of SARM1 - mediated neurodegeneration.