Figure 6. A model for hSARM1 inhibition and activation.

In homeostasis, the cellular NAD+ concentration is high enough and binds to an allosteric site that drives hSARM1 compact conformation. In this conformation, the catalytic TIR domains (red) are docked on ARM domains (yellow) apart from each other and unable to form close dimers required for NAD+ catalysis. When cellular NAD+ levels drop as a result of reduced NAD+ synthesis (e.g. inhibition of NMNAT1/2) or increased NAD+ consumption, the inhibiting NAD+ molecules fall off hSARM1, leading to the disintegration of the ARM-TIR outer ring assembly. Still held by the constitutively assembled SAM inner ring, the now-released TIR domains are at a high local concentration that facilitates their dimerization and ensued NADase activity. When released from allosteric inhibition, hSARM1 is only subjected to competitive inhibition such as by its products ADPR and NAM, which are not found in high enough concentrations to block its activity entirely. This leads to an almost complete consumption of the NAD+ cellular pool and to an energetic catastrophe from which there may be no return.