Therapeutic enhancement of autophagy may hold promise for Parkinson’s and other currently incurable neurodegenerative diseases. Targeting the VPS15 myristate could be an attractive path for therapeutic autophagy enhancement.

Molecular dynamics by @hummerlab.bsky.social showed how the transition occurs and how the active state is aligned with the plane of the membrane to facilitate entry of the PI substrate lipid.

The VPS15 pseudokinase binds to GTP, not ATP, thanks to an Arg residue at the gatekeeper position which is unique in the kinome. GTP binding controls the VPS34 conformation. @lazaroulab.bsky.social knocked out N-myristoylation and GTP binding, which dysregulates autophagy.