Exchange of water for sterol underlies sterol egress from a StARkin domain

Previously we identified Lam/GramD1 proteins, a family of endoplasmic reticulum membrane proteins with sterol-binding StARkin domains (Gatta et al. eLife 2015), which are implicated in intracellular sterol homeostasis. Here we show how these proteins exchange sterol molecules with membranes. An aperture at one end of the StARkin domain enables sterol to enter/exit the binding pocket. Strikingly, the wall of the pocket is longitudinally fractured, exposing bound sterol to solvent. Large-scale atomistic molecular dynamics simulations reveal that sterol egress involves widening of the fracture, penetration of water into the cavity and consequent destabilization of the bound sterol. The simulations identify polar residues along the fracture that are important for sterol release. Their replacement with alanine affects the ability of the StARkin domain to bind sterol, catalyze inter-vesicular sterol exchange and alleviate the nystatin-sensitivity oflam2D yeast cells. These data suggest an unprecedented, water-controlled mechanism of sterol discharge from a StARkin domain.
Source: eLife - Category: Biomedical Science Tags: Biochemistry and Chemical Biology Source Type: research