Exchange of water for sterol underlies sterol egress from a StARkin domain
- Weill Cornell Medical College, United States
Abstract
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 of lam2D yeast cells. These data suggest an unprecedented, water-controlled mechanism of sterol discharge from a StARkin domain.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 2 and 4.
Article and author information
Author details
George Khelashvili
Funding
National Institutes of Health (R37AG019391)
- David Eliezer
1923 Fund
- George Khelashvili
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2019, Khelashvili et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Exchange of water for sterol underlies sterol egress from a StARkin domain
eLife 8:e53444.
https://doi.org/10.7554/eLife.53444
