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

Khelashvili, George; Chauhan, Neha; Pandey, Kalpana; Eliezer, David; Menon, Anant K.

doi:10.7554/elife.53444

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

Journal Article · 03 December 2019 · eLife

DOI: https://doi.org/10.7554/elife.53444 · OSTI ID:1628917

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Cornell Univ., Ithaca, NY (United States). Weill Medical College. Dept. of Physiology and Biophysics; Cornell Univ., Ithaca, NY (United States). Weill Medical College. Inst. for Computational Biomedicine; DOE/OSTI
Cornell Univ., Ithaca, NY (United States). Weill Medical College. Dept. of Biochemistry

Previously we identified Lam/GramD1 proteins, a family of endoplasmic reticulum membrane proteins with sterol-binding StARkin domains that 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 lam2Δ yeast cells. These data suggest an unprecedented, water-controlled mechanism of sterol discharge from a StARkin domain.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1628917

Journal Information:: eLife, Journal Name: eLife Vol. 8; ISSN 2050-084X

Publisher:: eLife Sciences Publications, Ltd.Copyright Statement

Country of Publication:: United States

Language:: English

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