Multiple modes of cholesterol translocation in the human Smoothened receptor.

ABSTRACT: Smoothened (SMO), a member of the G Protein-Coupled Receptor superfamily, mediates Hedgehog signaling and is linked to cancer and birth defects. SMO responds to accessible cholesterol in the ciliary membrane, translocating it via a longitudinal tunnel to its extracellular domain. Reaching a complete mechanistic understanding of the cholesterol translocation process would help in the development of cancer therapies. Experimental data suggests two modes of translocation to support entry of cholesterol from outer and inner membrane leaflets, but the exact mechanism of translocation remains unclear. Using atomistic molecular dynamics simulations (~2 millisecond simulations) and biochemical assays of SMO mutants, we assess the energetic feasibilities of the two modes. We show that the highest e

SUBMITTER: Bansal PD 

PROVIDER: S-EPMC11623640 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature