How did ancient membrane transporters evolve into cholesterol sensors?

Cells need to know when enough nutrients and lipids are available to grow. Our recent work identified GPR155 as an unexpected cholesterol-sensing membrane protein that controls mTORC1, a master regulator of cell growth and metabolism, from the lysosome. Remarkably, GPR155 is related to plant PIN transporters, which move the hormone auxin to control plant growth. This project asks how an ancient transporter-like protein fold was repurposed during evolution into a sterol sensor in fungi and animals. Students will contribute to a larger program using cryo-EM, membrane protein biochemistry, sterol-binding assays, cross-linking mass spectrometry and cell-based signalling assays to understand how GPR155 recognises cholesterol and related sterols, and how this controls recruitment of the GATOR1 complex. Honours or PhD projects may focus on structural characterisation of selected GPR155 homologues, sterol-binding mechanisms, protein complex assembly, or functional analysis of mutations that alter cholesterol sensing and mTORC1 signalling.