Abstract

Mammals encode ~5000 integral membrane proteins that need to be inserted in a defined topology at the endoplasmic reticulum membrane. The majority of these membrane proteins have multiple transmembrane domains that have to be weaved back and forth across the lipid bilayer and assembled into a functional three-dimensional structure. How such multi-pass membrane proteins are made correctly is not well understood. My group has been studying the processes of membrane protein targeting, insertion, and folding. Starting with very simple model membrane proteins, we have taken a biochemical approach to identify and mechanistically dissect the factors involved in these processes. In this talk, I will describe our recent efforts at tackling the problem of how multi-pass membrane proteins are made. Using G-protein coupled receptors (GPCRs) as a particularly important example, we have begun to find that the textbook view of how multi-pass proteins are made is incomplete, or in some cases, incorrect. My talk will cover our recent discoveries of a new membrane protein insertase that acts early during GPCR biogenesis, a novel type of chaperone that helps during membrane protein folding, and the conceptual insights that have come from understanding how these factors work.