CAREER: Uncovering Novel Factors for Multipass Membrane Protein Biogenesis

California Institute Of Technology, Pasadena CA

Investigators

Abstract

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2). The goal of this work is to understand how a class of biologically essential proteins known as ‘membrane proteins’ are made in human cells. All cells are surrounded by a thin protective ‘skin’ known as a membrane, which is studded with proteins. These membrane proteins allow cells to both transmit and receive information and nutrients, and are thus are critical for how organisms respond and react to changes in their environment. Because these membrane proteins contain waxy, hydrophobic regions that must be guided-to and embedded within these membranes, they require specialized machinery for their synthesis. This project seeks to understand the cellular machinery used to make these membrane proteins. Coupled with this research, an integrated educational and outreach plan will be used to both highlight forgotten contributions to science, and increase exposure of students to biological research. American Rescue Plan funding will support this investigator at a critical stage in her career. The defining structural feature of a membrane protein is the presence of one or more transmembrane domains (TMDs) that must be inserted into the lipid bilayer. For multipass membrane proteins, these TMDs differ substantially in length and hydrophobicity, and thus rely on an incompletely understood set of factors for their biogenesis. This project seeks to identify and characterize the molecular players required for the insertion, folding, and stabilization of diverse multipass membrane proteins in human cells. Novel membrane protein biogenesis factors will be identified using genome wide genetic screens and biochemical analysis of the interactome of a panel of nascent membrane proteins. A combination of functional and structural strategies will be used to dissect the molecular role of these factors in membrane protein biogenesis using both in vitro reconstitution and single particle cryoelectron microscopy. This research will establish general principles of membrane protein biogenesis that will be relevant across all kingdoms of life. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.