Molecular Mechanisms of Membrane Protein Quality Control

• Applicant: Professor Dr. Matthias Feige
• Subject Area: Biochemistry ; Cell Biology
• Term: from 2015 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 283389967

Approximately one third of all human proteins are integral membrane proteins. These proteins are able to span the plasma membrane or the membranes of intracellular organelles and thus allow cells to interact with their environment and maintain homeostasis. Most integral membrane proteins are produced at the endoplasmic reticulum (ER), where they are co-translationally integrated into the hydrophobic lipid bilayer via the Sec61 translocon. At a first glance counterintuitive, polar residues are very common in transmembrane (TM) segments. These fulfill important functional and structural roles, but may compromise membrane integration. How the cell can scrutinize proper integration of membrane proteins into the lipid bilayer remains unclear. This is of particular relevance as various human diseases are caused by genetic mutations that introduce polar residues into TM segments, often leading to impaired transport out of the ER. To begin to understand molecular mechanisms of membrane protein quality control, we have established the gap junction protein connexin 32 (Cx32) as a model system during the first funding period. Mutations in Cx32 underlie Charcot-Marie-Tooth disease, one of the most common inherited neurological disorders. We could show that mutations in Cx32 can compromise its membrane integration and cellular transport. Furthermore, we have identified a network of chaperones and quality control factors that aid and control lipid bilayer integration of this multipass membrane protein. Building on these findings, within the proposed project we will further investigate mechanistic links between membrane integration and quality control. In particular, we will analyze the role of ERdj proteins and ubiquitin E3 ligases in membrane protein biosynthesis. In the second part of the project, we will investigate a potential role of Cx32 proteolysis in its quality control, which points towards a novel mechanism of how membrane proteins are scrutinized in the endoplasmic reticulum.Together, based on a model protein of immediate medical relevance, this project should provide detailed insights into the machinery and mechanisms that underlie membrane protein quality control in the cell.

• DFG Programme: Research Grants