Deciphering Cellular Networks for Membrane Protein Quality Control Decisions

Any cell and each of its organelles needs to interact with its environment.

Membrane proteins, which span the plasma membrane and the multiple endomembranes of a eukaryotic cell, mediate these interactions. They allow cells to move, thrive and defend - and multicellular organisms to exist. Humans dedicate almost one third of their genes to membrane proteins.

Failures in membrane protein biogenesis or function cause numerous human diseases from cancer to neurological disorders.By far most eukaryotic membrane proteins are produced at one organelle, the endoplasmic reticulum (ER), where a dedicated protein folding and quality control machinery supports and controls protein structure formation.

In contrast to our comprehensive understanding for secreted proteins, our understanding how cells support and control the biogenesis of membrane proteins is still limited. To further advance our understanding in this key area in molecular cell biology is the major aim of this proposal.

Using recent biochemical and cell biological techniques combined with newly developed tools, we will address the following major questions:How do cellular quality control factors determine the folding state of a membrane protein?Which molecular signatures underlie the decision to chaperone or to degrade a membrane protein?How do chaperones collaborate in membrane protein biogenesis?Which further membrane protein chaperones and quality control factors exist in the mammalian ER?Answers to these questions will be major steps forward in our understanding of the inner workings of cells but also of the mechanisms underlying membrane protein-associated diseases.

Three objectives will serve this goal:Objective 1: Define signatures of intramembrane quality control decisionsObjective 2: Dissect chaperone synergies in membrane protein biogenesisObjective 3: Identify novel membrane protein chaperones by functionally validated interactome analyses