Introduction
Compartmentalization by membranes is a highly conserved principle of evolution. It allows for otherwise incompatible chemical reactions to occur in parallel in a cell and enables functional specialization of the various intracellular organelles. Compartmentalization, however, also demands for routes across membranes. A highly diverse group of transmembrane proteins facilitates selective transport of matter and information through the different cellular membranes that separate a cell and its various intracellular organelles from their surroundings. Integral membrane proteins represent roughly 25 % of all protein-coding genes of the human genome and over 50 % of modern drug targets. They serve critical roles in metabolism, lipid biosynthesis, cell adhesion and signal transduction. Failures in membrane protein biogenesis cause numerous severe diseases from neurological disorders to cancer.
In eukaryotic cells, the endoplasmic reticulum (ER) is the site of biogenesis of almost all membrane proteins. Folding of transmembrane proteins poses particular challenges to the cell since they span three topologically distinct environments: the ER lumen, the hydrophobic lipid bilayer and the cytosol. Furthermore, many membrane proteins contain suboptimal or labile structural elements for functional reasons, which additionally render them intrinsically unstable and vulnerable to misfolding.
The abundance of membrane proteins combined with the complexity and the challenges of their biogenesis demand for a sophisticated quality control (QC) system inside and at the ER membrane. This system facilitates and controls correct folding, topogenesis and assembly. Currently, it mostly remains unknown how the ERQC machinery scrutinizes structure formation inside the membrane, which molecular signatures are recognized as misfolded and how they can be distinguished from functionally relevant features and folding intermediates. Furthermore, the molecular setup and mechanisms of membrane protein chaperone machineries remain ill-defined. Using a broad array of techniques, our lab addresses the following key topics in molecular cell biology:
