Most chaperones do not act in isolation, but often form complex molecular assemblies with other (co-)chaperones and folding enzymes. Such systems are well known for soluble proteins. For example, the lectin chaperones calnexin and calreticulin interact with the protein disulfide isomerase family member ERp57 and the peptidyl-prolyl-isomerase cyclophilin B, recruiting them to unfolded glycoproteins. In contrast, quality control networks for membrane proteins are much less understood. The human genome encodes about 20,000 transmembrane domains, which vary greatly in their sequences, biophysical properties, location within the protein, and orientation within the membrane. Given this diversity and the need for reliable and robust quality control processes, we must assume that multiple factors collaborate in the biogenesis and quality control of every membrane protein in order to fulfill the clients’ specific needs. As an example, a study from our group revealed that the ER membrane protein complex (EMC), the Hsp70 chaperone BiP, and the E3 ligase gp78 collaborate to recognize, integrate and, if necessary, degrade the misfolded gap junction membrane protein connexin 32 (Coelho et al., 2019, Nature Communications [read]). 

In general, we aim to understand chaperone synergies in membrane protein biogenesis on a mechanistic and structural level. We use systematic and mechanistic experimental approaches to analyze which features different, potentially complementary quality control factors recognize in misfolded clients, how they “communicate” with each other, and which biological processes depend on such collaborations. Ultimately, this will allow us to understand how robust quality control decisions are made for the diverse cellular membrane protein repertoire.