It is key for the homeostasis of any cell to be able to detect and handle faulty proteins. Whereas partially folded soluble proteins generally expose hydrophobic surfaces as a hallmark of incomplete structure formation, the signatures that allow cells to detect folding defects in the membrane mostly remain unclear. Once recognized as faulty or immature, membrane proteins may either undergo chaperoning – or they may be degraded. Chaperoning versus degradation is a key decision in the life of any membrane protein and its molecular determinants are thus of utmost importance to be defined. So far, our insights into substrate-intrinsic features that commit a membrane protein to chaperoning versus ER associated degradation (ERAD) are very limited. One research area in our lab is thus to define signatures for membrane protein quality control decisions. We use computational and experimental approaches to gain deep mechanistic and systematic insights into molecular features recognized by membrane protein chaperones and ERAD factors.

As an example, we discovered a novel client recognition mode of the ER chaperone calnexin, mediated by its transmembrane domain. To achieve this, we employed a de novo designed model protein to systematically assess the features engaged by the chaperone and investigated them computationally and experimentally (Bloemeke et al., 2022, EMBO Journal [read]).