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

• Final Report Year: 2023

Final Report Abstract

Membrane proteins are key for multicellular life. They allow cells to communicate, interact and take up as well as secrete various molecules, e.g. food sources versus toxins. A prerequisite for the correct functioning of membrane proteins is their correct structure formation. Principles of this process remain ill-understood, despite the fact that many membrane proteins fail to acquire a correct structure, which cells need to detect and remedy, in order to avoid diseases, many of which are caused by faulty membrane proteins. This project advanced our understanding of how human cells make and control their membrane proteins. We could show that several protein folding helpers, molecular chaperones, synergistically work together to aid and control structure formation in membrane proteins. Since our studies were based on diseases-causing mutants of Connexin 32, insights into Chracot-Marie-Tooth disease also emerged from our work. We could furthermore show that a very abundant cellular chaperone has a broader range of substrate recognition than previously thought, which helps in explaining its importance for human development. Lastly, our work uncovered that a protease that cleaves of targeting signals in cells also is involved in degrading faulty membrane proteins. A direct link between this protease and Alzheimer’s disease seems to exist, which makes our work a basis for future studies in this direction. Our work on this new protease function has amongst other been highlighted on the University of Cologne and TUM university homepages and has been picked up by many news outlets. Together, our work has advanced our understanding of how cells make a very important class of proteins and now provides rich grounds for future studies with an impact on human health and disease.

Publications

• A network of chaperones prevents and detects failures in membrane protein lipid bilayer integration. Nature Communications, 10(1).
  Coelho, João P. L.; Stahl, Matthias; Bloemeke, Nicolas; Meighen-Berger, Kevin; Alvira, Carlos Piedrafita; Zhang, Zai-Rong; Sieber, Stephan A. & Feige, Matthias J.
  
• Intramembrane client recognition potentiates the chaperone functions of calnexin. The EMBO Journal, 41(24).
  Bloemeke, Nicolas; Meighen‐Berger, Kevin; Hitzenberger, Manuel; Bach, Nina C.; Parr, Marina; Coelho, Joao PL; Frishman, Dmitrij; Zacharias, Martin; Sieber, Stephan A. & Feige, Matthias J.
  
• The human signal peptidase complex acts as a quality control enzyme for membrane proteins. Science, 378(6623), 996-1000.
  Zanotti, Andrea; Coelho, João P. L.; Kaylani, Dinah; Singh, Gurdeep; Tauber, Marina; Hitzenberger, Manuel; Avci, Dönem; Zacharias, Martin; Russell, Robert B.; Lemberg, Marius K. & Feige, Matthias J.