ERGIC · Structural studies on the membrane receptor p58-ERGIC-53
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2005-11-01 → 2007-10-31
- EU contribution
- €165,921
- Participants
- 1
- Scheme
- EIF
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Results in brief
Final Activity Report Summary - ERGIC (Structural studies on the membrane receptor p58-ERGIC-53)
This project concerned the glycoprotein-recognising transport protein ERGIC-53 along the ER-Golgi secretory pathway. ERGIC-53 is known to be responsible for the specific transport of certain blood coagulation factors, and mutations in either ERGIC-53 or its co-activator protein MCFD2 lead to an inherited bleeding disorder due to defects in the blood coagulation system. Here, we could show with purified proteins that ERGIC-53 and MCFD2 interact directly and that the complex is a high-affinity one. This result is rather surprising, as it was expected that such a transporter complex would rather be of transient nature. It could also be shown that the binding is calcium-dependent and that the carbohydrate binding domain of ERGIC-53 is both necessary and sufficient for binding. Mutations to the calcium-binding residues of MCFD2 disrupt the binding.
Data: CORDIS, © European Union
Project objective
With this proposal, funding is applied to conduct research on a membrane-bound receptor p58/ERGIC-53 at the Karolinska Institutet in Stockholm, Sweden. p58/ERGIC-53 is a calcium-dependent, mannose-selective animal lectin that acts as a glycoprotein cargo receptor in the endoplasmic reticulum (ER) and mediates specific transport of target proteins to the Golgi complex.Mutations in p58/ERGIC-53 cause a bleeding disorder due to deficiency of blood coagulation factors V and VIII, which are known to be secreted specifically by p58/ERGIC-53.The crystal structure of the carbohydrate recognition domain of p58/ERGIC-53 is known, but structural information on the full-length protein, as well as complexes with cargo proteins and coactivators, are needed to understand the mechanisms of protein transport along the ER-Golgi secretory pathway.The aim of this study is to determine crystal structures of longer constructs of p58/ERGIC-53 and of complexes with mannose and high-mannose cargo proteins. In addition, a complex with a coactivator MCFD2, which is an EF-hand protein, will be pursued.These data are expected to provide us with the structural basis for understanding receptor-cargo interactions in this family of membrane-bound receptors. The host laboratory has excellent facilities for molecular biology, protein production and purification as well as X-ray crystallography. I myself as the applicant have thorough knowledge in these methods and especially in crystal structure determination.Thus, the goals set are possible to reach within a time frame of two years, for which funding is applied. The planned visit will be the second post-doctoral period outside the home country for theme and will serve as an important step towards an independent academic career.
Original text from CORDIS.
Participants
- KAROLINSKA INSTITUTET · STOCKHOLMCoordinatorSweden
Links
Data: CORDIS, © European Union