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Structural studies on the membrane receptor p58-ERGIC-53


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.

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