My laboratory focuses on the role of the early secretory pathway deficiencies in human diseases. Up to one third of all cellular proteins traverse the secretory pathway en route to their final intra- or extra-cellular destinations. Many secretory proteins are thought to require cargo receptors for efficient ER-to-Golgi transport. The best known mammalian cargo receptor is the LMAN1–MCFD2 protein complex. Mutations in either genes lead to a bleeding disorder called combined deficiency of factor V and factor VIII.
We are using biochemistry, cell biology and mouse models to characterize the organization of the LMAN1-MCFD2 complex and elucidate how it recognizes and binds properly folded proteins in the ER and selectively releases its cargo in the post-ER compartments. Using knowledges gained, we can improve factor VIII secretion in vivo and in vitro that will benefit patients with hemophilia A. Recent evidence suggests additional functions of this cargo receptor complex beyond the transport of clotting factors. We are trying to understand its role in other biological processes such as cancer development and identify additional proteins that are secreted through this pathway.
Proteins that exit the ER are packaged into COPII-coated vesicles. Mammalian cells contain multiple isoforms of the COPII proteins. Recent genetic studies have attributed distinct human disorders to mutations in specific COPII isoforms. We are using mouse models to study the mechanisms of inherited diseases caused by deficiencies of individual COPII isoforms and gain insight into the in vivo functions of these important proteins.
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