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J. Biol. Chem., Vol. 280, Issue 27, 25881-25886, July 8, 2005

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LMAN1 and MCFD2 Form a Cargo Receptor Complex and Interact with Coagulation Factor VIII in the Early Secretory Pathway^*

Bin Zhang, Randal J. Kaufman¶||**, and David Ginsburg||**¶¶

From the Life Sciences Institute, the Departments of ^¶Biological Chemistry, Internal Medicine, Human Genetics, and the^|| Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan 48109

Mutations in LMAN1 (ERGIC-53) and MCFD2 are the causes of a human genetic disorder, combined deficiency of coagulation factor V and factor VIII. LMAN1 is a type 1 transmembrane protein with homology to mannose-binding lectins. MCFD2 is a soluble EF-hand-containing protein that is retained in the endoplasmic reticulum through its interaction with LMAN1. We showed that endogenous LMAN1 and MCFD2 are present primarily in complex with each other with a 1:1 stoichiometry, although MCFD2 is not required for oligomerization of LMAN1. Using a cross-linking-immunoprecipitation assay, we detected a specific interaction of both LMAN1 and MCFD2 with factor VIII, with the B domain as the most likely site of interaction. We also present evidence that this interaction is independent of the glycosylation state of factor VIII but requires native calcium concentration in the endoplasmic reticulum. The interaction of MCFD2 with factor VIII appeared to be independent of LMAN1-MCFD2 complex formation. These results suggest that LMAN1 and MCFD2 form a cargo receptor complex and that the primary sorting signals residing in the B domain direct the binding of factor VIII to LMAN1-MCFD2 through calcium-dependent protein-protein interactions. MCFD2 may function to specifically recruit factor V and factor VIII to sites of transport vesicle budding within the endoplasmic reticulum lumen.

Received for publication, February 25, 2005 , and in revised form, April 25, 2005.

^* This work was supported in part by by Project Grant PO1 HL057346 from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

A recipient of a Career Development Award from the National Hemophilia Foundation.

^** Investigators of the Howard Hughes Medical Institute.

^¶¶ To whom correspondence should be addressed: Life Sciences Institute, 210 Washtenaw Ave., Ann Arbor, MI 48109-0650. Tel.: 734-647-4808; Fax: 734-936-2888; E-mail: ginsburg{at}umich.edu.

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