HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

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

This Article Full Text Full Text (PDF) All Versions of this Article: 280/27/25881    most recent M502160200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhang, B. Articles by Ginsburg, D. Search for Related Content PubMed PubMed Citation Articles by Zhang, B. Articles by Ginsburg, D. Social Bookmarking                      What's this?

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J. D. Malhotra, H. Miao, K. Zhang, A. Wolfson, S. Pennathur, S. W. Pipe, and R. J. Kaufman Antioxidants reduce endoplasmic reticulum stress and improve protein secretion PNAS, November 25, 2008; 105(47): 18525 - 18530. [Abstract] [Full Text] [PDF]

				B. Zhang, M. Spreafico, C. Zheng, A. Yang, P. Platzer, M. U. Callaghan, Z. Avci, N. Ozbek, J. Mahlangu, T. Haw, et al. Genotype-phenotype correlation in combined deficiency of factor V and factor VIII Blood, June 15, 2008; 111(12): 5592 - 5600. [Abstract] [Full Text] [PDF]

				B. Nyfeler, V. Reiterer, M. W. Wendeler, E. Stefan, B. Zhang, S. W. Michnick, and H.-P. Hauri Identification of ERGIC-53 as an intracellular transport receptor of {alpha}1-antitrypsin J. Cell Biol., February 25, 2008; 180(4): 705 - 712. [Abstract] [Full Text] [PDF]

				B. Nyfeler, Y. Kamiya, F. Boehlen, K. Yamamoto, K. Kato, P. de Moerloose, H.-P. Hauri, and M. Neerman-Arbez Deletion of 3 residues from the C-terminus of MCFD2 affects binding to ERGIC-53 and causes combined factor V and factor VIII deficiency Blood, February 1, 2008; 111(3): 1299 - 1301. [Abstract] [Full Text] [PDF]

				Y. Kamiya, D. Kamiya, K. Yamamoto, B. Nyfeler, H.-P. Hauri, and K. Kato Molecular Basis of Sugar Recognition by the Human L-type Lectins ERGIC-53, VIPL, and VIP36 J. Biol. Chem., January 25, 2008; 283(4): 1857 - 1861. [Abstract] [Full Text] [PDF]

				D. Yamaguchi, N. Kawasaki, I. Matsuo, K. Totani, H. Tozawa, N. Matsumoto, Y. Ito, and K. Yamamoto VIPL has sugar-binding activity specific for high-mannose-type N-glycans, and glucosylation of the {alpha}1,2 mannotriosyl branch blocks its binding Glycobiology, October 1, 2007; 17(10): 1061 - 1069. [Abstract] [Full Text] [PDF]

				M. Renna, M. G. Caporaso, S. Bonatti, R. J. Kaufman, and P. Remondelli Regulation of ERGIC-53 Gene Transcription in Response to Endoplasmic Reticulum Stress J. Biol. Chem., August 3, 2007; 282(31): 22499 - 22512. [Abstract] [Full Text] [PDF]

				K. R. Viel, D. K. Machiah, D. M. Warren, M. Khachidze, A. Buil, K. Fernstrom, J. C. Souto, J. M. Peralta, T. Smith, J. Blangero, et al. A sequence variation scan of the coagulation factor VIII (FVIII) structural gene and associations with plasma FVIII activity levels Blood, May 1, 2007; 109(9): 3713 - 3724. [Abstract] [Full Text] [PDF]

				V. M. Olkkonen and E. Ikonen When intracellular logistics fails - genetic defects in membrane trafficking J. Cell Sci., December 15, 2006; 119(24): 5031 - 5045. [Abstract] [Full Text] [PDF]

				B. Zhang, B. McGee, J. S. Yamaoka, H. Guglielmone, K. A. Downes, S. Minoldo, G. Jarchum, F. Peyvandi, N. B. de Bosch, A. Ruiz-Saez, et al. Combined deficiency of factor V and factor VIII is due to mutations in either LMAN1 or MCFD2 Blood, March 1, 2006; 107(5): 1903 - 1907. [Abstract] [Full Text] [PDF]