LMAN1 and MCFD2 form a cargo receptor complex and interact with coagulation factor VIII in the early secretory pathway.

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Zhang B, Kaufman RJ, Ginsburg D

LMAN1 and MCFD2 form a cargo receptor complex and interact with coagulation factor VIII in the early secretory pathway.

J Biol Chem. 2005 Jul 8;280(27):25881-6. Epub 2005 May 10.

PubMed ID

15886209 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Antihemophilic factor, human recombinant	Multiple coagulation factor deficiency protein 2	Protein	Humans	Unknown	Modulator	Details
Lonoctocog alfa	Multiple coagulation factor deficiency protein 2	Protein	Humans	Unknown	Modulator	Details
Moroctocog alfa	Multiple coagulation factor deficiency protein 2	Protein	Humans	Unknown	Modulator	Details