title: LMAN1 is a molecular chaperone for the secretion of coagulation factor VIII.
abstract: Combined deficiency of both coagulation factors (F)V and VIII is a rare autosomal recessive bleeding disorder caused by null expression of LMAN1 (previously termed ERGIC-53) in a majority of affected individuals. Previously, a requirement for a functional LMAN1 cycling pathway between the ER and Golgi was demonstrated for efficient secretion of FV and FVIII (Moussalli et al. J Biol Chem 1999; 274: 32569), however, the molecular nature of the interaction between LMAN1 and its cargo was not characterized. Using coimmunoprecipitation of LMAN1 and FVIII from transfected HeLa and COS-1 cells, we demonstrate an interaction between LMAN1 and FVIII in vivo. The interaction was mediated via high mannose-containing asparagine-linked oligosaccharides that are densely situated within the B domain of FVIII, as well as protein-protein interactions. These results are interpreted based on the recent determination of the crystal structure of the carbohydrate recognition domain of LMAN1.
authors: Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109-0650, USA.
authors: M A
authors: MA
authors: Cunningham
authors: S W
authors: SW
authors: Pipe
authors: B
authors: B
authors: Zhang
authors: H-P
authors: HP
authors: Hauri
authors: D
authors: D
authors: Ginsburg
authors: R J
authors: RJ
authors: Kaufman
mesh_terms: D005166:Factor V Deficiency; D005169:Factor VIII / Q000378:metabolism*; D006367:HeLa Cells; D006467:Hemophilia A; D006801:Humans; D037241:Mannose-Binding Lectins / Q000172:deficiency / Q000378:metabolism* / Q000502:physiology; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism* / Q000502:physiology; D018832:Molecular Chaperones / Q000378:metabolism* / Q000502:physiology; D009844:Oligosaccharides; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D014162:Transfection
chemical_list: C084004:LMAN1 protein, human; D037241:Mannose-Binding Lectins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D009844:Oligosaccharides; D005169:Factor VIII