Abstract
LMAN1 is a glycoprotein receptor, mediating transfer from the ER to the ER-Golgi intermediate compartment. Together with the co-receptor MCFD2, it transports coagulation factors V and VIII. Mutations in LMAN1 and MCFD2 can cause combined deficiency of factors V and VIII (F5F8D). We present the crystal structure of the LMAN1/MCFD2 complex and relate it to patient mutations. Circular dichroism data show that the majority of the substitution mutations give rise to a disordered or severely destabilized MCFD2 protein. The few stable mutation variants are found in the binding surface of the complex leading to impaired LMAN1 binding and F5F8D.
Copyright (c) 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Blood Coagulation Disorders, Inherited / genetics
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Blood Coagulation Disorders, Inherited / metabolism*
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Circular Dichroism
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Crystallography, X-Ray
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Factor V / metabolism*
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Factor V Deficiency / genetics
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Factor V Deficiency / metabolism
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Factor VIII / metabolism*
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Humans
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Mannose-Binding Lectins / chemistry*
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Mannose-Binding Lectins / genetics
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Mannose-Binding Lectins / metabolism*
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Membrane Proteins / chemistry*
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mutation
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Protein Structure, Secondary
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Vesicular Transport Proteins / chemistry*
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Vesicular Transport Proteins / genetics
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Vesicular Transport Proteins / metabolism*
Substances
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LMAN1 protein, human
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MCFD2 protein, human
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Mannose-Binding Lectins
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Membrane Proteins
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Vesicular Transport Proteins
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Factor V
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Factor VIII