Crystal structure of the LMAN1-CRD/MCFD2 transport receptor complex provides insight into combined deficiency of factor V and factor VIII

FEBS Lett. 2010 Mar 5;584(5):878-82. doi: 10.1016/j.febslet.2010.02.009. Epub 2010 Feb 9.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blood Coagulation Disorders, Inherited / genetics
  • Blood Coagulation Disorders, Inherited / metabolism*
  • Circular Dichroism
  • Crystallography, X-Ray
  • Factor V / metabolism*
  • Factor V Deficiency / genetics
  • Factor V Deficiency / metabolism
  • Factor VIII / metabolism*
  • Humans
  • Mannose-Binding Lectins / chemistry*
  • Mannose-Binding Lectins / genetics
  • Mannose-Binding Lectins / metabolism*
  • Membrane Proteins / chemistry*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mutation
  • Protein Structure, Secondary
  • Vesicular Transport Proteins / chemistry*
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism*

Substances

  • LMAN1 protein, human
  • MCFD2 protein, human
  • Mannose-Binding Lectins
  • Membrane Proteins
  • Vesicular Transport Proteins
  • Factor V
  • Factor VIII