Crystal structure of the LMAN1-CRD/MCFD2 transport receptor complex provides insight into combined deficiency of factor V and factor VIII.
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.
Wigren
Edvard
E
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.
Bourhis
Jean-Marie
JM
Kursula
Inari
I
Guy
Jodie E
JE
Lindqvist
Ylva
Y
D025861:Blood Coagulation Disorders, Inherited / Q000235:genetics / Q000378:metabolism*; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D005165:Factor V / Q000378:metabolism*; D005166:Factor V Deficiency / Q000235:genetics / Q000378:metabolism; D005169:Factor VIII / Q000378:metabolism*; D006801:Humans; D037241:Mannose-Binding Lectins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D017433:Protein Structure, Secondary; D033921:Vesicular Transport Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
C084004:LMAN1 protein, human; C475146:MCFD2 protein, human; D037241:Mannose-Binding Lectins; D008565:Membrane Proteins; D033921:Vesicular Transport Proteins; D005165:Factor V; D005169:Factor VIII