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

Wigren, Edvard; Bourhis, Jean-Marie; Kursula, Inari; Guy, Jodie E.; Lindqvist, Ylva

doi:10.1016/j.febslet.2010.02.009

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Volume 584, Issue 5 , Pages 878-882, 5 March 2010

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

Edited by Kaspar Locher

Dept. of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden

Received 12 January 2010; received in revised form 29 January 2010; accepted 1 February 2010. published online 05 February 2010.

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.