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

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.

Structured summary

MINT-7557086: lman1 (uniprotkb:P49257) and mcfd2 (uniprotkb:Q8NI22) bind (MI:0407) by X-ray crystallography (MI:0114)

Keywords: Glycoprotein transport, ER quality control, Protein complex, Crystal structure, ERGIC-53

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

Corresponding author. Address: Dept. of Medical Biochemistry and Biophysics, Tomtebodavägen 6, Karolinska Institutet, S-17177 Stockholm, Sweden.

1 Present address: IBCP UMR 5086 CNRS, 7, Passage du Vercors, 69367 Lyon cedex 07, France.

2 Present address: Helmholtz Centre for Infection Research and University of Hamburg, CSSB-HZI at DESY, Notkestrasse 85, Bldg. 25b, 22607 Hamburg, Germany.

PII: S0014-5793(10)00103-1

doi:10.1016/j.febslet.2010.02.009

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