Membrane Interaction of the Factor VIIIa Discoidin Domains in Atomistic Detail.
A recently developed membrane-mimetic model was applied to study membrane interaction and binding of the two anchoring C2-like discoidin domains of human coagulation factor VIIIa (FVIIIa), the C1 and C2 domains. Both individual domains, FVIII C1 and FVIII C2, were observed to bind the phospholipid membrane by partial or full insertion of their extruding loops (the spikes). However, the two domains adopted different molecular orientations in their membrane-bound states; FVIII C2 roughly was positioned normal to the membrane plane, while FVIII C1 displayed a multitude of tilted orientations. The results indicate that FVIII C1 may be important in modulating the orientation of the FVIIIa molecule to optimize the interaction with FIXa, which is anchored to the membrane via its γ-carboxyglutamic acid-rich (Gla) domain. Additionally, a structural change was observed in FVIII C1 in the coiled main chain leading the first spike. A tight interaction with one lipid per domain, similar to what has been suggested for the homologous FVa C2, is characterized. Finally, we rationalize known FVIII antibody epitopes and the scarcity of documented hemophilic missense mutations related to improper membrane binding of FVIIIa, based on the prevalent nonspecificity of ionic interactions in the simulated membrane-bound states of FVIII C1 and FVIII C2.
Global Research, Novo Nordisk A/S , DK-2760 Måløv, Denmark.|Department of Chemistry, Technical University of Denmark , DK-2800 Kgs. Lyngby, Denmark.
Jesper J
JJ
Madsen
Y Zenmei
YZ
Ohkubo
Department of Chemistry, Technical University of Denmark , DK-2800 Kgs. Lyngby, Denmark.
Günther H
GH
Peters
Global Research, Novo Nordisk A/S , DK-2760 Måløv, Denmark.
Johan H
JH
Faber
Emad
E
Tajkhorshid
Global Research, Novo Nordisk A/S , DK-2760 Måløv, Denmark.
Ole H
OH
Olsen
D000939:Epitopes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D005169:Factor VIII / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006467:Hemophilia A / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008567:Membranes, Artificial; D020125:Mutation, Missense; D010743:Phospholipids / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
D000939:Epitopes; D008567:Membranes, Artificial; D010743:Phospholipids; C078147:F8 protein, human; D005169:Factor VIII