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dc.contributor.authorHuang, Mingdong
dc.contributor.authorFurie, Barbara C.
dc.contributor.authorFurie, Bruce
dc.date.accessioned2019-10-05T09:47:26Z
dc.date.issued2004
dc.identifier.citationHuang, Mingdong, Barbara C. Furie, and Bruce Furie. 2004. “Crystal Structure of the Calcium-Stabilized Human Factor IX Gla Domain Bound to a Conformation-Specific Anti-Factor IX Antibody.” Journal of Biological Chemistry 279 (14): 14338–46. https://doi.org/10.1074/jbc.m314011200.
dc.identifier.issn0021-9258
dc.identifier.issn1083-351X
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:41483197*
dc.description.abstractThe binding of Factor IX to membranes during blood coagulation is mediated by the N-terminal gamma-carboxyglutamic acid-rich (Gla) domain, a membrane-anchoring domain found on vitamin K-dependent blood coagulation and regulatory proteins. Conformation-specific anti-Factor IX antibodies are directed at the calcium-stabilized Gla domain and interfere with Factor IX-membrane interaction. One such antibody, 10C12, recognizes the calcium-stabilized form of the Gla domain of Factor IX. We prepared the fully carboxylated Gla domain of Factor IX by solid phase peptide synthesis and crystallized Factor IX-(1- 47) in complex with Fab fragments of the 10C12 antibody. The overall structure of the Gla domain in the Factor IX-(1 - 47)-antibody complex at 2.2 Angstrom is similar to the structure of the Factor IX Gla domain in the presence of calcium ions as determined by NMR spectroscopy (Freedman, S. J., Furie, B. C., Furie, B., and Baleja, J. D. (1995) Biochemistry 34, 12126 - 12137) and by x-ray crystallography (Shikamoto, Y., Morita, T., Fujimoto, Z., and Mizuno, H. (2003) J. Biol. Chem. 278, 24090 - 24094). The complex structure shows that the complementarity determining region loops of the 10C12 antibody form a hydrophobic pocket to accommodate the hydrophobic patch of the Gla domain consisting of Leu-6, Phe-9, and Val-10. Polar interactions also play an important role in the antibody-antigen recognition. Furthermore, the calcium coordination network of the Factor IX Gla domain is different than in Gla domain structures of other vitamin K-dependent proteins. We conclude that this antibody is directed at the membrane binding site in the omega loop of Factor IX and blocks Factor IX function by inhibiting its interaction with membranes.
dc.language.isoen_US
dc.publisherAmerican Society for Biochemistry and Molecular Biology
dash.licenseLAA
dc.titleCrystal Structure of the Calcium-stabilized Human Factor IX Gla Domain Bound to a Conformation-specific Anti-factor IX Antibody
dc.typeJournal Article
dc.description.versionVersion of Record
dc.relation.journalThe Journal of Biological Chemistry
dash.depositing.authorFurie, Bruce::a70ea04c5f50553870d8c22ddc9b6e92::600
dc.date.available2019-10-05T09:47:26Z
dash.workflow.comments1Science Serial ID 106198
dc.identifier.doi10.1074/jbc.M314011200
dash.source.volume279;14
dash.source.page14338-14346


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