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Factor IX Zutphen: a Cys18-->Arg mutation results in formation of a heterodimer with alpha 1-microglobulin and the inability to form a calcium-induced conformation.

Abstract
Factor IX Zutphen is a variant factor IX molecule isolated from the blood of a patient with severe haemophilia B. The molecular defect in factor IX Zutphen is a Cys18-->Arg mutation as a result of a T-->C transition at residue 6427 of the factor IX gene of the patient. The mutation disrupts the disulphide bond in the Gla-domain between Cys18 and Cys23. The remaining free cysteine residue results in the formation of a 95 kDa complex with alpha 1-microglobulin through an intermolecular disulphide bond. The same complex circulates at high levels in plasma of carriers of the mutation. The variant molecule has a calcium-binding defect, which is shown not to be caused by incomplete gamma-carboxylation. Factor IX Zutphen can not bind to phospholipids and can not be activated by factor XIa or by factor VIIa-tissue factor complex. Two sequential metal ion-dependent conformational transitions (factor IX-->factor IX'-->factor IX*) have been proposed for human factor IX [Liebman (1987) J. Biol. Chem. 262, 7605-7612], based upon the metal ion requirements for binding to anti-factor IX:Mg(II) antibodies, which are specific for the factor IX' conformation, and anti-factor IX:Ca(II) antibodies, which are specific for the factor IX* conformation. We used these conformation-specific antibodies, and antibodies raised against a synthetic peptide corresponding to residues 35-50 of human factor IX [anti-factor IX(35-50)] to study the metal ion-induced conformation of factor IX Zutphen. The disruption of the disulphide bond in the Gla-domain, maybe in combination with the complex with alpha 1-microglobulin, destabilized the factor IX' conformation. The formation of the factor IX* conformation was prevented independent of the presence of alpha 1-microglobulin. The disulphide bond in the Gla-domain is therefore essential for the calcium-dependent conformation and function of factor IX.
AuthorsE G Wojcik, M van den Berg, I K van der Linden, S R Poort, R Cupers, R M Bertina
JournalThe Biochemical journal (Biochem J) Vol. 311 ( Pt 3) Pg. 753-9 (Nov 01 1995) ISSN: 0264-6021 [Print] England
PMID7487929 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Alpha-Globulins
  • Metals
  • alpha-1-microglobulin
  • factor IX Zutphen
  • 1-Carboxyglutamic Acid
  • Factor IX
  • Arginine
  • Cysteine
  • Calcium
Topics
  • 1-Carboxyglutamic Acid (analysis)
  • Alpha-Globulins (metabolism)
  • Amino Acid Sequence
  • Antibody Specificity
  • Arginine (genetics, metabolism)
  • Calcium (pharmacology)
  • Cysteine (genetics, metabolism)
  • Factor IX (chemistry, genetics, metabolism)
  • Humans
  • Metals (pharmacology)
  • Molecular Sequence Data
  • Mutation
  • Protein Binding
  • Protein Conformation
  • Structure-Activity Relationship

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