The propeptides of human protein C, factor VII, and factor IX are exchangeable with regard to directing gamma-carboxylation of these proteins.
The specificity of the propeptide sequence in directing vitamin K-dependent post-translational gamma-carboxylation has been assessed by examination of the extent of processing of chimeric constructs of blood coagulation factor VII (fVII), factor IX (fIX) and protein C (PC). One chimera consisted of a protein in which the gamma-carboxyglutamic acid (Gla)/helical stack domain of PC (amino acid residues 1 to 46) was replaced by that of fIX (residues 1 to 47) in an otherwise intact PC. Another consisted of the same construction of a fVII/PC Gla domain-based mutant protein. The final chimera contained the leader/propeptide sequence of PC (residues -42 to -1) replaced by that of fIX (residues -46 to -1). In each case, all Glu-precursor Gla residues in the Gla domains of the proteins were fully processed to Gla. These results demonstrate that the propeptides of fIX and PC are capable of directing gamma-carboxylation of the Gla regions of either protein, that the propeptide of PC can fully function in gamma-carboxylation of the Gla region of fVII, and further suggest that, with regard to gamma-carboxylation, communications between the propeptides and Gla domains in intact proteins are general in nature.
Geng
J P
JP
Department of Chemistry and Biochemistry, University of Notre Dame, Indiana 46556, USA.
Castellino
F J
FJ
D002264:Carboxylic Acids / Q000097:blood; D005164:Factor IX / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005167:Factor VII / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016296:Mutagenesis; D010455:Peptides / Q000097:blood*; D011486:Protein C / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011498:Protein Precursors / Q000502:physiology*; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000097:blood*
D002264:Carboxylic Acids; D010455:Peptides; D011486:Protein C; D011498:Protein Precursors; D011993:Recombinant Fusion Proteins; D005167:Factor VII; D005164:Factor IX