Defective propeptide processing of blood clotting factor IX caused by mutation of arginine to glutamine at position -4.
Blood clotting factor IX is synthesized as a precursor polypeptide that would be expected to be proteolytically cleaved in at least two positions during maturation to remove the prepeptide and propeptide regions. We show that a point mutation causing hemophilia B changes the amino acid at position -4 in the propeptide region of factor IX from an arginine to a glutamine, which results in the expression of a stable longer protein with 18 additional amino acids of the N-terminal propeptide region still attached. This suggests that in the normal maturation of factor IX the signal peptidase cleaves the peptide bond between amino acid residues -18 and -19, generating an unstable profactor IX intermediate. Further proteolytic processing to the mature factor IX depends on the arginine residue at -4. The significance of the homologous arginine residue in other processed proteins is discussed.
D000595:Amino Acid Sequence; D003001:Cloning, Molecular; D003429:Cross Reactions; D004262:DNA Restriction Enzymes; D005164:Factor IX / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D002836:Hemophilia B / Q000235:genetics*; D006801:Humans; D010447:Peptide Hydrolases / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D021382:Protein Sorting Signals / Q000378:metabolism*; D013379:Substrate Specificity
D021382:Protein Sorting Signals; D005164:Factor IX; D004262:DNA Restriction Enzymes; D010447:Peptide Hydrolases