The aa sequence of human factor IX (accession number P00470), showing the main protein domains: (1) The pre sequence (residues -46 to -19) and the pro sequence (-18 to -1); (2) the Gla domain (1 to 40), with 12 glutamic acid (E) residues, marked with an asterisk; (3) the epidermal growth factor (EGF) domain 1 (47 to 83), containing aspartic acid (D) at residue 64 which undergoes P-hydroxylation (arrow with a "P-OH" symbol); (4) EGF-like domain 2 (88 to 127); (5) the activation peptide domain (146 to 180), containing a tyrosine (Y) at residue 155 (in bold) which undergoes sulfation (vertical arrow with "SO4" symbol), and a serine (S) at residue 158 (in bold), which is phosphorylated (vertical arrow with an "PO4" symbol); (6) the catalytic domain (181 to 145, with the catalytic core residues H221, D269, and S365 underlined and in italics). Numbering on the right refers to aa residues. The protein domains are indicated in italics, and are separated by spaces in the sequence. The activation peptide (underlined) is cleaved from the polypeptide upon activation of FIX, generating the light chain and the heavy chain, which are subsequently linked together by a disulfide bridge between C132 and C289 (both cysteine residues are underlined and in bold), forming FIXa.
The activation peptide (AP) of FIX (residues 146 to 180) is separated from the EGF 2 domain by a short (19-aa) linker residue of unknown function. Within the AP region, O-linked oligosaccharides are linked to T159 and T169, where they are thought to play a role in the induction of a specific conformation required for zymogen activation . The AP region is cleaved and released from FIX during activation of the protease zymogen.
The last domain of mature hFIX is the C-terminal protease domain (residues 181 to 415). This catalytic domain contains a typical serine protease catalytic triad of S365, H221, and D269 (Figure 11.3), which converts FX into its activated form, FXa [23,24].
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