Proteins of the kallikrein-kinin system and factor XI. (A-B) Schematic diagrams of human protease precursors showing noncatalytic (white boxes) and catalytic (light gray boxes) domains. Positions of active site serine residues are indicated by black bars. Sites of proteolysis during activation are indicated by arrows. (A) Prekallikrein (PK) is a 93-kDa polypeptide that is cleaved after Arg³⁷¹ to form plasma kallikrein (PKa). FXI is a homodimer of 80-kDa polypeptides. Each polypeptide is converted to FXIa by cleavage after Arg³⁶⁹. The noncatalytic portions of PK and FXI contain 4 apple domains, designated A1 to A4. The location of a Cys³²¹-Cys³²⁶ intrachain disulfide bond in PK is indicated above A4. *The location of Cys³²¹ in the A4 domain of FXI. In placental mammals and the opossum, Cys³²¹ forms an interchain disulfide bond connecting the 2 subunits of the FXI dimer. (B) Human plasma kininogens come in high-molecular weight (HK) and low-molecular weight (LK) forms that are products of alternatively spliced messenger RNAs from the Kng1 gene. HK and LK have similar D1, D2, D3, and D4 domains, but different D5 domains (D5_H and D5_L, respectively). The D6 (D6_H) domain is present only in HK and contains binding sites for PK and FXI. Cleavage sites for PKa in HK that release bradykinin are indicated by the black arrows. LK is cleaved at the sites indicated by black arrows by tissue kallikreins to release Lys-bradykinin (kallidin). (C) Pro-hepatocyte growth factor activator (pro-HGFA) is a 95-kDa polypeptide that is cleaved after Arg⁴⁰⁷ to form HGFA. FXII is an 80-kDa polypeptide that is converted to FXIIa by cleavage after Arg³⁵³. The Pro-HGFA and FXII noncatalytic domains are the fibronectin type 2 (F2), epidermal growth factor (EGF), fibronectin type 1 (F1), and kringle (K) domains. FXII also has a proline-rich region (PRR).