InterPro domain: IPR002395

The kininogens are multidomain proteins, belonging to the Type 3 cystatin family [ 1 ]. It contains three tandemly repeated type 2-like cystatin domains of which only the second and third (D2 and D3) exhibit cysteine peptidase inhibitory activity, and which belong to MEROPS inhibitor family I25B.

High molecular weight kininogen (HK) [ 2 ] is synthesised as a single polypeptide chain in the liver and secreted into the plasma, where it complexes with prekallikrein and factor XI. On cleavage by human plasma kallikrein, or factor XIIa, HK liberates bradykinin, which mimics inflammatory phenomena such as pain induction, vasodilation and increased vascular permeability. Kallikrein- cleavage yields the nonapeptide bradykinin, together with a cleaved product containing an N-terminal heavy chain, bound to a C-terminal light chain by a single inter-chain disulphide bridge.

Human kininogen maps to 3q26-qter [ 3 , 4 ]. It is intravascular, found in blood plasma, and as a result of diffusion, in synovial and amniotic fluids. As cysteine peptidase inhibitors, the kininogens are the major source of inhibitory activity in the circulation, for systemic protection against leaking lysosomal cysteine peptidases or enzymes derived from invading micro-organisms [ 5 ]. This activity depends on a number of factors, including the binding of cleaved HK to anionic surfaces [ 5 ], which is thought to be mediated through a His-Gly-rich region. Evidence has suggested that critical amino acid sequences within the His-Gly-rich region of HK serve as a primary structural feature for binding to a negatively charged surface [ 6 ].

1. Cystatins. Biochem. Soc. Symp. 59, 179-99
2. Subcommittee on contact activation. Nomenclature of kininogens. Thromb. Haemost. 60, 340-1
3. Chromosomal mapping of human kininogen gene (KNG) to 3q26----qter. Cytogenet. Cell Genet. 87, 24-6
4. The human kininogen gene (KNG) mapped to chromosome 3q26-qter by analysis of somatic cell hybrids using the polymerase chain reaction. Hum. Genet. , 189-92
5. Functional sites of bovine high molecular weight kininogen as a cofactor in kaolin-mediated activation of factor XII (Hageman factor). Biochemistry 19, 3215-20
6. The sequence HGLGHGHEQQHGLGHGH in the light chain of high molecular weight kininogen serves as a primary structural feature for zinc-dependent binding to an anionic surface. Protein Sci. 1, 151-60