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| kininogen 1 | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | KNG1 | ||||||
| Alt. symbols | KNG, BDK | ||||||
| NCBI gene | 3827 | ||||||
| HGNC | 6383 | ||||||
| OMIM | 612358 | ||||||
| RefSeq | NM_001102416 | ||||||
| UniProt | P01042 | ||||||
| Other data | |||||||
| Locus | Chr. 3 q21-qter | ||||||
| |||||||
High-molecular-weight kininogen (HMWK or HK) is a circulating plasma protein which participates in the initiation of blood coagulation, and in the generation of the vasodilator bradykinin via the kallikrein-kinin system. HMWK is inactive until it either adheres to binding proteins beneath an endothelium disrupted by injury, thereby initiating coagulation; or it binds to intact endothelial cells or platelets for functions other than coagulation.
In the past, HMWK has been called HMWK-kallikrein factor, Flaujeac factor (1975),[1] Fitzgerald factor (1975),[2] and Williams-Fitzgerald-Flaujeac factor, - the eponyms being for people first reported to have HMWK deficiency. Its current accepted name is to contrast it with low-molecular-weight kininogen (LMWK) which has a similar function to HMWK in the tissue (as opposed to serum) kinin-kallikrein system.
HMWK is an alpha-globulin with six functional domains. It circulates as a single-chain 626 amino acid polypeptide . The heavy chain contains domains 1, 2, and 3; the light chain, domains 5 and 6. Domain 4 links the heavy and light chains in addition to a disulfide bond between positions close to the N- and C-termini.[3]
The domains contain the following functional sites:
HMWK is one of four proteins which interact to initiate the contact activation pathway (also called the intrinsic pathway) of coagulation: the other three are Factor XII, Factor XI and prekallikrein. HMWK is not enzymatically active, and functions only as a cofactor for the activation of kallikrein and factor XII. It is also necessary for the activation of factor XI by factor XIIa.
HMWK is also a precursor of bradykinin;[4] this vasodilator is released through positive feedback by kallikrein. Cleavage by kallikein results in the liberation of two peptides, one of which is bradykinin, from HMWK's fourth domain.[3]
Cleavage by kallikrein also helps HMWK to optimally function as a coactivator. The cleavage results in a change in the conformation of HMWK that may increase the accessibility of its surface binding domain, which could explain cleaved HMWK's increased affinity for negatively charged surfaces.[3] The resulting severed light and heavy chains remain connected by the aforementioned disulfide bond near the original N- and C-termini.[3]
HMWK is a strong inhibitor of cysteine proteinases. Responsible for this activity are domains 2 and 3 on its heavy chain.[5]
Cleavage of HMWK by activated factor XI abrogates HMWK's ability to act as a cofactor, establishing negative feedback.[3][6]
The gene for both LMWK and HMWK is located on the 3rd chromosome (3q26).[7] Alternative splicing of the KNG1 gene transcript gives rise to processed mRNA that differs by what is included from the last two exons of the pre-mRNA.[8][9] Consequently, HMWK protein differs from LMWK only in having a larger light chain: the heavy chain and bradykinin portions are identical.[9]
Measurement of HMWK is usually done with mixing studies, in which plasma deficient in HMWK is mixed with the patient's sample and a partial thromboplastin time (PTT) is determined. Results are expressed in % of normal - a value under 60% indicates a deficiency.[citation needed]
The existence of HMWK was hypothesised in 1975 when several patients were described with a deficiency of a class of plasma protein and a prolonged bleeding time and PTT.[10] There is no increased risk of bleeding or any other symptoms, so the deficiency is a trait, not a disease.