kininogen 1 | |||||||
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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 | ||||||
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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.
Other names
[edit]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.
Structure and function
[edit]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:
- Domain 1 - calcium binding
- Domain 2 - cysteine protease inhibition
- Domain 3 - cysteine protease inhibition; platelet and endothelial cell binding
- Domain 4 - bradykinin generation
- Domain 5 - heparin and cell binding; antiangiogenic properties; binding to negatively charged surfaces
- Domain 6 - prekallikrein and factor XI binding (amino acids 420 to 510)(histidine rich)
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]
Genetics
[edit]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
[edit]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]
Clinical features
[edit]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.
References
[edit]- ^ Wuepper KD, Miller DR, Lacombe MJ (December 1975). "Flaujeac trait. Deficiency of human plasma kininogen". The Journal of Clinical Investigation. 56 (6): 1663–72. doi:10.1172/JCI108248. PMC 333145. PMID 127805.
- ^ Waldmann R, Abraham JP, Rebuck JW, Caldwell J, Saito H, Ratnoff OD (April 1975). "Fitzgerald factor: a hitherto unrecognised coagulation factor". Lancet. 1 (7913): 949–51. doi:10.1016/s0140-6736(75)92008-5. PMID 48123. S2CID 24923458.
- ^ a b c d e Weisel JW, Nagaswami C, Woodhead JL, DeLa Cadena RA, Page JD, Colman RW (1994). "The shape of high molecular weight kininogen. Organization into structural domains, changes with activation, and interactions with prekallikrein, as determined by electron microscopy". The Journal of Biological Chemistry. 269 (13): 10100–10106. doi:10.1016/S0021-9258(17)36995-8. PMID 8144509.
- ^ Stefan Offermanns, Walter Rosenthal (2008). Encyclopedia of Molecular Pharmacology. Springer. pp. 673–. ISBN 978-3-540-38916-3. Retrieved 11 December 2010.
- ^ Higashiyama S, Ohkubo I, Ishiguro H, Kunimatsu M, Sawaki K, Sasaki M (April 1986). "Human high molecular weight kininogen as a thiol proteinase inhibitor: presence of the entire inhibition capacity in the native form of heavy chain". Biochemistry. 25 (7): 1669–75. doi:10.1021/bi00355a034. PMID 3635411.
- ^ Scott CF, Silver LD, Purdon AD, Colman RW (1985). "Cleavage of human high molecular weight kininogen by factor XIa in vitro: Effect on structure and function". The Journal of Biological Chemistry. 260 (19): 10856–10863. doi:10.1016/S0021-9258(19)85161-X. PMID 3875612.
- ^ Fong D, Smith DI, Hsieh WT (June 1991). "The human kininogen gene (KNG) mapped to chromosome 3q26-qter by analysis of somatic cell hybrids using the polymerase chain reaction". Human Genetics. 87 (2): 189–92. doi:10.1007/BF00204179. PMID 2066106. S2CID 30895313.
- ^ Kitamura N, Kitagawa H, Fukushima D, Takagaki Y, Miyata T, Nakanishi S (1985). "Structural Organization of the Human Kininogen Gene and a Model for Its Evolution". The Journal of Biological Chemistry. 260 (15): 8610–8617. doi:10.1016/S0021-9258(17)39516-9. PMID 2989294.
- ^ a b Kniffin CL, Gross MB (3 June 2021) [Originally published 23 October 2008]. "KININOGEN 1; KNG1". Online Mendelian Inheritance in Man. *612358. Retrieved 31 January 2024.
- ^ Colman RW, Bagdasarian A, Talamo RC, Scott CF, Seavey M, Guimaraes JA, Pierce JV, Kaplan AP (December 1975). "Williams trait. Human kininogen deficiency with diminished levels of plasminogen proactivator and prekallikrein associated with abnormalities of the Hageman factor-dependent pathways". The Journal of Clinical Investigation. 56 (6): 1650–62. doi:10.1172/JCI108247. PMC 333144. PMID 1202089.