High-molecular-weight kininogen explained

kininogen 1
Hgncid:6383
Symbol:KNG1
Altsymbols:KNG, BDK
Entrezgene:3827
Omim:612358
Refseq:NM_001102416
Uniprot:P01042
Chromosome:3
Arm:q
Band:21
Locussupplementarydata:-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.

Other names

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

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.

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;[3] 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.[4]

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.[4] The resulting severed light and heavy chains remain connected by the aforementioned disulfide bond near the original N- and C-termini.[4]

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.[4] [6]

Genetics

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

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.

Clinical features

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.

Notes and References

  1. Wuepper KD, Miller DR, Lacombe MJ . Flaujeac trait. Deficiency of human plasma kininogen . The Journal of Clinical Investigation . 56 . 6 . 1663–72 . December 1975 . 127805 . 333145 . 10.1172/JCI108248 .
  2. Waldmann R, Abraham JP, Rebuck JW, Caldwell J, Saito H, Ratnoff OD . Fitzgerald factor: a hitherto unrecognised coagulation factor . Lancet . 1 . 7913 . 949–51 . April 1975 . 48123 . 10.1016/s0140-6736(75)92008-5 . 24923458 .
  3. Book: Stefan Offermanns. Walter Rosenthal. Encyclopedia of Molecular Pharmacology. 11 December 2010. 2008. Springer. 978-3-540-38916-3. 673– .
  4. Weisel JW, Nagaswami C, Woodhead JL, DeLa Cadena RA, Page JD, Colman RW. 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. 10.1016/S0021-9258(17)36995-8. free. 8144509. 1994.
  5. Higashiyama S, Ohkubo I, Ishiguro H, Kunimatsu M, Sawaki K, Sasaki M . 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 . April 1986 . 3635411 . 10.1021/bi00355a034 .
  6. Scott CF, Silver LD, Purdon AD, Colman RW. Cleavage of human high molecular weight kininogen by factor XIa in vitro: Effect on structure and function. 1985. The Journal of Biological Chemistry. 260. 19. 10.1016/S0021-9258(19)85161-X. 10856–10863. 3875612. free.
  7. Fong D, Smith DI, Hsieh WT . 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 . June 1991 . 2066106 . 10.1007/BF00204179 . 30895313 .
  8. Kitamura N, Kitagawa H, Fukushima D, Takagaki Y, Miyata T, Nakanishi S. Structural Organization of the Human Kininogen Gene and a Model for Its Evolution. The Journal of Biological Chemistry. 260. 15. 8610–8617. 10.1016/S0021-9258(17)39516-9. 1985. free. 2989294.
  9. Web site: KININOGEN 1; KNG1. Online Mendelian Inheritance in Man. 3 June 2021. 31 January 2024. Kniffin. Cassandra L.. Gross. Matthew B.. Originally published 23 October 2008.
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  10. Colman RW, Bagdasarian A, Talamo RC, Scott CF, Seavey M, Guimaraes JA, Pierce JV, Kaplan AP . 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 . December 1975 . 1202089 . 333144 . 10.1172/JCI108247 .