High-molecular-weight kininogen

Last updated
kininogen 1
Identifiers
Symbol KNG1
Alt. symbolsKNG, BDK
NCBI gene 3827
HGNC 6383
OMIM 612358
RefSeq NM_001102416
UniProt P01042
Other data
Locus Chr. 3 q21-qter
Search for
Structures Swiss-model
Domains InterPro

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.

Contents

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. [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]

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.[ citation needed ]

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.

Related Research Articles

<span class="mw-page-title-main">Coagulation</span> Process of formation of blood clots

Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism of coagulation involves activation, adhesion and aggregation of platelets, as well as deposition and maturation of fibrin.

<span class="mw-page-title-main">Antithrombin</span> Mammalian protein found in Homo sapiens

Antithrombin (AT) is a small glycoprotein that inactivates several enzymes of the coagulation system. It is a 464-amino-acid protein produced by the liver. It contains three disulfide bonds and a total of four possible glycosylation sites. α-Antithrombin is the dominant form of antithrombin found in blood plasma and has an oligosaccharide occupying each of its four glycosylation sites. A single glycosylation site remains consistently un-occupied in the minor form of antithrombin, β-antithrombin. Its activity is increased manyfold by the anticoagulant drug heparin, which enhances the binding of antithrombin to factor IIa (thrombin) and factor Xa.

<span class="mw-page-title-main">Factor XII</span> Mammalian protein involved in blood clotting

Coagulation factor XII, also known as Hageman factor, is a plasma protein. It is the zymogen form of factor XIIa, an enzyme of the serine protease class. In humans, factor XII is encoded by the F12 gene.

alpha-2-Macroglobulin Large plasma protein found in the blood

α2-Macroglobulin (α2M) or alpha-2-macroglobulin is a large plasma protein found in the blood. It is mainly produced by the liver, and also locally synthesized by macrophages, fibroblasts, and adrenocortical cells. In humans it is encoded by the A2M gene.

<span class="mw-page-title-main">Plasmin</span> Enzyme in human blood that degrades clots and other proteins

Plasmin is an important enzyme present in blood that degrades many blood plasma proteins, including fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein is encoded by the PLG gene.

The kinin–kallikrein system or simply kinin system is a poorly understood hormonal system with limited available research. It consists of blood proteins that play a role in inflammation, blood pressure control, coagulation and pain. Its important mediators bradykinin and kallidin are vasodilators and act on many cell types. Clinical symptoms include marked weakness, tachycardia, fever, leukocytosis and acceleration of ESR.

<span class="mw-page-title-main">Protein S</span>

Protein S is a vitamin K-dependent plasma glycoprotein synthesized in the liver. In the circulation, Protein S exists in two forms: a free form and a complex form bound to complement protein C4b-binding protein (C4BP). In humans, protein S is encoded by the PROS1 gene. Protein S plays a role in coagulation.

<span class="mw-page-title-main">Factor V</span> Mammalian protein found in humans

Factor V is a protein of the coagulation system, rarely referred to as proaccelerin or labile factor. In contrast to most other coagulation factors, it is not enzymatically active but functions as a cofactor. Deficiency leads to predisposition for hemorrhage, while some mutations predispose for thrombosis.

<span class="mw-page-title-main">Factor XI</span> Mammalian protein found in Homo sapiens

Factor XI or plasma thromboplastin antecedent is the zymogen form of factor XIa, one of the enzymes of the coagulation cascade. Like many other coagulation factors, it is a serine protease. In humans, Factor XI is encoded by the F11 gene.

The prothrombinase enzyme complex consists of factor Xa (a serine protease) and factor Va (a protein cofactor). The complex assembles on negatively charged phospholipid membranes in the presence of calcium ions. The prothrombinase complex catalyzes the conversion of prothrombin (factor II), an inactive zymogen, to thrombin (factor IIa), an active serine protease. The activation of thrombin is a critical reaction in the coagulation cascade, which functions to regulate hemostasis in the body. To produce thrombin, the prothrombinase complex cleaves two peptide bonds in prothrombin, one after Arg271 and the other after Arg320. Although it has been shown that factor Xa can activate prothrombin when unassociated with the prothrombinase complex, the rate of thrombin formation is severely decreased under such circumstances. The prothrombinase complex can catalyze the activation of prothrombin at a rate 3 x 105-fold faster than can factor Xa alone. Thus, the prothrombinase complex is required for the efficient production of activated thrombin and also for adequate hemostasis.

Kallikreins are a subgroup of serine proteases, enzymes capable of cleaving peptide bonds in proteins. In humans, plasma kallikrein has no known paralogue, while tissue kallikrein-related peptidases (KLKs) encode a family of fifteen closely related serine proteases. These genes are localised to chromosome 19q13, forming the largest contiguous cluster of proteases within the human genome. Kallikreins are responsible for the coordination of various physiological functions including blood pressure, semen liquefaction and skin desquamation.

<span class="mw-page-title-main">Plasma kallikrein</span>

Plasma kallikrein is an enzyme that catalyses the following chemical reaction:

Prekallikrein (PK), also known as Fletcher factor, is an 85,000 Mr serine protease that complexes with high-molecular-weight kininogen. PK is the precursor of plasma kallikrein, which is a serine protease that activates kinins. PK is cleaved to produce kallikrein by activated Factor XII.

Kininogens are precursor proteins for kinins, biologically active polypeptides involved in blood coagulation, vasodilation, smooth muscle contraction, inflammatory regulation, and the regulation of the cardiovascular and renal systems.

Renal tissue kallikrein is an enzyme.

<span class="mw-page-title-main">F13B</span> Mammalian protein found in Homo sapiens

Coagulation factor XIII B chain is a protein that in humans is encoded by the F13B gene.

<span class="mw-page-title-main">Kininogen 1</span> Protein-coding gene in the species Homo sapiens

Kininogen-1 (KNG1), also known as alpha-2-thiol proteinase inhibitor, Williams-Fitzgerald-Flaujeac factor or the HMWK-kallikrein factor is a protein that in humans is encoded by the KNG1 gene. Kininogen-1 is the precursor protein to high-molecular-weight kininogen (HMWK), low-molecular-weight kininogen (LMWK), and bradykinin.

<span class="mw-page-title-main">EGF-like domain</span> Protein domain named after the epidermal growth factor protein

The EGF-like domain is an evolutionary conserved protein domain, which derives its name from the epidermal growth factor where it was first described. It comprises about 30 to 40 amino-acid residues and has been found in a large number of mostly animal proteins. Most occurrences of the EGF-like domain are found in the extracellular domain of membrane-bound proteins or in proteins known to be secreted. An exception to this is the prostaglandin-endoperoxide synthase. The EGF-like domain includes 6 cysteine residues which in the epidermal growth factor have been shown to form 3 disulfide bonds. The structures of 4-disulfide EGF-domains have been solved from the laminin and integrin proteins. The main structure of EGF-like domains is a two-stranded β-sheet followed by a loop to a short C-terminal, two-stranded β-sheet. These two β-sheets are usually denoted as the major (N-terminal) and minor (C-terminal) sheets. EGF-like domains frequently occur in numerous tandem copies in proteins: these repeats typically fold together to form a single, linear solenoid domain block as a functional unit.

<span class="mw-page-title-main">Calpain-1 catalytic subunit</span> Protein-coding gene in the species Homo sapiens

Calpain-1 catalytic subunit(CANP 1) is a protein that in humans is encoded by the CAPN1 gene.

<span class="mw-page-title-main">Contact activation system</span>

In the contact activation system or CAS, three proteins in the blood, factor XII (FXII), prekallikrein (PK) and high molecular weight kininogen (HK), bind to a surface and cause blood coagulation and inflammation. FXII and PK are proteases and HK is a non-enzymatic co-factor. The CAS can activate the kinin–kallikrein system and blood coagulation through its ability to activate multiple downstream proteins. The CAS is initiated when FXII binds to a surface and reciprocal activation of FXII and PK occurs, forming FXIIa and PKa. FXIIa can initiate the coagulation cascade by cleaving and activating factor XI (FXI), which leads to formation of a blood clot. Additionally, the CAS can activate the kinin–kallikrein system when PKa cleaves HK to form cHK, releasing a peptide known as bradykinin (BK). BK and its derivatives bind to bradykinin receptors B1 and B2 to mediate inflammation.

References

  1. ↑ 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.
  2. ↑ 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.
  3. 1 2 3 4 5 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.
  4. ↑ Stefan Offermanns, Walter Rosenthal (2008). Encyclopedia of Molecular Pharmacology. Springer. pp. 673–. ISBN   978-3-540-38916-3 . Retrieved 11 December 2010.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. 1 2 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.
  10. ↑ 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.
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