Human Gene KNG1 (ENST00000644859.2) from GENCODE V43
Description: Homo sapiens kininogen 1 (KNG1), transcript variant 1, mRNA. (from RefSeq NM_001102416) RefSeq Summary (NM_001102416): This gene uses alternative splicing to generate two different proteins- high molecular weight kininogen (HMWK) and low molecular weight kininogen (LMWK). HMWK is essential for blood coagulation and assembly of the kallikrein-kinin system. Also, bradykinin, a peptide causing numerous physiological effects, is released from HMWK. Bradykinin also functions as an antimicrobial peptide with antibacterial and antifungal activity. In contrast to HMWK, LMWK is not involved in blood coagulation. Three transcript variants encoding different isoforms have been found for this gene. Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reduces or depletes angiotensin converting enzyme 2 (ACE2), which results in an increase in levels of des-Arg(9)-bradykinin, a bioactive metabolite of bradykinin that is associated with lung injury and inflammation. [provided by RefSeq, Jul 2020]. Gencode Transcript: ENST00000644859.2 Gencode Gene: ENSG00000113889.14 Transcript (Including UTRs) Position: hg38 chr3:186,717,359-186,744,410 Size: 27,052 Total Exon Count: 10 Strand: + Coding Region Position: hg38 chr3:186,717,543-186,742,331 Size: 24,789 Coding Exon Count: 10
ID:KNG1_HUMAN DESCRIPTION: RecName: Full=Kininogen-1; AltName: Full=Alpha-2-thiol proteinase inhibitor; AltName: Full=Fitzgerald factor; AltName: Full=High molecular weight kininogen; Short=HMWK; AltName: Full=Williams-Fitzgerald-Flaujeac factor; Contains: RecName: Full=Kininogen-1 heavy chain; Contains: RecName: Full=T-kinin; AltName: Full=Ile-Ser-Bradykinin; Contains: RecName: Full=Bradykinin; AltName: Full=Kallidin I; Contains: RecName: Full=Lysyl-bradykinin; AltName: Full=Kallidin II; Contains: RecName: Full=Kininogen-1 light chain; Contains: RecName: Full=Low molecular weight growth-promoting factor; Flags: Precursor; FUNCTION: (1) Kininogens are inhibitors of thiol proteases; (2) HMW-kininogen plays an important role in blood coagulation by helping to position optimally prekallikrein and factor XI next to factor XII; (3) HMW-kininogen inhibits the thrombin- and plasmin- induced aggregation of thrombocytes; (4) the active peptide bradykinin that is released from HMW-kininogen shows a variety of physiological effects: (4A) influence in smooth muscle contraction, (4B) induction of hypotension, (4C) natriuresis and diuresis, (4D) decrease in blood glucose level, (4E) it is a mediator of inflammation and causes (4E1) increase in vascular permeability, (4E2) stimulation of nociceptors (4E3) release of other mediators of inflammation (e.g. prostaglandins), (4F) it has a cardioprotective effect (directly via bradykinin action, indirectly via endothelium-derived relaxing factor action); (5) LMW-kininogen inhibits the aggregation of thrombocytes; (6) LMW- kininogen is in contrast to HMW-kininogen not involved in blood clotting. SUBCELLULAR LOCATION: Secreted, extracellular space. TISSUE SPECIFICITY: Secreted in plasma. T-kinin is detected in malignant ovarian, colon and breast carcinomas, but not in benign tumors. PTM: Bradykinin is released from kininogen by plasma kallikrein. PTM: Hydroxylation of Pro-383 occurs prior to the release of bradykinin. PTM: Phosphorylation sites are present in the extracellular medium. PTM: N- and O-glycosylated. O-glycosylated with core 1 or possibly core 8 glycans. POLYMORPHISM: The T-kinin peptide is missing residues 378 to 380, probably as a result of a naturally occurring variant. The complete sequence of the T-kinin peptide is therefore ISRPPGFSPFR. This peptide is associated with malignant tumors but not with benign ones. DISEASE: Defects in KNG1 are the cause of high molecular weight kininogen deficiency (HMWK deficiency) [MIM:228960]. HMWK deficiency is an autosomal recessive coagulation defect. Patients with HWMK deficiency do not have a hemorrhagic tendency, but they exhibit abnormal surface-mediated activation of fibrinolysis. SIMILARITY: Contains 3 cystatin kininogen-type domains. WEB RESOURCE: Name=Wikipedia; Note=High molecular weight kininogen entry; URL="http://en.wikipedia.org/wiki/High-molecular_weight_kininogen"; WEB RESOURCE: Name=SeattleSNPs; URL="http://pga.gs.washington.edu/data/kng/";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on P01042
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
AK303768 - Homo sapiens cDNA FLJ56836 complete cds, highly similar to Kininogen-1 precursor. AK298440 - Homo sapiens cDNA FLJ53075 complete cds, highly similar to Kininogen-1 precursor. AK315230 - Homo sapiens cDNA, FLJ96228, Homo sapiens kininogen (KNG), mRNA. AK290839 - Homo sapiens cDNA FLJ77940 complete cds, highly similar to Human alpha-2-thiol proteinase inhibitor mRNA. BC060039 - Homo sapiens kininogen 1, mRNA (cDNA clone MGC:61989 IMAGE:4593077), complete cds. AK223589 - Homo sapiens mRNA for kininogen 1 variant, clone: FCC130F01. K02566 - Human alpha-2-thiol proteinase inhibitor mRNA, complete coding sequence. JD514541 - Sequence 495565 from Patent EP1572962. BC026253 - Homo sapiens kininogen 1, mRNA (cDNA clone IMAGE:4716671), complete cds. CU687392 - Synthetic construct Homo sapiens gateway clone IMAGE:100022316 5' read KNG1 mRNA. KJ897102 - Synthetic construct Homo sapiens clone ccsbBroadEn_06496 KNG1 gene, encodes complete protein. KR711282 - Synthetic construct Homo sapiens clone CCSBHm_00022176 KNG1 (KNG1) mRNA, encodes complete protein. JD138328 - Sequence 119352 from Patent EP1572962. JD175974 - Sequence 156998 from Patent EP1572962. JD175975 - Sequence 156999 from Patent EP1572962. JD332461 - Sequence 313485 from Patent EP1572962. JD332462 - Sequence 313486 from Patent EP1572962. JD189002 - Sequence 170026 from Patent EP1572962. JD518432 - Sequence 499456 from Patent EP1572962. JD052093 - Sequence 33117 from Patent EP1572962. JD322241 - Sequence 303265 from Patent EP1572962.
Biochemical and Signaling Pathways
KEGG - Kyoto Encyclopedia of Genes and Genomes hsa04610 - Complement and coagulation cascades
BioCarta from NCI Cancer Genome Anatomy Project h_biopeptidesPathway - Bioactive Peptide Induced Signaling Pathway h_LairPathway - Cells and Molecules involved in local acute inflammatory response h_no1Pathway - Actions of Nitric Oxide in the Heart h_intrinsicPathway - Intrinsic Prothrombin Activation Pathway
Reactome (by CSHL, EBI, and GO)
Protein P01042 (Reactome details) participates in the following event(s):
R-HSA-158354 kininogen + C1q binding protein tetramer -> kininogen:C1q binding protein tetramer R-HSA-374331 Bradykinin receptors B1 and B2 bind to bradykinin R-HSA-158311 kallikrein:kininogen:C1q binding protein tetramer -> kallikrein + activated kininogen:C1q binding protein tetramer + bradykinin R-HSA-481007 Exocytosis of platelet alpha granule contents R-HSA-158218 prekallikrein + kininogen:C1q binding protein tetramer -> prekallikrein:kininogen:C1q binding protein tetramer R-HSA-749454 The Ligand:GPCR:Gi complex dissociates R-HSA-749452 The Ligand:GPCR:Gq complex dissociates R-HSA-158251 prekallikrein:kininogen:C1q binding protein tetramer -> kallikrein:kininogen:C1q binding protein tetramer R-HSA-749456 Liganded Gi-activating GPCRs bind inactive heterotrimeric G-protein Gi R-HSA-749448 Liganded Gq-activating GPCRs bind inactive heterotrimeric Gq R-HSA-8952289 FAM20C phosphorylates FAM20C substrates R-HSA-158313 factor XII -> factor XIIa R-HSA-380073 Liganded Gi-activating GPCR acts as a GEF for Gi R-HSA-379048 Liganded Gq/11-activating GPCRs act as GEFs for Gq/11 R-HSA-140837 Intrinsic Pathway of Fibrin Clot Formation R-HSA-375276 Peptide ligand-binding receptors R-HSA-114608 Platelet degranulation R-HSA-140877 Formation of Fibrin Clot (Clotting Cascade) R-HSA-418594 G alpha (i) signalling events R-HSA-416476 G alpha (q) signalling events R-HSA-373076 Class A/1 (Rhodopsin-like receptors) R-HSA-76005 Response to elevated platelet cytosolic Ca2+ R-HSA-109582 Hemostasis R-HSA-388396 GPCR downstream signalling R-HSA-500792 GPCR ligand binding R-HSA-381426 Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) R-HSA-8957275 Post-translational protein phosphorylation R-HSA-76002 Platelet activation, signaling and aggregation R-HSA-372790 Signaling by GPCR R-HSA-392499 Metabolism of proteins R-HSA-597592 Post-translational protein modification R-HSA-162582 Signal Transduction
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