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What We Have Learned from Structure of High Molecular Weight Kininogen

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What We Have Learned from Structure of High Molecular Weight Kininogen linica f C l To o x l ic a o n r l o u g Kolte and Zia J Clinic Toxicol 2011, 1:1 o y J Journal of Clinical Toxicology DOI: 10.4172/2161-0495.1000102e ISSN: 2161-0495 EditorialResearch Article OpenOpen Access Access What we have learned from Structure of High Molecular Weight Kininogen Kolte D1 and Shariat-Madar Zia1,2,3* 1Department of Pharmacology, University of Mississippi, University, Mississippi 38677-1848, USA 2Research Institute of Pharmaceutical Sciences. University of Mississippi, University, Mississippi 38677-1848, USA 3Light Microscopy Core, University of Mississippi, University, Mississippi 38677-1848, USA High molecular weight kininogen (HK, Williams-Fitzgerald- In summary, although our understanding of how HK interacts with Flaujeac factor) is an unique nonenzymatic cofactor of the plasma other proteins has shed some light on the distinct role(s) that each HK kallikrein kinin system (KKS), also known as contact activation system domain might play, many aspects of HK function still remain unclear. or intrinsic pathway, with multiple domains that regulate numerous Why is HK or each domain of HK uniquely vital to the functioning of biological pathways and cell functions including thrombosis, tissues and organs while HK deficiency is not lethal? Why does HK inflammation, and angiogenesis (Figure 1) [1,2]. HK, cleaved HK have diverse specific interaction partners? How does HK cross the (HKa), and each of HK domains are important at many points during blood brain barrier? Does the central nervous system have its own KKS, tissue remodeling and functioning following injury, establishing its which might be similar to its counterpart the renin-angiotensin system? role in vascular pathology and disease. Needless to say, the precise If human species is better off without having HK, PK, or FXII, what mechanisms underlying these effects still remain to be fully delineated. can we do to encourage DNA to delete their genes? More importantly, why are critical amino acid residues in HK, PK, and FXII protected HK, prekallikrein (PK, Fletcher Factor) and FXII (Hageman factor) from point mutation or deletion? Is it possible that maximal biologic are the key components of the KKS pathway of blood coagulation. adaptability of these proteins is truly essential at times of health, injury, This pathway is initiated when FXII comes in contact with negatively or illness? charged surfaces such as constituents of the sub endothelial matrix (glycosaminoglycans and collagen) and gets auto activated to the active Disclosure of conflict of interests serine protease factor XIIa (αFXIIa) in a reaction involving HK and The authors state that they have no conflict of interest. PK (Figure 1, 6). Of note, although complex and controversial, many other matching null hypotheses attempt to explain how activation of References the KKS pathway might occur under physiological conditions (Figure 1. Schmaier AH, McCrae KR (2007) The plasma kallikrein-kinin system: its 1, 1 through 5). However, there are increasing concerns regarding evolution from contact activation. J Thromb Haemos 5: 2323-2329. the quality and reporting of in vitro studies. Some of these concerns 2. Bryant JW, Shariat-Madar Z (2009) Human plasma kallikrein-kinin system: include autoactivation of PK, presence of kallikrein (an active form of physiological and biochemical parameters. Cardiovasc Hemato Agents Med PK) or encrypted activated FXII in the assay, presence of activated cells Chem 7: 234-250. and suppression or loss of antithrombotic activity of the endothelial 3. Simberg D , Wan-Ming Zhang , Sergei Merkulov , Keith McCrae , Ji-Ho Park, et surface under experimental conditions. Although many obstacles such al. (2009) Contact activation of kallikrein-kinin system by superparamagnetic iron oxide nanoparticles in vitro and in vivo. J Control Release. as problems of sensitivity and selectivity have affably been overcome, a search for alternative combination of methods is urgently needed to 4. Schmidtchen A, PasupuletiV, Morgelin M, Davoudi M, Alenfall J, et al. (2009) Boosting antimicrobial peptides by hydrophobic oligopeptide end tags. J Biol determine possible roles of KKS in health and disease. Chem 284: 17584-175943. HK has more interaction partners than any of the other blood coagulation factors. The emerging evidence suggests that HK also contribute to host responses to infection via a tight interaction with the microorganism surface proteins. This interaction leads to activation of KKS in human plasma, resulting in cleavage of HK, liberation of the potent proinflammatory peptide bradykinin, and initiation of the intrinsic pathway of coagulation. This initiation of programmed HK self-suicide marks the beginning of tissue healing via induction of inflammation and coagulation, the two host defense system. Notably, peptides derived from HK are used in novel approaches to reduce nanomaterial toxicity [3] and as antimicrobial peptides [4]. HK works like a wheel with many spokes, each with an unique *Corresponding author: Zia Shariat-Madar, The University of Mississippi, MS biological function. Take away a spoke and the wheel can continue to 38677-1848, USA, Tel: 662-915-5150; E-mail: [email protected] spin without concern of loss of its remaining functions, suggesting that Received July 13, 2011; Accepted July 13, 2011; Published July 15, 2011 while each domain can function independently, all HK domains are Citation: Kolte D, Zia S (2011) What we have learned from Structure of designed to work together to provide optimal benefit for cytoprotection High Molecular Weight Kininogen. J Clinic Toxicol 1:102e. doi:10.4172/2161- of normal tissues (Figure 1). On the other hand, take away the wheel 0495.1000102e and almost no physiological abnormality is apparent suggesting that Copyright: © 2011 Kolte D, et al. This is an open-access article distributed under alternative mechanism(s) exists that compensates, to certain extent, for the terms of the Creative Commons Attribution License, which permits unrestricted the deficiency of HK in humans. use, distribution, and reproduction in any medium, provided the original author and source are credited. J Clinic Toxicol ISSN: 2161-0495 JCT, an open access journal Volume 1 • Issue 1 • 1000102e Citation: Kolte D, Zia S (2011) What we have learned from Structure of High Molecular Weight Kininogen. J Clinic Toxicol 1:102e. doi:10.4172/2161- 0495.1000102e Page 2 of 2 Figure 1: Model proposed to describe the biological function and binding of HK, HK-PK complex, and their metabolites to vascular endothelium. Under physiological conditions, high molecular weight kininogen (HK), in the absence of prekallikrein (PK), activates bradykinin (BK) B2 receptors on endothelial cells to stimulate nitric oxide (NO) and prostacyclin (PGI2) production without an accompanying increase in endothelial permeability, suggesting that HK plays a cytoprotective role (1). In the presence of PK, the HK-PK complex assembles on endothelial cells via binding to a multi-protein complex consisting of urokinase plasminogen activator receptor (uPAR), complement C1q receptor (gC1qR) and cytokeratin 1 (CK1) (2). The membrane bound serine protease, prolylcarboxypeptidase (PRCP) or heat shock protein 90 (HSP90), activates PK to kallikrein, which in turn cleaves HK to produce BK and cleaved HK (HKa) (3). BK acting via its constitutively expressed B2 receptors induces NO and PGI2 production (4). Under physiological conditions, the small amount of BK produced serves as an antithrombotic, proangiogenic and cytoprotective peptide. The release of BK from HK increases the binding affinity of HKa to uPAR(5). The tight association between HKa and uPAR inhibits cell proliferation and angiogenesis via disruption of vitronectin-uPAR and uPA-uPAR interaction. Under pathological conditions, robust generation of kallikrein and BK promotes inflammation. Further, during endothelial damage, FXII can be autoactivated to FXIIa upon contact with negatively charged surfaces (e.g. components of the subendothelial matrix) (6). Besides PRCP, FXIIa can also activate PK to kallikrein, which can then amplify FXII activation several times. FXIIa- mediated activation of FXI then leads to activation of the intrinsic pathway of the coagulation system leading to thrombus formation at the site of injury. J Clinic Toxicol ISSN: 2161-0495 JCT, an open access journal Volume 1 • Issue 1 • 1000102e.
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