2020
DOI: 10.3390/biom10060828
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Heparin Blocks the Inhibition of Tissue Kallikrein 1 by Kallistatin through Electrostatic Repulsion

Abstract: Kallistatin, also known as SERPINA4, has been implicated in the regulation of blood pressure and angiogenesis, due to its specific inhibition of tissue kallikrein 1 (KLK1) and/or by its heparin binding ability. The binding of heparin on kallistatin has been shown to block the inhibition of KLK1 by kallistatin but the detailed molecular mechanism underlying this blockade is unclear. Here we solved the crystal structures of human kallistatin and its complex with heparin at 1.9 and 1.8 Å resolution, respectively.… Show more

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Cited by 9 publications
(9 citation statements)
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“…Heparin could bind across the positively charged surface area of chloropin around residues K126, K127, K268, and K269 to bridge chloropin and thrombin together and promote their interaction ( Figure 2B ). Therefore, the cofactor binding site of chloropin is distinctly different to those of antithrombin, PCI, kallistatin or vaspin ( Jin et al, 1997 ; Li et al, 2007 ; Ulbricht et al, 2017 ; Ma et al, 2020 ).…”
Section: Resultsmentioning
confidence: 99%
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“…Heparin could bind across the positively charged surface area of chloropin around residues K126, K127, K268, and K269 to bridge chloropin and thrombin together and promote their interaction ( Figure 2B ). Therefore, the cofactor binding site of chloropin is distinctly different to those of antithrombin, PCI, kallistatin or vaspin ( Jin et al, 1997 ; Li et al, 2007 ; Ulbricht et al, 2017 ; Ma et al, 2020 ).…”
Section: Resultsmentioning
confidence: 99%
“…The effect of low molecular weight heparin (LMWH) on the interactions between chloropin and thrombin was similarly assessed as previously described ( Wei et al, 2016 ; Ma et al, 2020 ). A total of 1 µM chloropin was incubated with different concentrations of LMWH (0, 0.005, 0.025, 0.05, 0.25, 0.5, 1, and 2.5 mg/mL) for 5 min at room temperature, and then mixed with 100 nM thrombin and the residual thrombin activity was measured using 0.2 mM S-2238 at different time intervals.…”
Section: Methodsmentioning
confidence: 99%
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“…SERPINA4, also known as Kallistatin (KS), is an inhibitor of tissue kallikrein and also inhibits the Wnt signaling pathway. Kallistatin mainly expressed in liver and broadly expressed in other tissues, such as the eye, kidney, heart, and blood vessels 25 . Studies show that the KKS system plays interesting roles in DKD.…”
Section: Discussionmentioning
confidence: 99%
“…Kallistatin mainly expressed in liver and broadly expressed in other tissues, such as the eye, kidney, heart, and blood vessels. 25 Studies show that the KKS system plays interesting roles in DKD.…”
Section: Protein Accessionmentioning
confidence: 99%