Polyamine-promoted autoactivation of plasma hyaluronan-binding protein

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Abstract

Background: Plasma hyaluronan-binding protein (PHBP), a protease implicated in extracellular proteolysis, consists of multiple domains: an N-terminal region (NTR), three epidermal growth factor (EGF)-like domains, a kringle domain, and a protease domain. PHBP circulates as a single-chain proenzyme (pro-PHBP), which is converted to an active, two-chain form through autoproteolysis. Objective: To understand the mechanism of autoactivation. Here, we report that polyamine induces the formation of pro-PHBP autoactivation complex, in which an intermolecular interaction between NTR and the third EGF-like domain (E3) plays a role. Methods: Using a series of pro-PHBP mutants that partially lack functional domains, polyamine-induced pro-PHBP autoactivation was investigated in terms of enzyme activity, protein interaction, and inhibition by carminic acid, an anthraquinone compound identified in this study. Results: Polyamine enhanced intermolecular binding of pro-PHBP, but not of mutant pro-PHBP that partially lacked NTR (ΔN). Carminic acid inhibited intermolecular pro-PHBP binding and specifically abolished polyamine-induced autoactivation. NTR bound to pro-PHBP and ΔN, but its binding was minimal to a mutant that lacked E3. The NTR-ΔN binding was inhibited by a combination of polyamine and carminic acid, but each compound alone was ineffective. Conclusions: We infer from the data that (i) polyamine modulates intramolecular NTR-E3 interaction to allow intermolecular binding between NTR and E3 in another pro-PHBP molecule to form an autoactivation complex, and (ii) carminic acid inhibits polyamine-modulated intermolecular NTR-E3 binding. Polyamine concentrations are higher in cells and tissues with inflammation and malignancy. Polyamine leakage from legions through cell death or tissue injury may account for physiologically relevant pro-PHBP activation. © 2009 International Society on Thrombosis and Haemostasis.

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Yamamichi, S., Nishitani, M., Nishimura, N., Matsushita, Y., & Hasumi, K. (2010). Polyamine-promoted autoactivation of plasma hyaluronan-binding protein. Journal of Thrombosis and Haemostasis, 8(3), 559–566. https://doi.org/10.1111/j.1538-7836.2009.03641.x

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