Histone-tryptase interaction: H2A N-terminal tail removal and inhibitory activity.
The involvement of tryptase, the trypsin-like serine proteinase of mast cell granules, in many (patho)physiological conditions is now recognized. In vitro this enzyme is known to act as a potent growth factor for fibroblasts and epithelial cells. Moreover, a role in inflammatory diseases and in dermatological disorders characterized by increased cell turnover has been suggested for this protease. In an attempt to understand the molecular basis of tryptase activity, we have investigated the interaction in vitro between bovine tryptase and histones. Here we show that tryptase cleaves histone H2A at a specific site (Arg20-Ala21), resulting in the removal of the N-terminal flexible fragment of the molecule. Furthermore, we demonstrate that the H2A major fragment (H2A*, 109 residues) generated by hydrolysis and lacking the N-terminal domain, is a noncompetitive, reversible and highly specific inhibitor (Ki = 29 nM) of tryptase enzymatic activity. H2A* is able to inhibit the hydrolysis of a small substrate as well as the cleavage of fibronectin, a high-molecular-weight substrate of tryptase.
Fiorucci
L
L
Department of Experimental Medicine and Biochemical Sciences, Tor Vergata University, via di Tor Vergata 135, Roma, 00133, Italia.
Erba
F
F
Ascoli
F
F
D000818:Animals; D002417:Cattle; D053818:Chymases; D004305:Dose-Response Relationship, Drug; D006657:Histones / Q000378:metabolism* / Q000494:pharmacology; D006868:Hydrolysis; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D053802:Tryptases
D006657:Histones; D010446:Peptide Fragments; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; C083294:chymase 2; D053818:Chymases; D053802:Tryptases