The structure of the human beta II-tryptase tetramer: Fo(u)r better or worse

Tryptases, the predominant serine proteinases of human mast cells, have rec ently been implicated as mediators in the pathogenesis of allergic and infl ammatory conditions, most notably asthma, Their distinguishing features, th eir activity as a heparin-stabilized tetramer and resistance to most protei naceous inhibitors, are perfectly explained by the 3-Angstrom crystal struc ture of human beta II-tryptase in complex with 4-amidinophenylpyruvic acid. The tetramer consists of four quasiequivalent monomers arranged in a flat frame-like structure. The active centers are directed toward a central pore whose narrow openings of approximately 40 Angstrom x 15 Angstrom govern th e interaction with macromolecular substrates and inhibitors. The tryptase m onomer exhibits the overall fold of trypsin-like serine proteinases but dif fers considerably in the conformation of six surface loops arranged around the active site. These loops border and shape the active site cleft to a la rge extent and form all contacts with neighboring monomers via two distinct interfaces. The smaller of these interfaces, which is exclusively hydropho bic, can be stabilized by the binding of heparin chains to elongated patche s of positively charged residues on adjacent monomers or, alternatively, by high salt concentrations in vitro. On tetramer dissociation, the monomers are likely to undergo transformation into a zymogen-like conformation that is favored and stabilized by intramonomer interactions. The structure thus provides an improved understanding of the unique properties of the biologic ally active tryptase tetramer in solution and will be an incentive for the rational design of mono- and multifunctional tryptase inhibitors.