The Crystal Structure of Human α1-Tryptase Reveals a Blocked Substrate-binding Region

Human mast cell tryptases represent a subfamily of trypsin-like serine proteinases implicated in asthma. Unlike β-tryptases, α-tryptases apparently are proteolytically inactive. We have solved the 2.2 Å crystal structure of mature human α1-tryptase. It reveals a frame-like tetrameric architecture that, surprisingly, does not require heparin-binding for stability. In marked contrast to β2-tryptase, the Ser214-Gly219 segment, which normally provides the template for substrate binding, is kinked in α-tryptase, thereby blocking its non-primed subsites. This so far unobserved subsite distortion is incompatible with productive substrate binding and processing. α-Tryptase apparently is trapped in this off-conformation by repulsions and attractions of the Asp216 side-chain. However, proteolytic activity could be generated by an induced-fit mechanism.