Three-Dimensional Structure Of Human Lung Tryptase Determined, An Enzyme Involved In Allergic Asthma

March 25, 1998

Tryptase, a proteolytic enzyme, is the predominant protein of human mast cells. Despite significant sequence similarity to other trypsin-like proteinases, tryptase possesses unique, as yet poorly understood, properties. Most prominently, it is enzymatically active only as a tetramer which requires the binding of heparin for stabilization, and is resistant to all known endogenous proteinase inhibitors. Together with other preformed mediators (e.g., histamine and proteoglycans), tryptase is stored in the secretory granules of mast cells and is released in various allergic and certain inflammatory disorders such as asthma, psoriasis, rheumatoid arthritis, interstitial cystitis, and multiple sclerosis. Tryptase has been implicated as a causal mediator of such disorders and its involvement in the pathogenesis of asthma has recently been supported by preliminary results of clinical trials with the first synthetic tryptase inhibitors.

The team at the Max Planck Institute of Biochemistry (P.J.B. Pereira, A. Bergner,
S. Macedo-Ribeiro, R. Huber and W. Bode) has now determined the crystal structure of human beta-tryptase provided by G. Matschiner, H. Fritz and C.P. Sommerhoff at the Department of Clinical Chemistry and Clinical Biochemistry at the Ludwig Maximilian University, Muenchen.

The structure, published in a Letter to Nature (Human beta-tryptase is a ring-like tetramer with active sites facing a central pore, P.J.B. Pereira, A. Bergner, S. Macedo-Ribeiro, R. Huber, G. Matschiner, H. Fritz, C.P. Sommerhoff and W. Bode, Nature 392, 306) on March 19, 1998, reveals four quasi-equivalent monomers arranged in a square flat ring. Each monomer contacts its neighbours at two different interfaces via six loop segments. These loops are located around the active site and differ considerably in length and conformation from those of other trypsin-like proteinases. The four active centres of the tetramer are directed towards an oval central pore, restricting access for macromolecular substrates and inhibitors. Heparin chains could stabilize the complex by binding to an elongated patch of positively charged residues spanning two adjacent monomers. This unique tetrameric architecture explains many of tryptase's distinct biochemical properties and will facilitate the understanding of its role in health and disease.

-end-


Max-Planck-Gesellschaft

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