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(NAS Colloquium) Proteolytic Processing and Physiological Regulation (1999) / Chapter Skim
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The structure of the human ßII-tryptase tetramer: Fo(u)r better or worse
Pages 10984-10991

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From page 10984...
... The active centers are directed toward a central pore whose narrow openings of approximately 40 A x 15 ~ govern the interaction with macromolecular substrates and inhibitors. The tryptase monomer exhibits the overall fold of trypsin-like serine proteinases but differs considerably in the conformation of six surface loops arranged around the active site.
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From page 10985...
... The tryptase monomers are grouped into tetrameric aggregates that form extended sheets. Each of these tryptase tetramers is clearly delimited from its neighbors in both directions.
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From page 10986...
... 3. The tryptase monomer in standard orientation, i.e., as seen approximately from the middle of the central pore of the tetramer toward the active site of monomer A (represented by Ser-195, His-57, and Asp-102~.
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From page 10987...
... The formation of this salt bridge after activation cleavage creates a functional substrate recognition site by reorienting the Asp-194 side chain from an external position in the zymogen, where it might hydrogen bond to a surface located His-40 Ser-32 pair forming the so-called "zymogen triad," to an internal position in the active molecule (30, 31~. This reorientation restructures the surrounding "activation domain," which in trypsin~ogen)
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From page 10988...
... , allowing favorable interactions with a distal basic group such as in pentamidine. The structural basis of the unexpected high affinity of bifunctional inhibitors containing suitably arranged adjacent imidazole moieties such as present in the inhibitor BABIM and closely related analogues (43, 44)
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From page 10989...
... , might even dock to adjacent active sites simultaneously to produce fragments of distinct length. The active centers of the tryptase monomers are also largely inaccessible for macromolecular inhibitors.
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From page 10990...
... The unusual substrate specificity, with a preference for peptidergic substrates, and the resistance to proteinaceous inhibitors other than LDTI are both caused by the limited accessibility of the active sites within the narrow central pore. The tetramer can be stabilized by heparin glycosaminoglycan chains larger than ~20 sugar residues, a length required to bridge the weaker of the two distinct monomer-monomer interfaces.
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From page 10991...
... Colloquium Paper: Sommerhoff et al.
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Key Terms

  • active site
  • tryptase tetramer
  • tryptase monomer
  • central pore
  • active centers

  • active sites
  • charged residues
  • positively charged
  • proteinaceous inhibitors
  • tryptase monomers

  • electron density
  • plasminogen activator
  • active center
  • hydrogen bonds
  • electrostatic potential

  • tryptase tetramers
  • exclusively hydrophobic
  • ldti molecule
  • surface loops
  • substrate binding

  • salt bridge
  • tryptase active
  • salt bridges
  • proteinase inhibitor
  • six surface

  • activation domain
  • unusual substrate
  • trypsin inhibitor
  • acidic residues
  • ldti molecules


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