Predicted three-dimensional structure of the protease inhibitor domain of the Alzheimer's disease beta-amyloid precursor.
Alzheimer's disease is characterized by the deposition of amyloid beta-protein as plaques and tangles in the brains of its victims. The amyloid precursor can be expressed with or without the inclusion of a protease inhibitor domain, the potential role of which in amyloidogenesis has prompted the generation of a model of its three-dimensional structure based on the known structure of a related inhibitor. The model structure predicts that the mutated residues are almost entirely on the surface of the inhibitor domain, while conserved residues constitute the hydrophobic core. In addition, several pairs of structurally complementary, or concerted, mutations are seen. These structural features provide strong evidence for the validity of the modeled structure, and it is suggested that the presence of complementary mutations may be used as a criterion for evaluating protein structures built by homology, in addition to the (spatial) location of the mutations. The terminal residues delimiting the domain are among those furthest from the protease binding site and are in close proximity to one another, thus suggesting the ability of the domain to function as a structural cassette within the context of a larger protein. The electrostatic potentials of the inhibitor and of the related bovine pancreatic trypsin inhibitor reveal how two inhibitors with very different net charges can bind with approximately the same binding constant to trypsin and suggest a mutation of trypsin that might selectively enhance the binding of the amyloid inhibitor domain. The model provides a structural basis for understanding the functional roles of residues in the domain and for designing simpler molecules to test as pharmacologic agents for intervention in Alzheimer's disease.
Struthers
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Biosym Technologies, Inc., San Diego, California 92121.
Kitson
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Hagler
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D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000235:genetics*; D001665:Binding Sites; D015195:Drug Design; D001330:Electronic Data Processing; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D015203:Reproducibility of Results; D013237:Stereoisomerism; D014361:Trypsin Inhibitors / Q000737:chemistry* / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D014361:Trypsin Inhibitors