X-ray crystal structure of the protease inhibitor domain of Alzheimer's amyloid beta-protein precursor.
Alzheimer's amyloid beta-protein precursor contains a Kunitz protease inhibitor domain (APPI) potentially involved in proteolytic events leading to cerebral amyloid deposition. To facilitate the identification of the physiological target of the inhibitor, the crystal structure of APPI has been determined and refined to 1.5-A resolution. Sequences in the inhibitor-protease interface of the correct protease target will reflect the molecular details of the APPI structure. While the overall tertiary fold of APPI is very similar to that of the Kunitz inhibitor BPTI, a significant rearrangement occurs in the backbone conformation of one of the two protease binding loops. A number of Kunitz inhibitors have similar loop sequences, indicating the structural alteration is conserved and potentially an important determinant of inhibitor specificity. In a separate region of the protease binding loops, APPI side chains Met-17 and Phe-34 create an exposed hydrophobic surface in place of Arg-17 and Val-34 in BPTI. The restriction this change places on protease target sequences is seen when the structure of APPI is superimposed on BPTI complexed to serine proteases, where the hydrophobic surface of APPI faces a complementary group of nonpolar side chains on kallikrein A versus polar side chains on trypsin.
Hynes
T R
TR
Protein Engineering Department, Genentech Inc., South San Francisco, California 94080.
Randal
M
M
Kennedy
L A
LA
Eigenbrot
C
C
Kossiakoff
A A
AA
D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000737:chemistry*; D011487:Protein Conformation; D011498:Protein Precursors / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D012689:Sequence Homology, Nucleic Acid; D015842:Serine Proteinase Inhibitors; D014961:X-Ray Diffraction
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D011480:Protease Inhibitors; D011498:Protein Precursors; D015842:Serine Proteinase Inhibitors