X-ray crystal structure of the protease inhibitor domain of Alzheimer's amyloid. beta. -protein precursor

Journal Article · Mon Oct 01 04:00:00 EDT 1990 · Biochemistry; (USA)

DOI:https://doi.org/10.1021/bi00495a002· OSTI ID:5613158

Hynes, T R; Randal, M; Kennedy, L A; Eigenbrot, C; Kossiakoff, A A ^[1]

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1. Genentech Inc., San Francisco, CA (USA) Univ. of California, San Francisco (USA)

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-{Angstrom} 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.

• OSTI ID: 5613158
• Journal Information: Biochemistry; (USA), Journal Name: Biochemistry; (USA) Vol. 29:43; ISSN 0006-2960; ISSN BICHA
• Country of Publication: United States
• Language: English

Related Subjects

550602* -- Medicine-- External Radiation in Diagnostics-- (1980-)
62 RADIOLOGY AND NUCLEAR MEDICINE
AMINO ACID SEQUENCE
COHERENT SCATTERING
DIFFRACTION
DISEASES
ENZYME ACTIVITY
ENZYME INHIBITORS
ENZYMES
HYDROLASES
MOLECULAR BIOLOGY
MOLECULAR STRUCTURE
NERVOUS SYSTEM DISEASES
PEPTIDE HYDROLASES
SCATTERING
SERINE PROTEINASES
TRYPSIN
X-RAY DIFFRACTION