 |
|
Title
|
|
X-ray crystal structure of the protease inhibitor domain of Alzheimer's amyloid beta-protein precursor.
|
|
|
Authors
|
|
T.R.Hynes,
M.Randal,
L.A.Kennedy,
C.Eigenbrot,
A.A.Kossiakoff.
|
|
|
Ref.
|
|
Biochemistry, 1990,
29,
10018-10022.
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
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.
|
|
|
|