Biomedical Engineering Reference
In-Depth Information
(a) APP
(b) Protease and Peptide Substrate Interactions
(i) Schechter and Berger Model
S3
S2
S1
S1
S2
S3
P3
P2
P1
P1
P2
P3
-NH-CH-CO-NH-CH-CO-NH-CH-CO
-
NH-CH-CO-NH-CH-CO-NH-CH-CO-
Cleavage Site
(ii)
Wild-Type -Secretase Cleavage Site: P3 to P3 Residues
Val Lys Met Asp Ala Glu
P3
P2
P1
P1
P2 P3
Figure 6.2
Model of APP and protease interactions at the b-secretase site. (a)
Interactions of amyloid precursor protein (APP) with proteases at the b-
secretase site for production of neurotoxic b-amyloid peptides (Ab). The
APP precursor protein undergoes proteolytic cleavages at the b-secretase
site and the g-secretase sites to generate Ab peptides, consisting primarily
of Ab(1-40) and Ab(1-42) that contain the same N-terminus with differ-
ences in their C-termini. The primary sequence of Ab peptides and
flanking residues at the secretase cleavage sites are illustrated. (b) Protease
active site interactions with APP at the b-secretase site: Schechter and
Berger model. (i) The active site domain of the enzyme is composed of
several subsites. The scheme shows an active site of six subsites, termed S1
to S3 and S1
0
to S3
0
. Subsites are located on both sides of the catalytic site
and are numbered from this point in either direction. The positions of
amino acid residues of the hexapeptide substrate are counted from the
point of cleavage and thus have the same numbering as the subsites they
occupy (P1 to P3 and P1
0
to P3
0
). Cleavage occurs between P1 and P1
0
.
23
(ii) Wild-type (WT) b-secretase cleavage site: P3 to P3
0
residues. Cleavage
of the WT b-secretase site of APP occurs between Met-
k
Asp which
represents the P1-P1
0
residues. The Val-Lys-Met residues represent the P3,
P2, and P1 residues, respectively; the Asp-Ala-Glu residues are the P1
0
,
P2
0
, and P3
0
residues, respectively.
residues adjacent to the cleavage site are important for recognition of the
peptide cleavage site by the protease, according to the model of substrate and
protease interactions of Schechter and Berger.
23,24
Interaction of a protease
cleaving the WT b-secretase site is discussed here. Cleavage of the WT
