Beta-amyloid peptide binds equivalently to binary and ternary alpha2-macroglobulin-protease complexes.
Mettenburg JM, Gonias SL. Beta-amyloid
peptide binds equivalently to binary and ternary
alpha2-Macroglobulin (alpha2M) is a protease inhibitor that has
separate binding sites
for transforming growth factor-beta (TGF-beta) and beta-amyloid
peptide (Abeta), both of which have been identified in the beta2M
sequence. In the 3D-structure of alpha2M, TGF-beta occupies the
alpha2M central cavity, overlapping with the space that can
accommodate up to two molecules of protease.
As a result, ternary alpha2M-protease complexes (2 mol
protease/mol alpha2M) have been reported to not bind TGF-beta. The
goal of the present study was to test whether binding of Abeta to
alpha2M is controlled by steric constraints imposed by associated
proteases, similarly to TGF-beta. We confirmed that binary
alpha2M-trypsin complex (1 mol trypsin/mol alpha2M) binds increased
amounts of TGF-beta1, compared with native alpha2M, while ternary
alpha2M-trypsin complex binds substantially decreased amounts of
TGF-beta1. By contrast, Abeta-binding to binary and ternary alpha2M
trypsin complex was equivalent. In both cases, binding was
substantially increased compared with the negligible level observed
with native alpha2M. Plasmin is a large protease (Mr approximately
82,000) that substantially occupies the alpha2M central cavity;
however, alpha2M-plasmin complex also bound increased amounts of
Abeta, compared with native alpha2M. We conclude that Abeta accesses
its binding site, in alpha2M, from outside the alpha2M central
cavity. The TGF-beta- and Abeta-binding sites are spatially
separated not only in the primary sequence of alpha2M, but also in
the 3D-structure.
External Link: PMID:
16003950
Comment:
We first note that alpha-2-macroglobulin has specific binding sites
for TGF-beta, and specific binding sites for beta-amyloid peptide.
This answers the question as to why the
alpha-2-macroglobulin-protease complex binds some molecules and not
others. Put simply, it has binding sites for the molecules that bind
to it.
This paper also reveals that if a molecule of alpha-2-macroglobulin
may bind with either one molecule or two molecules of tryspin it
will have variable binding capacity of TGF-beta. However, both forms
of activated alpha2-Macroglobulin (both binary and ternary alpha2M
trypsin complexes) have substantially increased binding for beta-amyloid
peptide. It is notable that the native (un-activated)
alpha-2-macroglobulin, has negligible binding to beta-amyloid
peptide.
It is the activated alpha2-Macroglobulin that binds TGF-beta, and
beta-amyloid peptide. Wobenzym® N provides systemic
enzymes that activate alpha2-Macroglobulin.
Joseph J Collins,
RN, ND