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apparent fulcrum of Arg300. This would be further in the same direction of the
relative rotation described for the zymogen form relative to the activated, mature
form (Iyer et al.
2006
). Such large rotations of the HPX domain relative to the
catalytic domain may well be attainable in solution. However, in the context of
early stages of collagenolysis where the exposure of the
3
=
4
to ΒΌ cleavage site is
limited by the packing of the triple helices all around it (Perumal et al.
2008
), the
utility of rotations and displacements of the domains may instead be sterically
restricted to inchworm-like ratcheting movements.
How the HPX domain might enhance collagenolysis remains an elusive ques-
tion. The MMP-1 HPX domain has been proposed to align the triple helix properly
for cleavage, particularly for longer triple helices of greater similarity to collagen
(Lauer-Fields et al.
2009
). One possibility for how the HPX domain might align the
triple helix is suggested by THP-induced HDX protection of the outer edge of the
first propeller blade (Fig.
6.7
). Among the suggested sites of contact with the triple
helix (Lauer-Fields et al.
2009
), this exposed
-strand of the first blade is nearest to
the active site cleft. It is conceivable that this proximal
b
-strand presents its
b
available edge to add a
-strand derived from a lower stability segment of the triple
helix, just as
8
FnI adds a
b
-strand from the collagenase cleavage site in collagen I
(see Sect.
6.3.2
). Such a hypothetical linearization by the first blade, if it were to
occur, could in principle foster strategic unwinding of the triple helix.
In summary, structural aspects of diverse interactions of matrix components
(GAGs, collagen triple helices, gelatin, and elastin) with the pro-, catalytic, FnII-
like, and HPX domains of MMPs have been considered. These typically increase
MMP activity by proper localization or positioning, but potentially by allosteric
effects as well. Concepts operable in exosite-mediated interactions of thrombin
with heparin, inhibitors, and protein substrates may in time prove to be relevant
to the interactions of MMPs and other extracellular proteases with ECM compo-
nents. Qualitative similarities among diverse interactions of MMPs with ECM
polymers regard how the latter often engage two domains of the MMP and how
that interaction guides the MMP to the place to stage its proteolytic attack.
b
Acknowledgments The author is grateful for the grant support of the NIH (GM57289 to SVD and
CA98799 to GB Fields) and American Heart Association (0855714G to SVD) sponsoring his
research into MMP interactions with matrix molecules.
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