Biology Reference
In-Depth Information
Fig.
6.3
) in MMP-12 (Bhaskaran et al.
2008
; Palmier et al.
2010
), and probably also
in MMP-1 and -8 (Chung et al.
2000
; Pelman et al.
2005
; Minond et al.
2006
) (see
Sect.
6.2.1.4
). Regarding the hypothesis of gelatin or triple helix occupying this
groove, reaching the catalytic site would require the triple helix to be bent by
90
.
While some readers may object to the possibility of a triple helix undergoing such
dramatic bending, the unwinding implied by a bending mechanism (see
Sect.
6.2.2.4
) has the potential to explain the requirement of the FnII-like modules
for unwinding of the triple helix (Tam et al.
2004
). A denatured or more intact triple
helix would also have to bend to reach the mouth of each interfacial bowl in FnII-like
modules 2 and 1. The distant separation of the main binding sites for gelatin and
triple helices in modules 2 and 3 of the CBD of MMP-2 (Fig.
6.4
) has the potential to
keep individual chains separated to expedite proteolysis.
MMP-2 and -9 were recently proposed to cooperate in type IV collagenolysis:
MMP-2 CBD binding of type IV collagen facilitates MMP-9 cleavage of an inde-
pendent site in type IV collagen (Gioia et al.
2009
). Binding of the type IV collagen
to two of the binding sites in the CBD (Fig.
6.4
) could in principle introduce a loop
and bending to the triple helix. This might underwind and melt it, thereby making it
more vulnerable to MMP-9 scission of the individual, freed strands.
>
6.3.2 Do FnII-Like Modules Add a Strand from a Triple Helix,
as Does
8-9
FnI?
A recently hypothesized mode of triple helix binding to the fibronectin-like
modules is considered next. Gelatin-binding fragments of fibronectin, particularly
8-9
FnI, were reported to bind two hotspots in the collagen triple helix, including the
3
=
4
cleavage site (Erat et al.
2009
). The peptide fragment from the
1(I) strand of
a
collagen I bound in linear fashion as an additional
b
-strand, in antiparallel orienta-
-sheet of
8
FnI (Erat et al.
2009
). The polyproline II helix confor-
mation of each chain of the collagen triple helix is very similar to the extended
conformation of a
tion with the
b
-strand, making it not so big a change in conformation. The
more significant change accompanying the addition of a
b
-sheet
of
8
FnI is the separation and unwinding of the chains of the triple helix necessary
for this addition. Indeed, the association with
8-9
FnI destabilizes a THP model of
homotrimeric type II collagen, corroborating the view that the association unwinds
and melts the triple helix (Erat et al.
2009
). By linearizing a chain of the triple
helix and increasing exposure of the other two chains, fibronectin module binding
(Erat et al.
2009
) may meet the apparent need for unwinding of the triple helix for
collagenolysis (Chung et al.
2004
). Fibronectin binding and destabilization of this
site can alternately be considered either to facilitate or sterically hinder cleavage
(Erat et al.
2009
). Since the RGER sequence adjacent to the
3
=
4
collagenase cleavage
site interacts with
8-9
FnI (Erat et al.
2009
) and potentially with the HPX domain of
MMP-1 (Perumal et al.
2008
), a functional overlap between the fibronectin II-like
-strand to the
b
b
