Biology Reference
In-Depth Information
insert modules and the C-terminal HPX domain was postulated at this key site (Erat
et al.
2009
).
Each FnII-like module of MMP-2 and -9 does have an exposed edge that in
principle could add a
-strand (Fig.
6.4
). However, further inspection of the inter-
face mapping results on FnII-like insert modules of MMP-2 and -9 presents a
conceptual obstacle in drawing an analogy between
8-9
FnI and CBD binding of
triple helices. The CBD residues interacting with triple helical or gelatin-like poly-
peptides have reproducibly mapped to bowl-like clusters above the small
b
-sheets
(Fig.
6.5
) (Collier et al.
1992
; Briknarova et al.
1999
,
2001
; Gehrmann et al.
2004
;
Xu et al.
2009
). These interaction bowls appear too distant from the edge strands of
the
b
b
-sheets (Figs.
6.4
and
6.5
) to support the
b
-strand addition hypothesis of triple
helix interaction and disruption.
6.4 C-Terminal HPX Domain
6.4.1 Requirement for Collagenolysis
Loss of the C-terminal HPX domain was reported to abrogate collagenolysis by
MMP-1 (Clark and Cawston
1989
; Murphy et al.
1992
), MMP-8 (Knauper et al.
1993
), MMP-13 (Knauper et al.
1997
), and MMP-2 (Patterson et al.
2001
). The
HPX domain of MMP-1 supports unwinding of the triple helix for its ensuing
hydrolysis, strand by strand, by the catalytic domain (Chung et al.
2004
). The nature
of structural and functional coordination between the catalytic and HPX domains of
collagenolytic MMPs is then a major question for interactions with protein fibrils
from the ECM such as collagens.
6.4.2 Loose Tethering Between Catalytic and HPX Domains
In the crystal structure of full-length MMP-12, the position and orientation of the
HPX domain is far removed (120
) from that in full-length MMP-1 and -2 structures
(Fig.
6.6
) that agree with each other (Bertini et al.
2008
). This possibility was not
surprising in view of early NMR and crystallography evidence of the mobility and
disorder of the linker between catalytic and HPX domains (Gooley et al.
1993
,
1994
; Van Doren et al.
1993
; Li et al.
1995
; Van Doren et al.
1995
). Loose tethering
in solution was clearly demonstrated recently in full-length MMP-12 where the
HPX and catalytic domains rapidly reorient relative to each other, again facilitated
by the mobility of the linker region (Bertini et al.
2008
). Fitting of SAXS data
confirmed that full-length MMP-12 samples a multitude of interdomain orientations.
About half of these agree with the compact orientation in crystals, while the other
half have greater separation of the domains that sample diverse orientations, none
