Biology Reference
In-Depth Information
5.2.4 Structural Changes of pro-MMP-1 upon Activation: From
“Closed” to “Open” Conformation
In pro-MMP-1 the bait region is located between the first and second helices in the
pro-domain, but it is missing in the 3D crystal structure, suggesting that this region
is flexible. When the bait region is cleaved, removal of the N-terminal helix has an
impact on the stability of the two remaining helices and the peptide bond around the
junction of the pro-domain and the Cat domain becomes exposed. This allows
MMP-3 to specifically cleave the Gln
80
-Phe
81
bond, which fully activates MMP-1.
Another important feature of pro-MMP-1 is that the pro-domain interacts not only
with the catalytic domain, but also with the Hpx domain (Jozic et al.
2005
). This
keeps the Hpx domain closer to the Cat domain, resulting in a “closed” configura-
tion. After removal of the pro-domain during activation the structure of MMP-1 was
found to relax to an “open” configuration (Fig.
5.2a, b
). Such structural changes
explain the biochemical observation that proenzymes of MMP-1 and MMP-8 do
not bind to collagen I, but activated forms of these enzymes do (Knauper et al.
1993a
; Murphy et al.
1992
; Welgus et al.
1985
). Docking of the molecular structure
of native collagen with this open configuration of MMP-1 suggests that the groove
formed by the two segments of the catalytic domain and the two blades of Hpx
domain may be a site where collagen initially binds in MMP-1 (Fig.
5.2c, d
).
Hydrogen/deuterium exchange-mass spectrometry studies of MMP-1 with a triple
helical peptide containing the collagenase-cleavage site and mutagenesis studies
have suggested that Ile
270
and Arg
271
contribute to the recognition of triple helical
peptide (Lauer-Fields et al.
2009
), supporting the above hypothesis. On the other
Fig. 5.2 Putative interaction site of triple helical collagen in MMP-1. (a) The ribbon structure of
pro-MMP-1 (1SU3.pdb). The pro-domain is shown in
red
, the catalytic domain in salmon, the
linker region in
blue
and the Hpx domain in
green
. The relative arrangement of the Cat and Hpx is
compact, due to a direct interaction between the pro and Hpx domains. (b) Superimposition of
human MMP-1 (linker-Hpx domain in
blue
; 2CLT.pdb) and porcine MMP-1 (linker-Hpx domain
in
red
; 1FBL.pdb) on pro-MMP-1 (linker-Hpx domains in
green
). This demonstrates the different
relative conformations of the Cat-Hpx domains observed in available crystal structures. In the
active forms a cleft opens up between the Cat and Hpx domains. (c, d) Active human MMP-1
shown as a surface structure. Type I collagen was positioned in the cleft between the catalytic and
Hpx domains. Regions of potential contact with collagen are shown in
blue
. Y191 is highlighted
in
cyan
