Biology Reference
In-Depth Information
fibroblasts (Hummel et al.
1998
). It is only active in an acidic environment and
therefore the sites of its action are specialized in resorbing bones and intracellular
digestion of phagocytosed collagens (Everts et al.
2003
).
This chapter reviews the structure and function of collagenolytic MMPs and
what is currently known about the structural basis of those enzymes to confer triple
helicase activity. We will also discuss how insoluble collagens may be digested by
vertebrate collagenases. We also describe how cathepsin K, crab collagenase and
bacterial collagenases degrade interstitial collagens.
5.2 Domain Structures of Collagenolytic MMPs
and Their Activation Steps
5.2.1 Domain Compositions
Six MMPs have been characterized as enzymes with triple helicase activity. Based
on domain structure arrangement, they are grouped into the so-called “collagenases”
(MMP-1, -8, -13 and -18), gelatinase A (MMP-2) and membrane-anchored MMP
(MT1-MMP or MMP-14). All have a signal peptide and four collagenases and
gelatinase A are secreted from the cell as inactive proenzymes.
Secreted collagenases consist of a propeptide domain, a catalytic metalloprotei-
nase (Cat) domain, a linker (also called “hinge”) region and a hemopexin-like
(Hpx) domain. Pro-MMP-2 has three fibronectin type II motifs that are inserted in
the catalytic domain, otherwise its domain arrangement is similar to other MMPs.
The pro-domain contains a characteristic three-helix bundle with a left-handed twist
which is also observed for those of MMP-1,-2, -3 and -9 (Jozic et al.
2005
; Becker
et al.
1995
; Elkins et al.
2002
; Morgunova et al.
1999
). This is a compact, stable
structure supported by the hydrophobic core formed within the bundle. It has the so-
called “cysteine switch” sequence PRCGXPD whose cysteine residue coordinates
with the catalytic Zn
2
þ
ion bound to three histidines, the HEXGHXXGXXH motif,
conserved in all MMPs (Van Wart and Birkedal-Hansen
1990
). The Cat domain
consists of three
-strands with one catalytic zinc ion, and one
structural zinc and three calcium ions which stabilize the 3D structure. The overall
peptide folds of the Cat domains of MMPs are essentially superimposable. The Hpx
domain is an ellipsoidal shape consisting of a four-bladed
a
helices and five
b
-propeller structure with
a single disulphide bond between the first and the fourth blades. Each blade is made
up of four antiparallel
b
-strands and the four blades have similar scaffolds arranged
almost symmetrically around the central core axis. One calcium ion and a chloride
are found in the centre of the propeller. The linker regions of MMPs, which connect
the Cat and the Hpx domains, are variable in length.
MMP-14 is plasma membrane-bound through its transmembrane domain and
activated intracellularly by a furin-like pro-protein convertase (Sato et al.
1996
).
Thus the active MMP-14 is expressed on the cell surface as a type I transmembrane
b
