Biology Reference
In-Depth Information
GAGs Glycosaminoglycans
HDX Hydrogen/deuterium exchange
HDXMS Hydrogen/deuterium exchange detected by mass spectrometry
HPX
Hemopexin
HS
Heparan sulfate
NMR
Nuclear magnetic resonance
PAR
Protease-activated receptor
SAXS
Small angle X-ray scattering
THP
Triple helical peptide
Two decades of determinations of extracellular protease structures have focused
mainly upon discovering their 3D folds, details of their active sites, and how they
interact with drug lead compounds (Maskos
2005
; Bode
2006
). The matrix metal-
loproteinases (MMPs) are introduced in Chap. 1. Structures of complexes of MMPs
with extracellular matrix (ECM) components are few and precious, leaving a large
and open frontier regarding the nature of these interactions. Structural insights
into MMP interactions with components of the ECM have been gained largely by
mapping the interfaces of such complexes by a variety of approaches including
NMR spectroscopy, mass spectrometry, X-ray methods, mutagenesis, and compar-
ison of behavior of different combinations of MMP domains. Examples of each of
the domains found in MMPs have been found to interact with polymers from the
matrix. ECM components considered herein include glycosaminoglycans (GAGs),
collagen triple helices, gelatin, and elastin fibrils. Recent structural insights and
hypotheses regarding these interactions are surveyed, starting with the prodomain
and proceeding through catalytic domain, insertion of fibronectin II-like repeats,
and then on to the C-terminal hemopexin (HPX) domain.
6.1 Prodomain and Activating ECM Interactions
6.1.1
Initiation of Activation: Rapid Changes in Coordination
of Zinc in Active Site
Two reports have documented cases of disengagement of the prodomain of MMP-9
from its usual cysteine coordination of the zinc in the active site,
without proteolysis
or
prior to proteolysis
. The zymogen of MMP-9 can be activated
without proteoly-
sis
upon association with gelatin (Bannikov et al.
2002
) or upon association with the
irreversibly inactivated serine protease of tissue kallikrein (Rosenblum et al.
2007
).
Within the first 1.4 s of pro-MMP-9 association with active tissue kallikrein, three
successive intermediates appeared prior to the first proteolysis event, rapidly
establishing the coordination environment of the active MMP. The intermediates
differed in coordination of the active-site zinc relative to both the zymogen and
