CHAPTER 21
Biomolecular Interaction of Matrix Metalloproteinases
and Their Inhibitors TIMPs
H. TSCHEsCHE I and M. FARR I
1
Abstract
Matrix metalloproteinases are a family of enzymes that altogether degrade
almost all constituents of the extracellular matrix including collagens, laminin,
elastin and fibronectin. Therefore, they are highly involved in the remodelling of
the extracelluar matrix during embryogenesis, growth and development, and
repair of tissues. Otherwise dysregulated proteolytic activity of matrix metalloproteinases is a key feature of a variety of diseases encompassing rheumatoid
arthritis, multiple sclerosis, liver fibrosis, parodontosis, tumor formation and
metastasis. In physiological processes the matrix metalloproteinases are precisely
regulated by gene expression, secretion and activation of pro enzymes and inhibition by their endogenous inhibitors, the tissue inhibitors of metalloproteinases
(TIMPs). These proteins control the activation of the zymogens, especially of
progelatinases, and the proteolytic activity of the mature enzymes. Besides ternary and quaternary complexes of gelatinases the typical complex between a
matrix metalloproteinase and a TIMP is bimolecular and leads to a high affinity,
quasi irreversible inhibition of the enzyme. Within the last few years several
three-dimensional structures of MMPs and MMP-inhibitor complexes have been
determined showing the polypeptide fold, domain organization, the architecture
of the active site and binding modes of TIMPs and synthetic inhibitors. Based on
these structural data enzyme kinetics and biomolecular analysis have clarified
structure-funcion correlations of activation, proteolytic activity and inhibition
by TIMPs.
2
Structure and Function of Matrix Metalloproteinases
The matrix metalloproteinases (MMPs, matrixins) form a family of about twenty
zinc- and calcium-dependent endopeptidases that degrade most of the constituents of the extracellular matrix, for example interstitial and basement membrane
collagens, gelatin, proteoglycans, aggrecan, elastin, fibronectin, entactin, vitronectin and laminin. Therefore they are highly involved in physiological processes
1 University of Bielefeld, Biochemistry I, D-33615 Bielefeld, Germany.
Biomolecular Interaction of Matrix Metalloproteinases
and Their Inhibitors TIMPs
H. TSCHEsCHE I and M. FARR I
1
Abstract
Matrix metalloproteinases are a family of enzymes that altogether degrade
almost all constituents of the extracellular matrix including collagens, laminin,
elastin and fibronectin. Therefore, they are highly involved in the remodelling of
the extracelluar matrix during embryogenesis, growth and development, and
repair of tissues. Otherwise dysregulated proteolytic activity of matrix metalloproteinases is a key feature of a variety of diseases encompassing rheumatoid
arthritis, multiple sclerosis, liver fibrosis, parodontosis, tumor formation and
metastasis. In physiological processes the matrix metalloproteinases are precisely
regulated by gene expression, secretion and activation of pro enzymes and inhibition by their endogenous inhibitors, the tissue inhibitors of metalloproteinases
(TIMPs). These proteins control the activation of the zymogens, especially of
progelatinases, and the proteolytic activity of the mature enzymes. Besides ternary and quaternary complexes of gelatinases the typical complex between a
matrix metalloproteinase and a TIMP is bimolecular and leads to a high affinity,
quasi irreversible inhibition of the enzyme. Within the last few years several
three-dimensional structures of MMPs and MMP-inhibitor complexes have been
determined showing the polypeptide fold, domain organization, the architecture
of the active site and binding modes of TIMPs and synthetic inhibitors. Based on
these structural data enzyme kinetics and biomolecular analysis have clarified
structure-funcion correlations of activation, proteolytic activity and inhibition
by TIMPs.
2
Structure and Function of Matrix Metalloproteinases
The matrix metalloproteinases (MMPs, matrixins) form a family of about twenty
zinc- and calcium-dependent endopeptidases that degrade most of the constituents of the extracellular matrix, for example interstitial and basement membrane
collagens, gelatin, proteoglycans, aggrecan, elastin, fibronectin, entactin, vitronectin and laminin. Therefore they are highly involved in physiological processes
1 University of Bielefeld, Biochemistry I, D-33615 Bielefeld, Germany.