Matrix Metalloproteinase Biology E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Veröffentlichungsjahr: 2015

Beschreibung

Discussing recent advances in the field of matrix metalloproteinase (MMP) research from a multidisciplinary perspective, Matrix Metalloproteinase Biologyis a collection of chapters written by leaders in the field of MMPs.  The book focuses on the challenges of understanding the mechanisms substrate degradation by MMPs, as well as how these enzymes are able to degrade large, highly ordered substrates such as collagen. All topics addressed are considered in relation to disease progression including roles in cancer metastasis, rheumatoid arthritis and other inflammatory diseases.

The text first provides an overview of MMPs, focusing on the history, the development and failures of small molecule inhibitors in clinical trials, and work with TIMPS, the endogenous inhibitors of MMPs. These introductory chapters establish the foundation for later discussion of the recent progress on the design of different types of inhibitors, including novel antibody based therapeutics. The following section emphasizes research using novel methods to further the study of the MMPs. The third and final section focuses on in vivo research, particularly with respect to cancer models, degradation of the extracellular matrix, and MMP involvement in other disease states.

Written and edited by leaders in the field, Matrix Metalloproteinase Biology addresses the rapidly growth in MMP research, and will be an invaluable resource to advanced students and researchers studying cell and molecular biology.

Leseprobe

Table of Contents

Cover

Title Page

Copyright

List of Contributors

Chapter 1: Matrix Metalloproteinases: From Structure to Function

1.1 Introduction

1.2 Structures of MMPs

1.3 Overview of MMP substrate specificity

1.4 Selective mechanisms of action

Acknowledgments

References

Chapter 2: Dynamics and Mechanism of Substrate Recognition by Matrix Metalloproteases

2.1 Introduction

2.2 Conformational flexibility of MMPs is inexorably linked to collagen proteolysis

2.3 Dynamics of MMP-2 and MMP-9 interaction with gelatin

2.4 Surface diffusion: a common mechanism for substrate interaction adapted by MMP-2 and MMP-9

2.5 Dynamics of MMP interaction with collagen fibrils

2.6 Mechanism of interaction of MMP-1, MMP-2, MMP-9, and MMP-14 with collagen substrate involves surface diffusion

2.7 Mechanism of MMP-1 diffusion on native collagen fibrils

2.8 Triple helical collagen cleavage–diffusion coupling

2.9 Conclusions

References

Chapter 3: Matrix Metalloproteinases: From Structure to Function

3.1 Introduction

3.2 Classification and structural features

3.3 Catalytic mechanism

3.4 Intra- and inter-domain flexibility

3.5 Elastin and collagen degradation

References

Chapter 4: Metzincin Modulators

4.1 Inhibitors

Summary and future directions

References

Chapter 5: Therapeutics Targeting Matrix Metalloproteinases

5.1 Introduction

5.2 Peptidomimetic MMP inhibitors

5.3 Structure-based MMPI drug design

5.4 Mechanism-based MMPI design

5.5 Allosteric MMPI design

5.6 Macromolecular MMP inhibitors

5.7 Chemically-Modified tetracyclines

5.8 Alternative approaches

5.9 MMPs as anti-targets

5.10 Conclusions

References

Chapter 6: Matrix Metalloproteinase Modification of Extracellular Matrix-Mediated Signaling

6.1 Introduction

6.2 The extracellular matrix as a source for signaling ligands

6.3 ECM and mechanosensory signal transduction

6.4 Matrix remodeling and modification of mechano-sensory signaling

6.5 Conclusions and future directions

References

Chapter 7: Meprin and ADAM Metalloproteases: Two Sides of the Same Coin?

7.1 Introduction

7.2 Meprin metalloproteases

7.3 Structure of meprin α and meprin β

7.4 Proteomics for the identification of meprin substrates

7.5 Meprins in health and disease

7.6 Proteolytic back-and-forth of meprins and ADAMs

7.7 Collagen fibril formation

7.8 Angiogenesis and cancer

7.9 Inflammation

7.10 ADAM Proteases

7.11 The ADAM family of proteases

7.12 Orchestration of different pathways by ADAM17

7.13 Regulation of ADAM17 activity

7.14 Role of ADAM17

in vivo

7.15 Role of ADAM17 in humans

References

Chapter 8: Subtracting Matrix out of the Equation: New Key Roles of Matrix Metalloproteinases in Innate Immunity and Disease

8.1 The tale of a Frog's tail

8.2 The MMP family

8.3 Making the cut as immune regulators

8.4 Enter the “omics” era: genomics, proteomics and degradomics

8.5 ECM versus Non-ECM MMP substrates

8.6 Moonlighting protein substrates: intracellular proteins cleaved outside the cell

8.7 Intracellular protein substrates cleaved inside the cell by MMPs

8.8 Non-proteolytic roles of MMPs: missed in the myth?

8.9 The fairy TAIL of a frog Has an unexpected ending

Acknowledgements

References

Chapter 9: MMPs: From Genomics to Degradomics

9.1 Introduction

9.2 Degradomics – an overview

9.3 Conclusions

Acknowledgments

References

Chapter 10: MMPs in Biology and Medicine

10.1 Introduction

10.2 Functional roles of MMPs and ADAMs

10.3 MMPs as diagnostic and prognostic biomarkers of cancer

10.4 MMPs/ADAMs as diagnostic and prognostic biomarkers for non-neoplastic diseases

10.5 MMPs as biomarkers of therapeutic efficacy

10.6 MMP-specific molecular imaging for noninvasive disease detection

10.7 Conclusions

Acknowledgments

References

Index

End User License Agreement

Pages

ix

x

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

103

104

105

106

107

108

109

110

111

112

113

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

215

216

Guide

Cover

Table of Contents

Begin Reading

List of Illustrations

Chapter 1: Matrix Metalloproteinases: From Structure to Function

Figure 1.1 General domain organization of MMPs.

Figure 1.2 Typical structure of the CAT domain of MMPs. Characteristic structural elements are highlighted with arrows. Figure generated using MMP-8 structure (PDB 2OY2) [4].

Figure 1.3 Mechanism of proteolysis catalyzed by MMPs. (Figure prepared based on mechanism proposed by Lovejoy et al. [5]).

Figure 1.4 Fibronectin type II-like module structure and organization. (a) General orientation of FN2 modules of MMP-2. (b) Top view of FN2 modules. Figure prepared using MMP-2 structure (PDB 1CK7) [8].

Figure 1.5 Comparison of MMP linker lengths and sequences. Table was generated after alignment of human MMPs using sequences from the Uniprot database [19] and SeaView 4 [20] and Jalview [21] programs.

Figure 1.6 Typical structure of the HPX domain. The propeller-like structure is composed of four blades (I-IV) and stabilized by a single disulfide bridge, designated with an arrow. In the central tunnel, up to four different ions have been identified (here Ca

2+

is orange and Cl

−

is yellow). This Figure was generated using the HPX domain of MT1-MMP (PDB 3C7X) [23].

Figure 1.7 Structure of TM domain and cytoplasmic tail (residues 518–582) of human MT1-MMP generated by homology modeling [50, 51].

Figure 1.8 Mechanism of the initial steps of collagenolysis. (a) Closed (left) and open/extended (right) forms of MMP-1 in equilibrium. (b) The extended protein binds THP chains 1T-2T at Val23-Leu26 with the HPX domain and the residues around the cleavage site with the CAT domain. The THP is still in a compact conformation. (c) Closed FL-MMP-1 interacting with the released 1T chain (in magenta). (d) After hydrolysis, both peptide fragments (C- and N-terminal) are initially bound to the active site. (e) The C-terminal region of the N-terminal peptide fragment is released. (Reprinted with permission from [16]. Copyright (2012) American Chemical Society).

Chapter 3: Matrix Metalloproteinases: From Structure to Function

Figure 3.1 Structural organization of human MMPs with the corresponding linker length.

Figure 3.2 Ribbon representation of the inactive human proMMP-2. The prodomain, catalytic domain, fibronectin domains, and hemopexin domain are shown in yellow, red, blue, and orange, respectively. The catalytic and the structural zinc ions are represented as magenta spheres and calcium ions as green spheres.

Figure 3.3 Stereo view of the catalytic (a) and hemopexin-like (b) domains of MMP-12 represented as ribbons. In the catalytic domain α-helices, β-strands, and loops are organized in a L1-β1-L2-α1-L3-β2-L4-β3-L5-β4-L6-β5-L7-α2-L8-α3 topology. The catalytic (Zn1) and the structural (Zn2) zinc ions are shown as magenta spheres of arbitrary radius. The first (Ca1), the second (Ca2), the third (Ca3) calcium ions and the calcium ion in the hemopexin-like domain are shown as blue spheres. The three histidines that bind the catalytic zinc and the catalytically relevant glutamate are represented as cyan sticks. Strands and helices are labeled with numbers and greek letters. The hemopexin-like domain is constituted by four β-sheets of four antiparallel β-strands that folds in a symmetric four-blade propeller [53, 67]. The central deep tunnel filled by water molecules is closed by a calcium ion (Ca4) at the bottom.

Figure 3.4 Proteolysis of the collagen fragment ProGlnGlyIleAlaGly by MMP-12. (a) Active site of the free enzyme before the interaction with the substrate. (b) Calculated model of the gemdiol intermediate. (c) X-ray structure of the two-peptide intermediate obtained by soaking the active uninhibited MMP-12 crystals with the collagen peptide. (d) Adduct of MMP-12 with the peptide fragment IleAlaGly after the release of the C-terminal fragment.

Figure 3.5 Pattern of residues interacting with elastin fragments in the isolated catalytic and hemopexin-like domains (a) and in the full length protein (b). The larger effects observed in the full length protein suggest cooperativity of the two domains in binding of elastin fragments.

Figure 3.6 Closed (left) and open/extended (right) forms of FL-MMP-1 in equilibrium. The catalytic zinc ion is represented as a magenta sphere.

Figure 3.7 Proposed mechanism for collagenolysis. In panel (a), from the top (the experimentally-driven docked complex between FL-MMP-1 and THP) to the bottom (the unwounded THP bound to the X-ray closed conformation of FL-MMP-1) the intermediate and energetically possible structures generated by HADDOCK [112] to provide a smooth conformational transition between the initial and final states. In panel (b), starting from the experimentally-driven docked complex between FL-MMP-1 and THP (top), the closed FL-MMP-1 interacting with the released 1T chain (in red), the hydrolysis of the 1T chain with both peptide fragments still in place, and the complex with the C-terminal region of the N-terminal peptide released from the active site (bottom).

Figure 3.8 Interaction of FL-MMP-1 with the substrate. In the panel, from the top to the bottom: (a) structure with the highest MO, (b–c) two morphing intermediate steps, (d)the experimentally-driven docked complex where the hemopexin-like domain and the catalytic domain bind the triple-helical collagen. The structure with the highest MO e morphing structures were aligned to the hemopexin-like domain of the docked complex. FL-MMP-1 and THP are represented as white and yellow surfaces, respectively. In blue is the MMP consensus sequence HE

XX

H

XX

G

XX

H and the cleavage site (

Gly-Ile

) in the first chain of THP. The catalytic zinc ion is represented as an orange sphere. To facilitate visualizing the movement of the catalytic domain with respect to the hemopexin-like domain, the blue and red arrows indicate the direction of helices hA and hC of the catalytic domain defined by residues 130–141 and 250–258, respectively.

Chapter 4: Metzincin Modulators

Figure 4.1 Schematic representation of the ADAM17 proteins used in the present study. (a) Full-length ADAM17 (amino acids 1–824). (b) Soluble forms of the cysteine-rich domain (DE, amino acids 476–642), the disintegrin-like domain (D, amino acids 476–580) and the membrane proximal cysteine-rich extension (E, amino acids 581–642) expressed in

E

.

coli

. (c) ADAM17_DE consisting of the cysteine-rich domain (DE) followed by the transmembrane region (TM) of human ADAM17 (amino acids 475–694). Pro, pro-domain; CD, catalytic domain; TM, transmembrane region; IR, intracellular region. (Reproduced with permission from Yamamoto K., Trad A., Baumgart A., Huske L., Lorenzen I., Chalaris A., Grotzinger J., Dechow T., Scheller J., and Rose-John S. (2012) A novel bispecific single-chain antibody for ADAM17 and CD3 induces T-cell-mediated lysis of prostate cancer cells.

Biochem J

, 445 (1) 135-144. © the Biochemical Society).

Figure 4.2 Design and expression of ADAM17-specific A300E-BiTE. Schematic representation of generation of A300E-BiTE. To identify cDNA sequences of V

H

and V

L

of mouse monoclonal antibody, ten primer sets and seven primer sets were used to amplify V

H

and V

L

cDNA. After analysis of DNA sequences from V

H

and V

L

fragments the construct of A300E-scFv and BiTE were introduced into pET23a and pcDNA3.1 vectors respectively. Linker indicates flexible linker (Gly4Ser). The c-Myc and His6 tags are fused for detection and purification respectively. (Reproduced with permission from Yamamoto K., Trad A., Baumgart A., Huske L., Lorenzen I., Chalaris A., Grotzinger J., Dechow T., Scheller J., and Rose-John S. (2012) A novel bispecific single-chain antibody for ADAM17 and CD3 induces T-cell-mediated lysis of prostate cancer cells.

Biochem J

, 445 (1) 135–144. © the Biochemical Society).

Figure 4.3 Experimental overview. (a) The human TACE ectodomain consists of an amino-terminal metalloprotease catalytic domain (light red) and a carboxyl-terminal noncatalytic Dis-Cys domain (light blue) (I-TASSER model). We exploited this multidomain topology to develop a truly specific ADAM inhibitor using two-step antibody phage display. (b) (i) First, the catalytic site of TACE ectodomain was blocked during primary antibody phage-display selections using the small-molecule inhibitor CT1746. This prevented the selection of antibodies with catalytic-cleft epitopes that could cross-react with non-target metalloproteases. (ii) Primary screening revealed the inhibitory scFv antibody clone D1. This scFv bound specifically to the TACE Dis-Cys domain through its variable heavy (V

H

) domain. (iii) A D1-V

H

-bias antibody phage display library was produced to introduce new variable light (neo-V

L

) chains while maintaining the TACE specificity provided by the D1-V

H

. Secondary selections were performed in the absence of CT1746 in order to provide the neo-V

L

chains with uninterrupted access to the TACE catalytic site. (iv) Secondary screening identified several neo-VL scFvs capable of binding the isolated TACE catalytic domain. Due to Dis-Cys domain binding through the D1-V

H

these “cross-domain” antibodies maintained their strict specificity for TACE. D1-V

H

-neo-V

L

scFv clone A12 (D1(A12)) exhibited the highest affinity for the TACE ectodomain and is the most selectively potent cell-surface ADAM inhibitor ever described. (Reproduced with permission from Tape, C. J., Willems, S. H., Dombernowsky, S. L., Stanley, P. L., Fogarasi, M., Ouwehand, W., McCafferty, J., and Murphy, G. (2011) Cross-domain inhibition of TACE ectodomain

Proc Natl Acad Sci

U S A 108, 5578–5583).

Figure 4.4 Collagen-based, peptidomimetic hydroxamates. (Reproduced with permission from Fisher, J. F., and Mobashery, S. (2006) Recent advances in MMP inhibitor design.

Cancer Metastasis Rev

25, 115–136. Copyright © 2006, Springer).

Figure 4.5 Nomenclature used for enzyme and substrate subsites. The arrow marks the site of protease hydrolysis. (Reproduced with permission from Lauer-Fields, J., Brew, K., Whitehead, J. K., Li, S., Hammer, R. P., and Fields, G. B. (2007) Triple-helical transition state analogues: a new class of selective matrix metalloproteinase inhibitors.

J Am Chem Soc

129, 10408–10417).

Figure 4.6 Sequence of triple-helical peptide containing phosphinate group.

Figure 4.7 A comparison of disulfide topology and sequences of human N-TIMP-1 and sarafotoxin 6b. (Adapted from Lauer-Fields, J. L., Cudic, M., Wei, S., Mari, F., Fields, G. B., and Brew, K. (2007) Engineered sarafotoxins as tissue inhibitor of metalloproteinases-like matrix metalloproteinase inhibitors.

J Biol Chem

282, 26948–26955. Rights holder: AMERICAN SOC FOR BIOCHEMISTRY & MOLECULAR BIOLOGY).

Figure 4.8 Inhibition of MMP-13 by 30 different compounds, as monitored by RP-HPLC and fluorescence spectroscopy. The change in RP-HPLC peak areas or relative fluorescence units for 10 nM MMP-13 hydrolysis of 10 μM fTHP-15 or 5 μM Knight fSSP was monitored at an inhibitor concentration of 100 μM. Assays were performed in triplicate. (Reproduced with permission from Lauer-Fields, J. L., Minond, D., Chase, P. S., Baillargeon, P. E., Saldanha, S. A., Stawikowska, R., Hodder, P., and Fields, G. B. (2009) High throughput screening of potentially selective MMP-13 exosite inhibitors utilizing a triple-helical FRET substrate.

Bioorg Med Chem

17, 990–1005. © PERGAMON).

Figure 4.9 Lineweaver–Burk plot of MMP-13 inhibition of fTHP-15 hydrolysis by compound 20 (a) or 24 (b). (Reproduced with permission from Roth, J., Minond, D., Darout, E., Liu, Q., Lauer, J., Hodder, P., Fields, G. B., and Roush, W. R. (2011) Identification of novel, exosite-binding matrix metalloproteinase-13 inhibitor scaffolds.

Bioorg Med Chem Lett

21, 7180–7184. © PERGAMON).

Figure 4.10 β-Gal-(1→3)-GalNAc (TF antigen) and

N

-acetylglucosamine (GlcNAc) found on TNFα and IL6-R.

Figure 4.11 Results of the pilot “scaffold ranking” screen of TPIMS drug-like library against ADAM10 and 17. Shown is an ADAM10 (a) and ADAM17 (b) screen using glycosylated (red checked bars) and non-glycosylated substrate (blue bars). The arrow indicates library containing potential exosite inhibitors of ADAM17. All assays were performed in triplicate. Activity and selectivity of all libraries were confirmed in reversed-phase HPLC-based assays. (c), basic scaffold of library 1344. (Adapted from Minond, D., Cudic, M., Bionda, N., Giulianotti, M., Maida, L., Houghten, R. A., and Fields, G. B. (2012) Discovery of novel inhibitors of a disintegrin and metalloprotease 17 (ADAM17) using glycosylated and non-glycosylated substrates

J Biol Chem

287, 36473–36487. Rightsholder: AMERICAN SOC FOR BIOCHEMISTRY & MOLECULAR BIOLOGY).

Figure 4.12 Results of the positional scan analysis of library 1344 against ADAM10 and -17. Positional scan of R

1

(a), R

2

(b), R

3

(c), and R

4

(d) defined moieties against ADAM10 (red bars) and ADAM17 (blue bars) using glycosylated substrate. (Adapted from Minond, D., Cudic, M., Bionda, N., Giulianotti, M., Maida, L., Houghten, R. A., and Fields, G. B. (2012) Discovery of novel inhibitors of a disintegrin and metalloprotease 17 (ADAM17) using glycosylated and non-glycosylated substrates.

J Biol Chem

287, 36473–36487. Rightsholder: AMERICAN SOC FOR BIOCHEMISTRY & MOLECULAR BIOLOGY).

Figure 4.13 Results of dose response study of most ADAM17 selective and potent individual compounds. Structures of individual compounds are shown as inserts. (Adapted from Minond, D., Cudic, M., Bionda, N., Giulianotti, M., Maida, L., Houghten, R. A., and Fields, G. B. (2012) Discovery of novel inhibitors of a disintegrin and metalloprotease 17 (ADAM17) using glycosylated and non-glycosylated substrates.

J Biol Chem

287, 36473–36487. Rightsholder: AMERICAN SOC FOR BIOCHEMISTRY & MOLECULAR BIOLOGY).

Figure 4.14 Characterization of mechanism of inhibition of ADAM17 catalytic domain and ectodomain by compound #15. (a) Yonetani-Theorell plot of glycosylated substrate hydrolysis by ADAM17 in the presence of AHA and compound #15. Note the non-parallel lines of best fit indicating mutually non-exclusive binding by two inhibitors. Structure of N-hydroxyacetamide (AHA) shown as insert. (b) Lineweaver-Burke plot of glycosylated substrate hydrolysis by ADAM17 in the presence of compound #15. Dose response study of inhibition of ADAM17 catalytic domain and ectodomain by (c) AHA and (d) compound #15. (Adapted from Minond, D., Cudic, M., Bionda, N., Giulianotti, M., Maida, L., Houghten, R. A., and Fields, G. B. (2012) Discovery of novel inhibitors of a disintegrin and metalloprotease 17 (ADAM17) using glycosylated and non-glycosylated substrates

J Biol Chem

287, 36473–36487. Rightsholder: AMERICAN SOC FOR BIOCHEMISTRY & MOLECULAR BIOLOGY).

Chapter 7: Meprin and ADAM Metalloproteases: Two Sides of the Same Coin?

Figure 7.1 Domain structure and function of meprin α, meprin β and ADAM17. The functions of the domains are indicated in the figure.

Figure 7.2 Physiological functions of ADAM17, meprin α, and meprin β. Both proteases orchestrate different processes in development and during the activation of the immune system.

Chapter 8: Subtracting Matrix out of the Equation: New Key Roles of Matrix Metalloproteinases in Innate Immunity and Disease

Figure 8.1 (a) All 773 reported human MMP substrates distributed for each of the 23 human MMPs. (b) All 773 reported human MMP substrates: the ECM substrates are shown in blue and the non-ECM substrates are shown in green.

Figure 8.2 (a) Gene Ontology (GO) terms enrichment of all 246 reported non-ECM human MMP substrates. (b) Pathway enrichment analysis of the 246 reported non-ECM human MMP substrates.

Chapter 9: MMPs: From Genomics to Degradomics

Figure 9.1 Biological activity of an individual MMP within a local tumor microenvironment. MMPs are central regulators of tumor extracellular environment in terms of both extracellular matrix (ECM) turnover and the signaling milieu controlling cell function. Proteolytic balance is tightly controlled at the protein level by activation of individual MMPs from inactive zymogens (proMMPs) and by the binding of inhibitors. Upon activation, each MMP mediates specific effects on the local microenvironment, dependent on its substrate repertoire. These effects derive either down-stream of the MMPs individual ECM substrates or via activation and/or inactivation of signaling molecules, such as cytokines and growth factors. In consequence, the proteolytic balance influences gene expression and behavior of cancer as well as stromal cells, which in turn are major determinants of the proteolytic balance, the local ECM composition and signaling milieu.

Figure 9.2 Local proteolytic network consisting of interrelated protease systems. The biological effects of an individual MMP (as depicted in Figure 9.1.) are embedded in the interaction with other MMPs that exhibit partially over-lapping but also distinct substrate specificities, forming the local MMP system. Individual proteolytic systems are interrelated, mutually influencing each other in the modulation of protease activity, substrate availability, and action within a tissue.

Figure 9.3 Interconnectivity of local proteolytic networks within an organism. Local proteolytic tissue networks (as depicted in Figure 9.2.) within an organism communicate with each other over a distance via the circulatory system, forming the proteolytic internet. Information is transmitted systemically via up-regulation or down-regulation of soluble factors such as cytokines, hormones, as well as secreted protease inhibitors such as TIMP-1 and PAI-1. The status of homeostasis in the regional proteolytic network of an organ is thereby reported to other tissues in the body. Accordingly, any manipulation of a single member of the proteolytic network results in a re-adaptation. This process is subject to a multitude of net effects that altogether impact on the formation of a new homeostasis, which determines the susceptibility of the organism to disease.

Figure 9.4 Degradomes and degradomics approaches. The transcriptional degradome defines the translational degradome, of which the activity degradome represents the active proteases. Individual active proteases give rise to partial overlapping substrate degradomes. All together, they define the proteolytic potential of a system. For each level of complexity powerful degradomics techniques have been developed. CLIP-CHIP

TM

, Hu/Mu ProtIn, dedicated protease microarrays; SRM, selected reaction monitoring; STEP, STandard of Expressed Protein peptides; ABPs, activity-based probes; PSPs, proteolytic signature peptides; TAILS, terminal amine isotopic labeling of substrates; COFRADIC, combined diagonal fractional chromatography; Subtiligase, engineered peptide ligase for modification of protein N termini.

Figure 9.5 Integrated strategy to elucidate physiological MMP substrates. Multiple candidate substrates from unbiased

in vitro

and cell-based experiments serve as templates for the development of targeted SRM assays that are applied in appropriate

in vivo

models. KO, knockout; WT, wild-type; SRM, selected reaction monitoring.

Chapter 10: MMPs in Biology and Medicine

Figure 10.1 Basic domain structure of MMP and ADAM family members. The characteristic domain structure of MMPs includes (i) the signal peptide domain, which guides the enzyme into the rough endoplasmic reticulum during synthesis, (ii) the propeptide domain, which sustains the latency of these enzymes until it is removed or disrupted, (iii) the catalytic domain, which houses the highly conserved Zn

2+

binding region and is responsible for enzyme activity, (iv) the hemopexin domain, which determines the substrate specificity of MMPs, and (v) a small hinge region, which enables the hemopexin region to present substrate to the active core of the catalytic domain. The subfamily of membrane-type MMPs (MT-MMPs) possesses an additional transmembrane domain and an intracellular domain. MMPs are produced in a latent form and most are activated by extracellular proteolytic cleavage of the propeptide. MT-MMPs also contain a cleavage site for furin proteases, providing the basis for furin-dependent activation of latent MT-MMPs prior to secretion. ADAMs are multidomain proteins composed of propeptide, metalloprotease, disintegrin-like, cysteine-rich, and epidermal growth factor-like domains. Membrane-anchored ADAMs contain a transmembrane and cytoplasmic domain. ADAMTSs have at least one Thrombospondin type I Sequence Repeat (TSR) motif [1]. (Reprinted with permission © (2009) American Society of Clinical Oncology. All rights reserved).

Figure 10.2 Multiple functions of MMPs in cancer progression. (Counterclockwise) MMPs degrade components of ECM, facilitating angiogenesis, tumor cell invasion and metastasis. MMPs modulate the interactions between tumor cells by cleaving E-cadherin, and between tumor cells and ECM by processing integrins, which also enhances the invasiveness of tumor cells. MMPs also process and activate signaling molecules, including growth factors and cytokines, making these factors more accessible to target cells by either liberating them from the ECM (e.g., VEGF and bFGF) and inhibitory complexes (e.g., TGF-β), or by shedding them from cell surface (e.g., HB-EGF) [1]. (Reprinted with permission © (2009) American Society of Clinical Oncology. All rights reserved).

List of Tables

Chapter 2: Dynamics and Mechanism of Substrate Recognition by Matrix Metalloproteases

Table 2.1 Motion parameters of MMPs on substrate surfaces.

Chapter 4: Metzincin Modulators

Table 4.1 Sequences of sarafotoxin analogs.

Table 4.2 Apparent Ki values of Srt variants for different MMPs (μM).

Table 4.3 Amino acid residues encountered in positions 16–20 of TIMPs used to create a combinatorial pool for sarafotoxin S4 engineering.

Table 4.4 Inhibition of MMP-1, MMP-2, MMP-8, MMP-9, MMP-13, and MMP-14 activity by compounds 4, 20, and 24.

Table 4.5 Kinetic parameters for ADAM hydrolysis of glycosylated and non-glycosylated substrates.

Table 4.6 IC

50

values for phage-displayed TIMP-2 variants from the screening of libraries that mutate three regions on TIMP-2.

Chapter 8: Subtracting Matrix out of the Equation: New Key Roles of Matrix Metalloproteinases in Innate Immunity and Disease

Table 8.1 MMP-truncation products of CC chemokines.

Table 8.2 Reported ECM and non-ECM substrates for all 24 human MMPs taken from TopFIND [39].

Table 8.3 Non-proteolytic roles of MMPs.

Chapter 10: MMPs in Biology and Medicine

Table 10.1 Candidate MMP and ADAM biomarkers of cancer.

Table 10.2 Candidate MMP and ADAM biomarkers of non-malignant diseases.

Table 10.3 MMPs/TIMPs as biomarkers for therapeutic efficacy in clinical trials.

Matrix Metalloproteinase Biology

Edited by

Irit Sagi

Professor of Biological Chemistry and Biophysics, Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel

Jean P. Gaffney

Assistant Professor of Chemistry at Baruch College, Department of Natural Sciences, City University of New York, New York, NY, USA

Copyright © 2015 by Wiley-Blackwell. All rights reserved

Published by John Wiley & Sons, Inc., Hoboken, New Jersey

Published simultaneously in Canada

No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, [phone], fax [phone], or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, [phone], fax [phone], or online at http://www.wiley.com/go/permission.

Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.

For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at [phone], outside the United States at [phone] or fax [phone].

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com.

Library of Congress Cataloging-in-Publication Data:

Matrix metalloproteinase biology / edited by Irit Sagi and Jean P. Gaffney.

p. ; cm.

Includes bibliographical references and index.

ISBN 978-1-118-77232-4 (cloth)

I. Sagi, Irit, editor. II. Gaffney, Jean P., editor.

[DNLM: 1. Matrix Metalloproteinases. QU 136]

QP552.M47

572′.696–dc23

2015000037

List of Contributors

Christoph Becker-Pauly

Biochemisches Institut

Medizinische Fakultät

Christian-Albrechts-Universität zu Kiel

Kiel, Germany

Jian Cao

Department of Medicine

State University of New York at Stony Brook

Stony Brook, NY, USA

Jillian Cathcart

Department of Medicine

State University of New York at

Stony Brook Stony Brook, NY, USA

Ivan E. Collier

Departments of Medicine

Division of Dermatology

Washington University School of Medicine

St. Louis, MO, USA

Howard C. Crawford

Department of Cancer Biology

Mayo Clinic

Jacksonville, FL, USA

Antoine Dufour

Department of Oral Biological & Medical

Sciences and Department of Biochemistry and Molecular Biology

Centre for Blood

Research University of British Columbia

Vancouver, BC, Canada

Gregg B. Fields

Torrey Pines Research Institute for

Molecular Studies

Port St. Lucie, FL, USA

Marco Fragai

Magnetic Resonance Center and Department of Chemistry

University of Florence

Florence, Italy

Gregory I. Goldberg

Departments of Medicine

Biochemistry and Molecular Biophysics

Washington University School of Medicine

St. Louis, MO, USA

Barbara Grünwald

Institute for Experimental Oncology and Therapy Research

Klinikum rechts der Isar

Technische Universität München

Munich, Germany

Di Jia

Vascular Biology Program and Department of Surgery

Boston Children's Hospital and Harvard

Medical School

Boston, MA, USA

Ulrich auf dem Keller

Department of Biology

Institute of Molecular Health Sciences

ETH Zurich,

Zurich, Switzerland

Achim Krüger

Institute for Experimental Oncology and Therapy Research

Klinikum rechts der Isar

Technische Universität München

Munich, Germany

Claudio Luchinat

Magnetic Resonance Center and Department of Chemistry

University of Florence

Florence, Italy

Dmitriy Minond

Cancer Research

Torrey Pines Research Institute for Molecular Studies

Port St. Lucie, FL, USA

Marsha A. Moses

Vascular Biology Program and Department of Surgery

Boston Children's Hospital and Harvard

Medical School

Boston, MA, USA

Christopher M. Overall

Department of Oral Biological & Medical

Sciences and Department of Biochemistry and Molecular Biology

Centre for Blood Research

University of British Columbia

Vancouver, BC, Canada

Ashleigh Pulkoski-Gross

Department of Medicine

State University of New York at Stony Brook

Stony Brook, NY, USA

Stefan Rose-John

Biochemisches Institut

Medizinische Fakultät

Christian-Albrechts-Universität zu Kiel

Kiel, Germany

Roopali Roy

Vascular Biology Program and Department of Surgery

Boston Children's Hospital and Harvard

Medical School

Boston, MA, USA

Pascal Schlage

Department of Biology

Institute of Molecular Health Sciences

ETH Zurich, Zurich, Switzerland

M. Sharon Stack

Harper Cancer Research Institute

University of Notre Dame

South Bend, IN, USA

Maciej J. Stawikowski

Torrey Pines Research Institute

Torrey Pines, FL, USA

Stanley Zucker

VA Medical Center

Northport, NY, USA

Chapter 1Matrix Metalloproteinases: From Structure to Function

Maciej J. Stawikowski1 and Gregg B. Fields2

Departments of Chemistry and Biology, Torrey Pines Institute for Molecular Studies, Port St. Lucie, USA

1.1 Introduction

Members of the matrix metalloproteinase (MMP) family are known to catalyze the hydrolysis of a great variety of biological macromolecules. Proteomic approaches have significantly expanded the number of known MMP substrates. However, the mechanisms by which macromolecular substrates are processed have often proved elusive. X-ray crystallography and NMR spectroscopy have yielded detailed information on structures of MMP domains and, in a few cases, full-length MMPs. As structures of MMPs and their substrates have been reported, examination of MMP•substrate complexes has provided insight into mechanisms of action. We examine the structures of MMPs and their substrates and consider how the various structural elements of MMPs contribute to the hydrolysis of biological macromolecules.