Crystal structure of the haemopexin-like C-terminal domain of gelatinase A

Libson, Andrew M.; Gittis, Apostolos G.; Collier, Ivan E.; Marmer, Barry L.; Goldberg, Gregory I.; Lattman, Eaton E.

doi:10.1038/nsb1195-938

Cited by 79 publications

(59 citation statements)

References 13 publications

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“…Last, since inductive coupled plasma mass spectrometry analysis did not measure any Zn 2ϩ ions in the rC domain and 1,10-phenanthroline did not alter the binding properties of the rC domain, these data failed to confirm the presence of a structural Zn 2ϩ ion in the C domain of gelatinase A. Together, these data indicate that the Zn 2ϩ ion modeled in a potential binding site on module IV of the C domain was likely an artifact of crystallization in 150 mM Zn 2ϩ acetate (16). The central Ca 2ϩ ion was also more effective than the disulfide bond in maintaining the structural integrity of the rC domain at 22°C.…”

Section: Ca 2ϩ -Dependent Fibronectin Binding By the Mmp-2 C Domaincontrasting

confidence: 39%

“…In addition, a potential Zn 2ϩ ion was also modeled in hemopexin module IV (16). In support of an important structural and/or functional role for the Ca 2ϩ ions and a possible Zn 2ϩ ion for binding of the rC domain to matrix components, the apo-rC domain was found to have lost binding potential for Affi-Gel heparin (Fig.…”

Section: Ca 2ϩ -Dependent Fibronectin Binding By the Mmp-2 C Domainmentioning

confidence: 99%

“…The recently published three-dimensional structures of the collagenase (18) and gelatinase A C domains (16,17) show a divalent ion, modeled as a Ca 2ϩ ion, in the central channel of the four-bladed ␤-propeller structure, together with either a Na ϩ -Cl Ϫ (16) or Ca 2ϩ -Cl Ϫ (17) ion pair. In addition, a potential Zn 2ϩ ion was also modeled in hemopexin module IV (16).…”

Section: Ca 2ϩ -Dependent Fibronectin Binding By the Mmp-2 C Domainmentioning

confidence: 99%

“…Three-dimensional structure analysis of the C domain of gelatinase A (16,17) and collagenase-1 (18) has revealed a four-bladed ␤-propeller structure with a central Ca 2ϩ ion, a potential Zn 2ϩ ion binding site, and either a Ca 2ϩ -Cl Ϫ (17) or a Na ϩ -Cl Ϫ (16) ion pair in the central channel. Even though the primary and tertiary structures of the MMP C domains share extensive homology, they possess a range of different properties that are MMP-specific.…”

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confidence: 99%

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The Hemopexin-like Domain (C Domain) of Human Gelatinase A (Matrix Metalloproteinase-2) Requires Ca2+ for Fibronectin and Heparin Binding

Wallon¹,

Overall

1997

Journal of Biological Chemistry

106

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The binding properties of the COOH-terminal hemopexin-like domain (C domain) of human gelatinase A (matrix metalloproteinase-2, 72-kDa gelatinase) were investigated to determine whether the C domain has binding affinity for extracellular matrix and basement membrane components. Recombinant C domain (rC domain) (Gly 417 -Cys 631 ) was expressed in Escherichia coli, and the purified protein, identified using two antipeptide antibodies, was determined by electrospray mass spectrometry to have a mass of 25,925 Da, within 0.1 Da of that predicted. As assessed by microwell substrate binding assays and by column affinity chromatography, the matrix proteins laminin, denatured type I collagen, elastin, SPARC (secreted protein that is acidic and rich in cysteine), tenascin, and Matrigel The matrix metalloproteinases (MMPs)1 constitute a family of proteolytic enzymes that together can degrade all components of the extracellular matrix and basement membranes, with each MMP having a distinct substrate preference (1, 2). MMP activity plays a major role during physiological and pathological processes, including embryogenesis, metastasis (3, 4), and inflammatory diseases (5, 6). Most soluble MMPs are secreted as proenzymes and share homologous primary and tertiary structures organized into distinct structural domains, with some differences in domain composition and number (6). These functionally and structurally defined domains include the NH 2 -terminal zymogen domain containing the conserved PRCGXPD motif involved in enzyme latency (7) and a Zn 2ϩ and Ca 2ϩ ion binding catalytic domain. As with other proteinases, the specificity of peptide bond cleavage is determined by the S and SЈ subsite defining amino acid residues (8). Equally important are discrete substrate binding domains, or smaller functional modules, located outside of the active site, which form specialized exosites (9) to target proteolytic activity in tissues and are essential for cleavage of some substrates. Immediately adjacent to the catalytic site in gelatinase A (MMP-2, 72-kDa gelatinase) and gelatinase B (MMP-9, 92-kDa gelatinase) is a fibronectin type II-like module triple repeat (10, 11), which forms a collagen binding domain (CBD) with strong affinity for elastin and denatured types I (12, 13), IV, and V collagens, and native types I, V, and X collagens (9, 13), 2 proteins degraded by the gelatinases. Following the catalytic domain is a variably long linker, which in collagenase-1 (MMP-1) may be important for triple helicase activity (14). The linker connects to the COOH-terminal domain (C domain), comprising four he-

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Section: Ca 2ϩ -Dependent Fibronectin Binding By the Mmp-2 C Domaincontrasting

confidence: 39%

Section: Ca 2ϩ -Dependent Fibronectin Binding By the Mmp-2 C Domainmentioning

confidence: 99%

Section: Ca 2ϩ -Dependent Fibronectin Binding By the Mmp-2 C Domainmentioning

confidence: 99%

mentioning

confidence: 99%

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The Hemopexin-like Domain (C Domain) of Human Gelatinase A (Matrix Metalloproteinase-2) Requires Ca2+ for Fibronectin and Heparin Binding

Wallon¹,

Overall

1997

Journal of Biological Chemistry

106

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“…The hemopexin C domain of MMPs is stabilized by one or two Ca 2ϩ ions in the central pore of the domain (43,44). Fibronectin and heparin binding by the gelatinase A hemopexin C domain is Ca 2ϩ ion-dependent, being disrupted by divalent cation chelators (32).…”

Section: Timp-2 Binding Properties Of Mt1-mmp and Gelatinase Amentioning

confidence: 99%

Domain Interactions in the Gelatinase A·TIMP-2·MT1-MMP Activation Complex

Overall¹,

Tam²,

McQuibban³

et al. 2000

Journal of Biological Chemistry

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Matrix Metalloproteinases

Bode

Maskos

2004

Handbook of Metalloproteins

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The matrix metalloproteinases (MMPs) constitute a family of (in man) 23 different extracellular soluble/cell surface–anchored multidomain zinc endopeptidases, all of which exhibit a common catalytic domain of a metzincin‐like topology, that is, possess a Met‐containing tight turn and carry an extended His‐Glu‐Xaa‐Xaa‐His‐Xaa‐Xaa‐Gly‐Xaa‐Xaa‐His zinc‐binding consensus segment enwrapping the catalytic zinc, with the three histidine imidazole side chains and a nucleophilic water ligating the catalytic zinc, and the glutamine side chain presumably acting as a proton shuttle. The MMPs are involved not only in extracellular matrix degradation but also in a number of other biological processes such as shedding of membrane‐bound growth factor and cytokine precursors, pro‐proteinase activation, or inhibitor inactivation. Normally, their proteolytic activity is precisely regulated by endogenous protein inhibitors, in particular, by the tissue inhibitors of metalloproteinases (TIMPs). Disruption of this balance results in serious diseases such as arthritis, tumor growth, and metastasis, thus rendering the MMPs attractive targets for inhibition therapy. Individual vertebrate MMPs have been named according to their presumed substrates or classified by sequential (chronological) numbers, which run from MMPs 1 to 28. These MMPs are synthesized with an N‐terminal signal sequence, a pro‐domain, and a catalytic domain containing the catalytic zinc, a structural zinc, and up to three calcium ions. Additionally, most MMPs possess a C‐terminal ion containing hemopexin‐like domain, which, in the membrane‐bound MMPs, is followed by a transmembrane helix and a cytoplasmic domain, or a glycosil phosphatidyl inositol (GPI) anchor. This overview presents common and special structural features of the MMPs, in particular of their catalytic domain.

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Crystal structure of the haemopexin-like C-terminal domain of gelatinase A

Abstract: The crystal structure of the haemopexin-like C-terminal domain of gelatinase A reveals that it is a four-bladed beta-propeller protein. The four blades are arranged around a channel-like opening in which Ca2+ and a Na-Cl+ ion pair are bound.

Cited by 79 publications

References 13 publications

The Hemopexin-like Domain (C Domain) of Human Gelatinase A (Matrix Metalloproteinase-2) Requires Ca2+ for Fibronectin and Heparin Binding

The Hemopexin-like Domain (C Domain) of Human Gelatinase A (Matrix Metalloproteinase-2) Requires Ca2+ for Fibronectin and Heparin Binding

Domain Interactions in the Gelatinase A·TIMP-2·MT1-MMP Activation Complex

Matrix Metalloproteinases

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