Molecular cloning and characterization of Ac-TMP-2, a tissue inhibitor of metalloproteinase secreted by adult Ancylostoma caninum☆

Zhan, Bin; Gupta, Richi; Wong, Susan; Bier, Stacia; Jiang, Desheng; Goud, Gaddam Narsa; Hotez, Peter J.

doi:10.1016/j.molbiopara.2008.08.008

Cited by 14 publications

(24 citation statements)

References 41 publications

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“…96,97 Adult hookworms have been shown to secrete TIMP homologues or netrin-like proteins that might modulate inflammatory responses, specifically at the site of attachment to the intestinal mucosa. Ac-TMP-1 and Ac-TMP-2 are TIMPs that have been identified from ES products of adult A caninum, 98,99 and Ac-TMP-2 has been localized to the esophageal glands of the parasite, 99 supporting the hypothesis that Ac-TMPs are released from the worm to act at the attachment site. Ac-TMP-1 is one of the most abundant proteins secreted by A caninum, with a release rate of 40 ng/h, 98 and although no MMP inhibitory function has been reported for this molecule, it has been shown to inhibit an endogenous metalloprotease, Ac-MTP-1.…”

Section: Molecular Mechanisms Associated With Host Defense and Immunementioning

confidence: 74%

Molecular mechanisms of hookworm disease: Stealth, virulence, and vaccines

Pearson¹,

Tribolet²,

Cantacessi³

et al. 2012

Journal of Allergy and Clinical Immunology

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Section: Molecular Mechanisms Associated With Host Defense and Immunementioning

confidence: 74%

Molecular mechanisms of hookworm disease: Stealth, virulence, and vaccines

Pearson¹,

Tribolet²,

Cantacessi³

et al. 2012

Journal of Allergy and Clinical Immunology

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“…Although the rAceES-2 used for structure determination had three nonnative N-terminal amino acids left after removal of the purification, a rAceES-2 construct with an intact native N-terminus also failed to inhibit human MMPs. By comparison, the dog hookworm MMP inhibitor A. caninum TIMP-2 (AcTMP-2), which does contain an N-terminal Cys-X-Cys motif, displayed submaximal (56-68% inhibition) inhibition of three of the ten human MMPs tested in an identical assay 24. We cannot rule out the possibility that AceES-2 specifically inhibits another mammalian MMP or protease that has not yet been tested.…”

mentioning

confidence: 97%

“…Beginning soon after infection, hookworms produce a number of excretory-secretory (ES) proteins that are thought to promote survival within the mammalian host, including inhibitors of thrombosis14,15,16 and complement,17 as well as fatty acid binding proteins18,19 and a small kunitz type inhibitor of host pancreatic enzymes 20. Hookworms also produce proteins that modulate host immune cells, including an inhibitor of neutrophils,21 an orthologue of the mammalian cytokine macrophage migration inhibitory factor (MIF),22 and two putative Tissue Inhibitors of Metalloproteases (TIMPs) 23,24. Hookworm ES proteins are believed to function together to facilitate blood feeding, digest tissue and prevent detection or damage by host immune factors at the site of intestinal attachment.…”

mentioning

confidence: 99%

“…Several small proteins from the nematode species A. duodenale, A. caninum, A. ceylanicum, Heterodera glycines and Caenorhabditis elegans have been annotated as TIMPs or NTR proteins 24,41,46,47. Since AceES-2 resembles the NTR domain of human TIMPs, we sought to align the sequences of AceES-2 with those of annotated nematode TIMPs and NTR proteins.…”

mentioning

confidence: 99%

“…For example, human TIMP-1 and TIMP-2 exhibit growth factor-like activity and can inhibit angiogenesis 48. In the case of hookworm proteins, injection of the recombinant AcTMP-1 into mice modulates the function of dendritic cells by inducing the expression of IL-10 and TGF-β and decreasing the expression of MHC molecules 23,24. These combined effects lead to the development of anti-inflammatory responses from CD4+ and CD8+ T cells and the suppression of proliferation responses in vitro.…”

mentioning

confidence: 99%

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Ancylostoma ceylanicum Excretory–Secretory Protein 2 Adopts a Netrin-Like Fold and Defines a Novel Family of Nematode Proteins

Kucera

Harrison

Cappello

et al. 2011

Journal of Molecular Biology

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Hookworms are human parasites that have devastating effects on global health, particularly in underdeveloped countries. Ancylostoma ceylanicum infects humans and animals, making it a useful model organism to study disease pathogenesis. A. ceylanicum excretory-secretory protein 2 (AceES-2), a highly immunoreactive molecule secreted by adult worms at the site of intestinal attachment, is partially protective when administered as a mucosal vaccine against hookworm anemia. The crystal structure of AceES-2 determined at 1.75 Å resolution shows that AceES-2 adopts a netrin-like fold similar to those found in tissue inhibitors of matrix metalloproteases (TIMPs), and in complement factors C3 and C5. However, recombinant AceES-2 does not significantly inhibit the ten most abundant human matrix metalloproteases, or complementmediated cell lysis. The presence of a highly acidic surface on AceES-2 suggests that it may function as a cytokine decoy receptor. Several small nematode proteins that have been annotated as TIMPs or netrin domain-containing proteins display sequence homology in structurally important regions of AceES-2's netrin-like fold. Together, our results suggest that AceES-2 defines a novel family of nematode netrin-like proteins, which may function to modulate the host immune response to hookworm and other parasites.

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The tissue inhibitors of metalloproteinases (TIMPs): An ancient family with structural and functional diversity

Brew

Nagase

2010

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

1,136

1,097

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Tissue inhibitors of metalloproteinases (TIMPs) are widely distributed in the animal kingdom and the human genome contains four paralogous genes encoding TIMPs 1 to 4. TIMPs were originally characterized as inhibitors of matrix metalloproteinases (MMPs), but their range of activities has now been found to be broader as it includes the inhibition of several of the disintegrin-metalloproteinases, ADAMs and ADAMTSs. TIMPs are therefore key regulators of the metalloproteinases that degrade the extracellular matrix and shed cell surface molecules. Structural studies of TIMP–MMP complexes have elucidated the inhibition mechanism of TIMPs and the multiple sites through which they interact with target enzymes, allowing the generation of TIMP variants that selectively inhibit different groups of metalloproteinases. Engineering such variants is complicated by the fact that TIMPs can undergo changes in molecular dynamics induced by their interactions with proteases. TIMPs also have biological activities that are independent of metalloproteinases; these include effects on cell growth and differentiation, cell migration, anti-angiogenesis, anti- and pro-apoptosis, and synaptic plasticity. Receptors responsible for some of these activities have been identified and their signaling pathways have been investigated. A series of studies using mice with specific TIMP gene deletions has illuminated the importance of these molecules in biology and pathology.

show abstract

Molecular cloning and characterization of Ac-TMP-2, a tissue inhibitor of metalloproteinase secreted by adult Ancylostoma caninum☆

Cited by 14 publications

References 41 publications

Molecular mechanisms of hookworm disease: Stealth, virulence, and vaccines

Molecular mechanisms of hookworm disease: Stealth, virulence, and vaccines

Ancylostoma ceylanicum Excretory–Secretory Protein 2 Adopts a Netrin-Like Fold and Defines a Novel Family of Nematode Proteins

The tissue inhibitors of metalloproteinases (TIMPs): An ancient family with structural and functional diversity

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