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Special Issue "Disintegrins: Structure-Function and Translational Potential"

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A special issue of Toxins (ISSN 2072-6651).

Deadline for manuscript submissions: closed (31 August 2011)

Special Issue Editors

Guest Editor
Dr. Frank S. Markland

Department of Biochemistry and Molecular Biology and Comprehensive Cancer, Center, University of Southern California, Keck School of Medicine, Cancer Research Laboratory #106, 1303 N. Mission Road, Los Angeles, CA 90033, USA
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Phone: (323) 224-7981
Fax: +1 323 224 7679
Interests: protein chemistry and structure/ function interrelationships; snake venom components with procoagulant and anticoagulant activities; snake venom platelet aggregation inhibitors (disintegrins); disintegrins as anti-angiogenic agents; disintegrins and wound healing; novel fibrinolytic agents (structure and modeling); thrombolytic therapy
Guest Editor
Dr. Steve Swenson

University of Southern California, Keck School of Medicine, Cancer Research Laboratory, 1303 N. Mission Road, Los Angeles, CA 90033, USA
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Fax: +1 323 224 7679
Guest Editor
Dr. Radu Minea

Department of Biochemistry and Molecular Biology, University of Southern California, Keck School of Medicine, USA
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Special Issue Information

Dear Colleagues,

Disintegrins are interesting molecules isolated as soluble proteins from snake venom. They are isolated from venom of different species in a variety of forms varying from short to medium to long polypeptide chains of approximately 49, 67 and 84 amino acids, respectively. Additionally, they are also found as homodimers or heterodimers with two identical or dissimilar chains, respectively, held together by two disulfide bonds. The structure of several disintegrins has been determined by solution NMR or X-ray crystallography. Interestingly, structural determination of one homodimeric disintegrin revealed that the two Arg-Gly-Asp (RGD) motifs on the individual chains are separated by 69Ǻ. In the monomeric and dimeric disintegrins the RGD motif is exposed in a 13 amino acid flexible loop that enables the disintegrins to bind with high affinity to integrins.

Disintegrins have interesting antagonist/agonist activity towards integrins and this has been taken advantage of in developing anti-tumor and anti-angiogenic strategies for the use of disintegrins. In animal models of breast, ovarian and prostate cancer and glioma, disintegrins have shown portent anti-tumor activity and studies are also underway to use disintegrins as imaging agents for cancer diagnostic purposes as well.

Another class of disintegrin-containing proteins is the ADAM (A Disintegrin And Metalloproteinase) family. These proteins, which represent the only mammalian proteins known to contain a disintegrin domain, are transmembrane proteins. The extracellular disintegrin domain may bind to integrins to facilitate metalloproteinase catalyzed events.

Dr. Frank S. Markland
Dr. Radu Minea
Dr. Steve Swenson
Guest Editors

Keywords

  • cancer
  • angiogenesis
  • snake venom
  • ADAM
  • integrin
  • disintegrin
  • signal transduction pathways
  • clinical translation

Published Papers (3 papers)

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Review

Open AccessReview Disintegrins from Hematophagous Sources
Toxins 2012, 4(5), 296-322; doi:10.3390/toxins4050296
Received: 23 February 2012 / Revised: 12 April 2012 / Accepted: 13 April 2012 / Published: 26 April 2012
Cited by 8 | PDF Full-text (2578 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Bloodsucking arthropods are a rich source of salivary molecules (sialogenins) which inhibit platelet aggregation, neutrophil function and angiogenesis. Here we review the literature on salivary disintegrins and their targets. Disintegrins were first discovered in snake venoms, and were instrumental in our understanding of
[...] Read more.
Bloodsucking arthropods are a rich source of salivary molecules (sialogenins) which inhibit platelet aggregation, neutrophil function and angiogenesis. Here we review the literature on salivary disintegrins and their targets. Disintegrins were first discovered in snake venoms, and were instrumental in our understanding of integrin function and also for the development of anti-thrombotic drugs. In hematophagous animals, most disintegrins described so far have been discovered in the salivary gland of ticks and leeches. A limited number have also been found in hookworms and horseflies, and none identified in mosquitoes or sand flies. The vast majority of salivary disintegrins reported display a RGD motif and were described as platelet aggregation inhibitors, and few others as negative modulator of neutrophil or endothelial cell functions. This notably low number of reported disintegrins is certainly an underestimation of the actual complexity of this family of proteins in hematophagous secretions. Therefore an algorithm was created in order to identify the tripeptide motifs RGD, KGD, VGD, MLD, KTS, RTS, WGD, or RED (flanked by cysteines) in sialogenins deposited in GenBank database. The search included sequences from various blood-sucking animals such as ticks (e.g., Ixodes sp., Argas sp., Rhipicephalus sp., Amblyomma sp.), tabanids (e.g., Tabanus sp.), bugs (e.g., Triatoma sp., Rhodnius prolixus), mosquitoes (e.g., Anopheles sp., Aedes sp., Culex sp.), sand flies (e.g., Lutzomyia sp., Phlebotomus sp.), leeches (e.g., Macrobdella sp., Placobdella sp.) and worms (e.g., Ancylostoma sp.). This approach allowed the identification of a remarkably high number of novel putative sialogenins with tripeptide motifs typical of disintegrins (>450 sequences) whose biological activity remains to be verified. This database is accessible online as a hyperlinked worksheet and displays biochemical, taxonomic, and gene ontology aspects for each putative disintegrin. It is also freely available for download (right click with the mouse) at links http://exon.niaid.nih.gov/transcriptome/RGD/RGD-Peps-WEB.xlsx (web version) and http://exon.niaid.nih.gov/transcriptome/RGD/RGD-sialogenins.zip (stand alone version). Full article
(This article belongs to the Special Issue Disintegrins: Structure-Function and Translational Potential)
Open AccessReview Snake Venom Disintegrins and Cell Migration
Toxins 2010, 2(11), 2606-2621; doi:10.3390/toxins2112606
Received: 24 August 2010 / Revised: 15 October 2010 / Accepted: 18 October 2010 / Published: 29 October 2010
Cited by 20 | PDF Full-text (282 KB) | HTML Full-text | XML Full-text
Abstract
Cell migration is a key process for the defense of pluricellular organisms against pathogens, and it involves a set of surface receptors acting in an ordered fashion to contribute directionality to the movement. Among these receptors are the integrins, which connect the cell
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Cell migration is a key process for the defense of pluricellular organisms against pathogens, and it involves a set of surface receptors acting in an ordered fashion to contribute directionality to the movement. Among these receptors are the integrins, which connect the cell cytoskeleton to the extracellular matrix components, thus playing a central role in cell migration. Integrin clustering at focal adhesions drives actin polymerization along the cell leading edge, resulting in polarity of cell movement. Therefore, small integrin-binding proteins such as the snake venom disintegrins that inhibit integrin-mediated cell adhesion are expected to inhibit cell migration. Here we review the current knowledge on disintegrin and disintegrin-like protein effects on cell migration and their potential use as pharmacological tools in anti-inflammatory therapy as well as in inhibition of metastatic invasion. Full article
(This article belongs to the Special Issue Disintegrins: Structure-Function and Translational Potential)
Open AccessReview ADAM-15 Disintegrin-Like Domain Structure and Function
Toxins 2010, 2(10), 2411-2427; doi:10.3390/toxins2102411
Received: 30 August 2010 / Revised: 13 October 2010 / Accepted: 18 October 2010 / Published: 19 October 2010
Cited by 7 | PDF Full-text (827 KB) | HTML Full-text | XML Full-text
Abstract
The ADAM (a disintegrin-like and metalloproteinase) proteins are a family of transmembrane cell-surface proteins with important functions in adhesion and proteolytic processing in all animals. Human ADAM-15 is the only member of the ADAM family with the integrin binding motif Arg-Gly-Asp (RGD) in
[...] Read more.
The ADAM (a disintegrin-like and metalloproteinase) proteins are a family of transmembrane cell-surface proteins with important functions in adhesion and proteolytic processing in all animals. Human ADAM-15 is the only member of the ADAM family with the integrin binding motif Arg-Gly-Asp (RGD) in its disintegrin-like domain. This motif is also found in most snake venom disintegrins and other disintegrin-like proteins. This unique RGD motif within ADAM-15 serves as an integrin ligand binding site, through which it plays a pivotal role in interacting with integrin receptors, a large family of heterodimeric transmembrane glycoproteins. This manuscript will present a review of the RGD-containing disintegrin-like domain structures and the structural features responsible for their activity as antagonists of integrin function in relation to the canonical RGD template. Full article
(This article belongs to the Special Issue Disintegrins: Structure-Function and Translational Potential)

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