Functional analyses yield detailedinsight into the mechanism of thrombin inhibition by the antihemostatic salivary protein cE5 from Anopheles gambiae (462 views) (PDF public 200 views)
Jbc Papers (ISSN: 0021-9258linking, 1083-351x), 2017 Jul 28; 292(30): 12632-12642.
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Paper type: Journal Article, Research Support, Non-U. S. Gov'T,
Impact factor: 4.125, 5-year impact factor: 5.498
Url: Not available.
Keywords: Animals , Anopheles Chemistry , Anticoagulants Pharmacology , Humans , Models, Molecular , Salivary Proteins And Peptides Pharmacology , Thrombin Antagonists, Inhibitors Metabolism , Crystal Structure , Enzyme Inhibitor , Hemostasis , Intrinsically Disordered Protein , Mosquito Saliva , Protein-Protein Interaction,
Affiliations:
*** IBB - CNR ***
From the Institute of Biostructures and Bioimaging, National Research Council, Via Mezzocannone 16, 80134 Naples, Italy.
IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal.
Instituto de Investigacao e Inovacao em Saude, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal.
the Department of Biology, Universita' degli Studi di Napoli Federico II, Via Cinthia, 80126 Naples, Italy.
the Department of Public Health and Infectious Diseases, Division of Parasitology, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy, and.
the Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, Rockville, Maryland 20852.
References:
Not available.
Jbc Papers (ISSN: 0021-9258linking, 1083-351x), 2017 Jul 28; 292(30): 12632-12642.
Export to BibTeX Export to EndNote
Paper type: Journal Article, Research Support, Non-U. S. Gov'T,
Impact factor: 4.125, 5-year impact factor: 5.498
Url: Not available.
Keywords: Animals , Anopheles Chemistry , Anticoagulants Pharmacology , Humans , Models, Molecular , Salivary Proteins And Peptides Pharmacology , Thrombin Antagonists, Inhibitors Metabolism , Crystal Structure , Enzyme Inhibitor , Hemostasis , Intrinsically Disordered Protein , Mosquito Saliva , Protein-Protein Interaction,
Affiliations:
*** IBB - CNR ***
From the Institute of Biostructures and Bioimaging, National Research Council, Via Mezzocannone 16, 80134 Naples, Italy.
IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal.
Instituto de Investigacao e Inovacao em Saude, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal.
the Department of Biology, Universita' degli Studi di Napoli Federico II, Via Cinthia, 80126 Naples, Italy.
the Department of Public Health and Infectious Diseases, Division of Parasitology, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy, and.
the Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, Rockville, Maryland 20852.
References:
Not available.
Functional analyses yield detailedinsight into the mechanism of thrombin inhibition by the antihemostatic salivary protein cE5 from Anopheles gambiae
Saliva of blood-feeding arthropods carries several antihemostatic compounds whose physiological role is to facilitate successful acquisition of blood. The identification of novel natural anticoagulants and the understanding of their mechanism of action may offer opportunities for designing new antithrombotics disrupting blood clotting. We report here an in-depth structural and functional analysis of the anophelin family member cE5, a salivary protein from the major African malaria vector Anopheles gambiae that specifically, tightly, and quickly binds and inhibits thrombin. Using calorimetry, functional assays, and complementary structural techniques, we show that the central region of the protein, encompassing amino acids Asp-31-Arg-62, is the region mainly responsible for alpha-thrombin binding and inhibition. As previously reported for the Anopheles albimanus orthologue anophelin, cE5 binds both thrombin exosite I with segment Glu-35-Asp-47 and the catalytic site with the region Pro-49-Arg-56, which includes the highly conserved DPGR tetrapeptide. Moreover, the N-terminal Ala-1-Ser-30 region of cE5 (which includes an RGD tripeptide) and the additional C-terminal serine-rich Asn-63-Glu-82 region (absent in orthologues from anophelines of the New World species A. albimanus and Anopheles darlingi) also played some functionally relevant role. Indeed, we observed decreased thrombin binding and inhibitory properties even when using the central cE5 fragment (Asp-31-Arg-62) alone. In summary, these results shed additional light on the mechanism of thrombin binding and inhibition by this family of salivary anticoagulants from anopheline mosquitoes.
Saliva of blood-feeding arthropods carries several antihemostatic compounds whose physiological role is to facilitate successful acquisition of blood. The identification of novel natural anticoagulants and the understanding of their mechanism of action may offer opportunities for designing new antithrombotics disrupting blood clotting. We report here an in-depth structural and functional analysis of the anophelin family member cE5, a salivary protein from the major African malaria vector Anopheles gambiae that specifically, tightly, and quickly binds and inhibits thrombin. Using calorimetry, functional assays, and complementary structural techniques, we show that the central region of the protein, encompassing amino acids Asp-31-Arg-62, is the region mainly responsible for alpha-thrombin binding and inhibition. As previously reported for the Anopheles albimanus orthologue anophelin, cE5 binds both thrombin exosite I with segment Glu-35-Asp-47 and the catalytic site with the region Pro-49-Arg-56, which includes the highly conserved DPGR tetrapeptide. Moreover, the N-terminal Ala-1-Ser-30 region of cE5 (which includes an RGD tripeptide) and the additional C-terminal serine-rich Asn-63-Glu-82 region (absent in orthologues from anophelines of the New World species A. albimanus and Anopheles darlingi) also played some functionally relevant role. Indeed, we observed decreased thrombin binding and inhibitory properties even when using the central cE5 fragment (Asp-31-Arg-62) alone. In summary, these results shed additional light on the mechanism of thrombin binding and inhibition by this family of salivary anticoagulants from anopheline mosquitoes.
Functional analyses yield detailedinsight into the mechanism of thrombin inhibition by the antihemostatic salivary protein cE5 from Anopheles gambiae
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Functional analyses yield detailedinsight into the mechanism of thrombin inhibition by the antihemostatic salivary protein cE5 from Anopheles gambiae
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18 Records (18 excluding Abstracts).
Total impact factor: 80.219 (80.219 excluding Abstracts).
Total 5 year impact factor: 71.241 (71.241 excluding Abstracts).
Total impact factor: 80.219 (80.219 excluding Abstracts).
Total 5 year impact factor: 71.241 (71.241 excluding Abstracts).
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