Beyond hemostasis: a snake venom serine protease with potassium channel blocking and potential antitumor activities
Autor(a) principal: | |
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Data de Publicação: | 2020 |
Outros Autores: | , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1038/s41598-020-61258-x http://hdl.handle.net/11449/201617 |
Resumo: | Snake venom serine proteases (SVSPs) are complex and multifunctional enzymes, acting primarily on hemostasis. In this work, we report the hitherto unknown inhibitory effect of a SVSP, named collinein-1, isolated from the venom of Crotalus durissus collilineatus, on a cancer-relevant voltage-gated potassium channel (hEAG1). Among 12 voltage-gated ion channels tested, collinein-1 selectively inhibited hEAG1 currents, with a mechanism independent of its enzymatic activity. Corroboratively, we demonstrated that collinein-1 reduced the viability of human breast cancer cell line MCF7 (high expression of hEAG1), but does not affect the liver carcinoma and the non-tumorigenic epithelial breast cell lines (HepG2 and MCF10A, respectively), which present low expression of hEAG1. In order to obtain both functional and structural validation of this unexpected discovery, where an unusually large ligand acts as an inhibitor of an ion channel, a recombinant and catalytically inactive mutant of collinein-1 (His43Arg) was produced and found to preserve its capability to inhibit hEAG1. A molecular docking model was proposed in which Arg79 of the SVSP 99-loop interacts directly with the potassium selectivity filter of the hEAG1 channel. |
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Beyond hemostasis: a snake venom serine protease with potassium channel blocking and potential antitumor activitiesSnake venom serine proteases (SVSPs) are complex and multifunctional enzymes, acting primarily on hemostasis. In this work, we report the hitherto unknown inhibitory effect of a SVSP, named collinein-1, isolated from the venom of Crotalus durissus collilineatus, on a cancer-relevant voltage-gated potassium channel (hEAG1). Among 12 voltage-gated ion channels tested, collinein-1 selectively inhibited hEAG1 currents, with a mechanism independent of its enzymatic activity. Corroboratively, we demonstrated that collinein-1 reduced the viability of human breast cancer cell line MCF7 (high expression of hEAG1), but does not affect the liver carcinoma and the non-tumorigenic epithelial breast cell lines (HepG2 and MCF10A, respectively), which present low expression of hEAG1. In order to obtain both functional and structural validation of this unexpected discovery, where an unusually large ligand acts as an inhibitor of an ion channel, a recombinant and catalytically inactive mutant of collinein-1 (His43Arg) was produced and found to preserve its capability to inhibit hEAG1. A molecular docking model was proposed in which Arg79 of the SVSP 99-loop interacts directly with the potassium selectivity filter of the hEAG1 channel.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)KU LeuvenFonds Wetenschappelijk OnderzoekSchool of Pharmaceutical Sciences of Ribeirão Preto University of São Paulo Av. do Café s/n°Toxicology and Pharmacology KU Leuven, O&N II Herestraat 49, PO 922Medical School of Roraima Federal University of Roraima Av. Capitão Ene Garcez 2413 Bairro AeroportoInstitute of Biosciences São Paulo State University (UNESP) Rua Prof. Dr. Antonio Celso Wagner Zanin 250University of Vila Velha Av. Comissário José Dantas de Melo 21 Boa Vista IIInstitute of Biosciences São Paulo State University (UNESP) Rua Prof. Dr. Antonio Celso Wagner Zanin 250FAPESP: 2011/23236-4FAPESP: 2015/00740-0FAPESP: 2015/17286-0FAPESP: 2016/04761-4FAPESP: 2016/24191-8FAPESP: 2017/14035-1FAPESP: 2018/14158-9CNPq: 307155/2017-0CAPES: 88881.186830/2018-01KU Leuven: CELSA 17/047Fonds Wetenschappelijk Onderzoek: GOA4919NUniversidade de São Paulo (USP)KU LeuvenBairro AeroportoUniversidade Estadual Paulista (Unesp)Boa Vista IIBoldrini-França, JoharaPinheiro-Junior, Ernesto LopesPeigneur, StevePucca, Manuela BertoCerni, Felipe AugustoBorges, Rafael Junqueira [UNESP]Costa, Tássia RafaellaCarone, Sante Emmanuel ImaiFontes, Marcos Roberto de Mattos [UNESP]Sampaio, Suely VilelaArantes, Eliane CandianiTytgat, Jan2020-12-12T02:37:19Z2020-12-12T02:37:19Z2020-12-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41598-020-61258-xScientific Reports, v. 10, n. 1, 2020.2045-2322http://hdl.handle.net/11449/20161710.1038/s41598-020-61258-x2-s2.0-85081653187Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengScientific Reportsinfo:eu-repo/semantics/openAccess2021-10-22T20:42:35Zoai:repositorio.unesp.br:11449/201617Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T14:55:31.697866Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Beyond hemostasis: a snake venom serine protease with potassium channel blocking and potential antitumor activities |
title |
Beyond hemostasis: a snake venom serine protease with potassium channel blocking and potential antitumor activities |
spellingShingle |
Beyond hemostasis: a snake venom serine protease with potassium channel blocking and potential antitumor activities Boldrini-França, Johara |
title_short |
Beyond hemostasis: a snake venom serine protease with potassium channel blocking and potential antitumor activities |
title_full |
Beyond hemostasis: a snake venom serine protease with potassium channel blocking and potential antitumor activities |
title_fullStr |
Beyond hemostasis: a snake venom serine protease with potassium channel blocking and potential antitumor activities |
title_full_unstemmed |
Beyond hemostasis: a snake venom serine protease with potassium channel blocking and potential antitumor activities |
title_sort |
Beyond hemostasis: a snake venom serine protease with potassium channel blocking and potential antitumor activities |
author |
Boldrini-França, Johara |
author_facet |
Boldrini-França, Johara Pinheiro-Junior, Ernesto Lopes Peigneur, Steve Pucca, Manuela Berto Cerni, Felipe Augusto Borges, Rafael Junqueira [UNESP] Costa, Tássia Rafaella Carone, Sante Emmanuel Imai Fontes, Marcos Roberto de Mattos [UNESP] Sampaio, Suely Vilela Arantes, Eliane Candiani Tytgat, Jan |
author_role |
author |
author2 |
Pinheiro-Junior, Ernesto Lopes Peigneur, Steve Pucca, Manuela Berto Cerni, Felipe Augusto Borges, Rafael Junqueira [UNESP] Costa, Tássia Rafaella Carone, Sante Emmanuel Imai Fontes, Marcos Roberto de Mattos [UNESP] Sampaio, Suely Vilela Arantes, Eliane Candiani Tytgat, Jan |
author2_role |
author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade de São Paulo (USP) KU Leuven Bairro Aeroporto Universidade Estadual Paulista (Unesp) Boa Vista II |
dc.contributor.author.fl_str_mv |
Boldrini-França, Johara Pinheiro-Junior, Ernesto Lopes Peigneur, Steve Pucca, Manuela Berto Cerni, Felipe Augusto Borges, Rafael Junqueira [UNESP] Costa, Tássia Rafaella Carone, Sante Emmanuel Imai Fontes, Marcos Roberto de Mattos [UNESP] Sampaio, Suely Vilela Arantes, Eliane Candiani Tytgat, Jan |
description |
Snake venom serine proteases (SVSPs) are complex and multifunctional enzymes, acting primarily on hemostasis. In this work, we report the hitherto unknown inhibitory effect of a SVSP, named collinein-1, isolated from the venom of Crotalus durissus collilineatus, on a cancer-relevant voltage-gated potassium channel (hEAG1). Among 12 voltage-gated ion channels tested, collinein-1 selectively inhibited hEAG1 currents, with a mechanism independent of its enzymatic activity. Corroboratively, we demonstrated that collinein-1 reduced the viability of human breast cancer cell line MCF7 (high expression of hEAG1), but does not affect the liver carcinoma and the non-tumorigenic epithelial breast cell lines (HepG2 and MCF10A, respectively), which present low expression of hEAG1. In order to obtain both functional and structural validation of this unexpected discovery, where an unusually large ligand acts as an inhibitor of an ion channel, a recombinant and catalytically inactive mutant of collinein-1 (His43Arg) was produced and found to preserve its capability to inhibit hEAG1. A molecular docking model was proposed in which Arg79 of the SVSP 99-loop interacts directly with the potassium selectivity filter of the hEAG1 channel. |
publishDate |
2020 |
dc.date.none.fl_str_mv |
2020-12-12T02:37:19Z 2020-12-12T02:37:19Z 2020-12-01 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1038/s41598-020-61258-x Scientific Reports, v. 10, n. 1, 2020. 2045-2322 http://hdl.handle.net/11449/201617 10.1038/s41598-020-61258-x 2-s2.0-85081653187 |
url |
http://dx.doi.org/10.1038/s41598-020-61258-x http://hdl.handle.net/11449/201617 |
identifier_str_mv |
Scientific Reports, v. 10, n. 1, 2020. 2045-2322 10.1038/s41598-020-61258-x 2-s2.0-85081653187 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Scientific Reports |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
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1808128436023066624 |