Molecular insights into the mechanism of calmodulin inhibition of the EAG1 potassium channel
Main Author: | |
---|---|
Publication Date: | 2016 |
Other Authors: | , , , , , , , |
Format: | Article |
Language: | eng |
Source: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Download full: | http://hdl.handle.net/10216/108672 |
Summary: | The human EAG1 potassium channel belongs to the superfamily of KCNH voltage-gated potassium channels that have roles in cardiac repolarization and neuronal excitability. EAG1 is strongly inhibited by Ca2+/calmodulin (CaM) through a mechanism that is not understood. We determined the binding properties of CaM with each one of three previously identified binding sites (BDN, BDC1, and BDC2), analyzed binding to protein stretches that include more than one site, and determined the effect of neighboring globular domains on the binding properties. The determination of the crystal structure of CaM The human EAG1 potassium channel belongs to the superfamily of KCNH voltage-gated potassium channels that have roles in cardiac repolarization and neuronal excitability. EAG1 is strongly inhibited by Ca2+/calmodulin (CaM) through a mechanism that is not understood. We determined the binding properties of CaM with each one of three previously identified binding sites (BDN, BDC1, and BDC2), analyzed binding to protein stretches that include more than one site, and determined the effect of neighboring globular domains on the binding properties. The determination of the crystal structure of CaM bound to BDC2 shows the channel fragment interacting with only the C lobe of calmodulin and adopting an unusual bent conformation. Based on this structure and on a functional and biochemical analysis of mutants, we propose a model for the mechanism of inhibition whereby the local conformational change induced by CaM binding at BDC2 lies at the basis of channel modulation. |
id |
RCAP_41d02f36f7110b8ec80e0497347c1aa1 |
---|---|
oai_identifier_str |
oai:repositorio-aberto.up.pt:10216/108672 |
network_acronym_str |
RCAP |
network_name_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository_id_str |
7160 |
spelling |
Molecular insights into the mechanism of calmodulin inhibition of the EAG1 potassium channelBinding SitesCalmodulinCrystallography, X-RayEther-A-Go-Go Potassium ChannelsHumansModels, MolecularMutationProtein BindingProtein ConformationThe human EAG1 potassium channel belongs to the superfamily of KCNH voltage-gated potassium channels that have roles in cardiac repolarization and neuronal excitability. EAG1 is strongly inhibited by Ca2+/calmodulin (CaM) through a mechanism that is not understood. We determined the binding properties of CaM with each one of three previously identified binding sites (BDN, BDC1, and BDC2), analyzed binding to protein stretches that include more than one site, and determined the effect of neighboring globular domains on the binding properties. The determination of the crystal structure of CaM The human EAG1 potassium channel belongs to the superfamily of KCNH voltage-gated potassium channels that have roles in cardiac repolarization and neuronal excitability. EAG1 is strongly inhibited by Ca2+/calmodulin (CaM) through a mechanism that is not understood. We determined the binding properties of CaM with each one of three previously identified binding sites (BDN, BDC1, and BDC2), analyzed binding to protein stretches that include more than one site, and determined the effect of neighboring globular domains on the binding properties. The determination of the crystal structure of CaM bound to BDC2 shows the channel fragment interacting with only the C lobe of calmodulin and adopting an unusual bent conformation. Based on this structure and on a functional and biochemical analysis of mutants, we propose a model for the mechanism of inhibition whereby the local conformational change induced by CaM binding at BDC2 lies at the basis of channel modulation.Elsevier (Cell Press)2016-10-042016-10-04T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10216/108672eng0969-212610.1016/j.str.2016.07.020Marques-Carvalho, MJOppermann, JMuñoz, EFernandes, ASGabant, GCadene, MHeinemann, SHSchönherr, RMorais-Cabral, JHinfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-29T14:18:29Zoai:repositorio-aberto.up.pt:10216/108672Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T23:58:32.561520Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Molecular insights into the mechanism of calmodulin inhibition of the EAG1 potassium channel |
title |
Molecular insights into the mechanism of calmodulin inhibition of the EAG1 potassium channel |
spellingShingle |
Molecular insights into the mechanism of calmodulin inhibition of the EAG1 potassium channel Marques-Carvalho, MJ Binding Sites Calmodulin Crystallography, X-Ray Ether-A-Go-Go Potassium Channels Humans Models, Molecular Mutation Protein Binding Protein Conformation |
title_short |
Molecular insights into the mechanism of calmodulin inhibition of the EAG1 potassium channel |
title_full |
Molecular insights into the mechanism of calmodulin inhibition of the EAG1 potassium channel |
title_fullStr |
Molecular insights into the mechanism of calmodulin inhibition of the EAG1 potassium channel |
title_full_unstemmed |
Molecular insights into the mechanism of calmodulin inhibition of the EAG1 potassium channel |
title_sort |
Molecular insights into the mechanism of calmodulin inhibition of the EAG1 potassium channel |
author |
Marques-Carvalho, MJ |
author_facet |
Marques-Carvalho, MJ Oppermann, J Muñoz, E Fernandes, AS Gabant, G Cadene, M Heinemann, SH Schönherr, R Morais-Cabral, JH |
author_role |
author |
author2 |
Oppermann, J Muñoz, E Fernandes, AS Gabant, G Cadene, M Heinemann, SH Schönherr, R Morais-Cabral, JH |
author2_role |
author author author author author author author author |
dc.contributor.author.fl_str_mv |
Marques-Carvalho, MJ Oppermann, J Muñoz, E Fernandes, AS Gabant, G Cadene, M Heinemann, SH Schönherr, R Morais-Cabral, JH |
dc.subject.por.fl_str_mv |
Binding Sites Calmodulin Crystallography, X-Ray Ether-A-Go-Go Potassium Channels Humans Models, Molecular Mutation Protein Binding Protein Conformation |
topic |
Binding Sites Calmodulin Crystallography, X-Ray Ether-A-Go-Go Potassium Channels Humans Models, Molecular Mutation Protein Binding Protein Conformation |
description |
The human EAG1 potassium channel belongs to the superfamily of KCNH voltage-gated potassium channels that have roles in cardiac repolarization and neuronal excitability. EAG1 is strongly inhibited by Ca2+/calmodulin (CaM) through a mechanism that is not understood. We determined the binding properties of CaM with each one of three previously identified binding sites (BDN, BDC1, and BDC2), analyzed binding to protein stretches that include more than one site, and determined the effect of neighboring globular domains on the binding properties. The determination of the crystal structure of CaM The human EAG1 potassium channel belongs to the superfamily of KCNH voltage-gated potassium channels that have roles in cardiac repolarization and neuronal excitability. EAG1 is strongly inhibited by Ca2+/calmodulin (CaM) through a mechanism that is not understood. We determined the binding properties of CaM with each one of three previously identified binding sites (BDN, BDC1, and BDC2), analyzed binding to protein stretches that include more than one site, and determined the effect of neighboring globular domains on the binding properties. The determination of the crystal structure of CaM bound to BDC2 shows the channel fragment interacting with only the C lobe of calmodulin and adopting an unusual bent conformation. Based on this structure and on a functional and biochemical analysis of mutants, we propose a model for the mechanism of inhibition whereby the local conformational change induced by CaM binding at BDC2 lies at the basis of channel modulation. |
publishDate |
2016 |
dc.date.none.fl_str_mv |
2016-10-04 2016-10-04T00:00:00Z |
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://hdl.handle.net/10216/108672 |
url |
http://hdl.handle.net/10216/108672 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
0969-2126 10.1016/j.str.2016.07.020 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Elsevier (Cell Press) |
publisher.none.fl_str_mv |
Elsevier (Cell Press) |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
|
_version_ |
1799135907734880256 |