Structural, Biochemical, and Functional Characterization of the Cyclic Nucleotide Binding Homology Domain from the Mouse EAG1 Potassium Channel.
Maria J Marques-Carvalho
(1)
,
Nirakar Sahoo
(2)
,
Frederick W Muskett
(3)
,
Ricardo S Vieira-Pires
(1, 4)
,
Guillaume Gabant
(5)
,
Martine Cadene
(5)
,
Roland Schönherr
(2)
,
João H Morais-Cabral
(1)
Guillaume Gabant
- Fonction : Auteur
- PersonId : 175225
- IdHAL : guillaume-gabant
- ORCID : 0000-0002-8677-2057
- IdRef : 188311963
Martine Cadene
- Fonction : Auteur
- PersonId : 175733
- IdHAL : martine-cadene
- ORCID : 0000-0003-4936-2662
- IdRef : 165291508
Résumé
KCNH channels are voltage-gated potassium channels with important physiological functions. In these channels, a C-terminal cytoplasmic region, known as the cyclic nucleotide binding homology (CNB-homology) domain displays strong sequence similarity to cyclic nucleotide binding (CNB) domains. However, the isolated domain does not bind cyclic nucleotides. Here, we report the X-ray structure of the CNB-homology domain from the mouse EAG1 channel. Through comparison with the recently determined structure of the CNB-homology domain from the zebrafish ELK (eag-like K(+)) channel and the CNB domains from the MlotiK1 and HCN (hyperpolarization-activated cyclic nucleotide-gated) potassium channels, we establish the structural features of CNB-homology domains that explain the low affinity for cyclic nucleotides. Our structure establishes that the "self-liganded" conformation, where two residues of the C-terminus of the domain are bound in an equivalent position to cyclic nucleotides in CNB domains, is a conserved feature of CNB-homology domains. Importantly, we provide biochemical evidence that suggests that there is also an unliganded conformation where the C-terminus of the domain peels away from its bound position. A functional characterization of this unliganded conformation reveals a role of the CNB-homology domain in channel gating.
Domaines
Biochimie, Biologie MoléculaireFormat du dépôt | Notice |
---|---|
Type de dépôt | Article dans une revue |
Titre |
en
Structural, Biochemical, and Functional Characterization of the Cyclic Nucleotide Binding Homology Domain from the Mouse EAG1 Potassium Channel.
|
Résumé |
en
KCNH channels are voltage-gated potassium channels with important physiological functions. In these channels, a C-terminal cytoplasmic region, known as the cyclic nucleotide binding homology (CNB-homology) domain displays strong sequence similarity to cyclic nucleotide binding (CNB) domains. However, the isolated domain does not bind cyclic nucleotides. Here, we report the X-ray structure of the CNB-homology domain from the mouse EAG1 channel. Through comparison with the recently determined structure of the CNB-homology domain from the zebrafish ELK (eag-like K(+)) channel and the CNB domains from the MlotiK1 and HCN (hyperpolarization-activated cyclic nucleotide-gated) potassium channels, we establish the structural features of CNB-homology domains that explain the low affinity for cyclic nucleotides. Our structure establishes that the "self-liganded" conformation, where two residues of the C-terminus of the domain are bound in an equivalent position to cyclic nucleotides in CNB domains, is a conserved feature of CNB-homology domains. Importantly, we provide biochemical evidence that suggests that there is also an unliganded conformation where the C-terminus of the domain peels away from its bound position. A functional characterization of this unliganded conformation reveals a role of the CNB-homology domain in channel gating.
|
Auteur(s) |
Maria J Marques-Carvalho
1
, Nirakar Sahoo
2
, Frederick W Muskett
3
, Ricardo S Vieira-Pires
1, 4
, Guillaume Gabant
5
, Martine Cadene
5
, Roland Schönherr
2
, João H Morais-Cabral
1
1
IBMC -
Instituto de Biologia Molecular e Celular
( 329440 )
- Porto
- Portugal
2
Jena University Hospital [Jena]
( 334431 )
- Bachstraße 18, 07743 Jena
- Allemagne
3
University of Leicester
( 300751 )
- University Rd, Leicester LE1 7RH
- Royaume-Uni
4
ICBAS -
Instituto de Ciências Biomédicas de Abel Salazar
( 329438 )
- Porto
- Portugal
5
CBM -
Centre de biophysique moléculaire
( 451 )
- Rue Charles Sadron 45071 ORLEANS CEDEX 2
- France
|
Langue du document |
Anglais
|
Nom de la revue |
|
Vulgarisation |
Non
|
Comité de lecture |
Oui
|
Audience |
Internationale
|
Date de publication |
2012-10-12
|
Date de publication électronique |
2012-06-23
|
Volume |
423
|
Numéro |
1
|
Page/Identifiant |
34-46
|
Domaine(s) |
|
DOI | 10.1016/j.jmb.2012.06.025 |
Pubmed Id | 22732247 |
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