2. Academic Validation
  3. Molecular Insights into the Mechanism of Calmodulin Inhibition of the EAG1 Potassium Channel

Molecular Insights into the Mechanism of Calmodulin Inhibition of the EAG1 Potassium Channel

  • Structure. 2016 Oct 4;24(10):1742-1754. doi: 10.1016/j.str.2016.07.020.
Maria João Marques-Carvalho 1,  Johannes Oppermann 2,  Eva Muñoz 3,  Andreia S Fernandes 1,  Guillaume Gabant 4,  Martine Cadene 4,  Stefan H Heinemann 2,  Roland Schönherr 2,  João Henrique Morais-Cabral 5
Affiliations

Affiliations

  • 1 Instituto de Biologia Molecular e Celular, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal.
  • 2 Department of Biophysics, Center for Molecular Biomedicine, Friedrich Schiller University Jena and Jena University Hospital, 07745 Jena, Germany.
  • 3 Software 4 Science Developments, 15782 Santiago de Compostela, Spain.
  • 4 Centre de Biophysique Moléculaire, CNRS UPR430, 45071 Orléans, France.
  • 5 Instituto de Biologia Molecular e Celular, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal. Electronic address: jcabral@ibmc.up.pt.
PMID: 27618660 DOI: 10.1016/j.str.2016.07.020
Abstract

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.

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