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Article

  • The EMBO Journal (2008) 27, 3164 - 3174
  • doi:10.1038/emboj.2008.231

Published online: 6 November 2008

Structural determinants of Kvbold beta1.3-induced channel inactivation: a hairpin modulated by PIP2

Niels Decher1,2,5, Teresa Gonzalez1,4,5, Anne Kathrin Streit2, Frank B Sachse1, Vijay Renigunta2, Malle Soom3, Stefan H Heinemann3, Jürgen Daut2 and Michael C Sanguinetti1

  1. Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT, USA
  2. Institute for Physiology and Pathophysiology, Department of Cell Physiology, University of Marburg, Marburg, Germany
  3. Department of Biophysics, Center for Molecular Biomedicine, Friedrich Schiller University Jena, Jena, Germany
  4. Instituto de Investigaciones Biomédicas 'Alberto Sols' CSIC/UAM, Departamento de Modelos Experimentales de Enfermedades Humanas, Madrid, Spain
  5. These authors contributed equally to this work

Correspondence to:

Niels Decher, Institute of Physiology and Pathophysiology, Philipps-University Marburg, Deutschhausstras zlige 1–2, Marburg, Hessen 35037, Germany. Tel.: +49 642 128 621 48; Fax: +49 642 128 689 60; E-mail: decher@staff.uni-marburg.de

Received 5 May 2008; Accepted 9 October 2008

Inactivation of voltage-gated Kv1 channels can be altered by Kvbeta subunits, which block the ion-conducting pore to induce a rapid ('N-type') inactivation. Here, we investigate the mechanisms and structural basis of Kvbeta1.3 interaction with the pore domain of Kv1.5 channels. Inactivation induced by Kvbeta1.3 was antagonized by intracellular PIP2. Mutations of R5 or T6 in Kvbeta1.3 enhanced Kv1.5 inactivation and markedly reduced the effects of PIP2. R5C or T6C Kvbeta1.3 also exhibited diminished binding of PIP2 compared with wild-type channels in an in vitro lipid-binding assay. Further, scanning mutagenesis of the N terminus of Kvbeta1.3 revealed that mutations of L2 and A3 eliminated N-type inactivation. Double-mutant cycle analysis indicates that R5 interacts with A501 and T480 of Kv1.5, residues located deep within the pore of the channel. These interactions indicate that Kvbeta1.3, in contrast to Kvbeta1.1, assumes a hairpin structure to inactivate Kv1 channels. Taken together, our findings indicate that inactivation of Kv1.5 is mediated by an equilibrium binding of the N terminus of Kvbeta1.3 between phosphoinositides (PIPs) and the inner pore region of the channel.

  • Keywords:

    • ion channel,
    • Kvbeta,
    • N-type inactivation,
    • phospholipids,
    • potassium