title: The C-terminal domain of Kv1.3 regulates functional interactions with the KCNE4 subunit.
abstract: The voltage-dependent K+channel Kv1.3 (also known as KCNA3), which plays crucial roles in leukocytes, physically interacts with KCNE4. This interaction inhibits the K+currents because the channel is retained within intracellular compartments. Thus, KCNE subunits are regulators of K+channels in the immune system. Although the canonical interactions of KCNE subunits with Kv7 channels are under intensive investigation, the molecular determinants governing the important Kv1.3- KCNE4 association in the immune system are unknown. Our results suggest that the tertiary structure of the C-terminal domain of Kv1.3 is necessary and sufficient for such an interaction. However, this element is apparently not involved in modulating Kv1.3 gating. Furthermore, the KCNE4-dependent intracellular retention of the channel, which negatively affects the activity of Kv1.3, is mediated by two independent and additive mechanisms. First, KCNE4 masks the YMVIEE signature at the C-terminus of Kv1.3, which is crucial for the surface targeting of the channel. Second, we identify a potent endoplasmic reticulum retention motif in KCNE4 that further limits cell surface expression. Our results define specific molecular determinants that play crucial roles in the physiological function of Kv1.3 in leukocytes.
authors: Molecular Physiology Laboratory, Departament de Bioquímica i Biomedicina Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, Avda. Diagonal 643, Barcelona 08028, Spain.|Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA.
authors: Laura
authors: L
authors: Solé
authors: Molecular Physiology Laboratory, Departament de Bioquímica i Biomedicina Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, Avda. Diagonal 643, Barcelona 08028, Spain.
authors: Sara R
authors: SR
authors: Roig
authors: Molecular Physiology Laboratory, Departament de Bioquímica i Biomedicina Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, Avda. Diagonal 643, Barcelona 08028, Spain.
authors: Albert
authors: A
authors: Vallejo-Gracia
authors: Molecular Physiology Laboratory, Departament de Bioquímica i Biomedicina Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, Avda. Diagonal 643, Barcelona 08028, Spain.
authors: Antonio
authors: A
authors: Serrano-Albarrás
authors: Molecular Physiology Laboratory, Departament de Bioquímica i Biomedicina Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, Avda. Diagonal 643, Barcelona 08028, Spain.|Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors: Ramón
authors: R
authors: Martínez-Mármol
authors: Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA.
authors: Michael M
authors: MM
authors: Tamkun
authors: Molecular Physiology Laboratory, Departament de Bioquímica i Biomedicina Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, Avda. Diagonal 643, Barcelona 08028, Spain afelipe@ub.edu.
authors: Antonio
authors: 0000-0002-7294-6431
authors: A
authors: Felipe
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D022181:COP-Coated Vesicles / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating; D019169:Jurkat Cells; D051664:Kv1.3 Potassium Channel / Q000737:chemistry* / Q000378:metabolism*; D007962:Leukocytes; D051379:Mice; D024642:Potassium Channels, Voltage-Gated / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D000072417:Protein Domains; D021122:Protein Subunits / Q000378:metabolism*; D051381:Rats
chemical_list: C498897:KCNE4 protein, human; C470587:KCNE4 protein, mouse; D051664:Kv1.3 Potassium Channel; D024642:Potassium Channels, Voltage-Gated; D021122:Protein Subunits
keywords: Channelosome; Intracellular retention; Potassium channels; Trafficking