title: A non-canonical di-acidic signal at the C-terminus of Kv1.3 determines anterograde trafficking and surface expression.
abstract: Impairment of Kv1.3 expression at the cell membrane in leukocytes and sensory neuron contributes to the pathophysiology of autoimmune diseases and sensory syndromes. Molecular mechanisms underlying Kv1.3 channel trafficking to the plasma membrane remain elusive. We report a novel non-canonical di-acidic signal (E483/484) at the C-terminus of Kv1.3 essential for anterograde transport and surface expression. Notably, homologous motifs are conserved in neuronal Kv1 and Shaker channels. Biochemical analysis revealed interactions with the Sec24 subunit of the coat protein complex II. Disruption of this complex retains the channel at the endoplasmic reticulum. A molecular model of the Kv1.3-Sec24a complex suggests salt-bridges between the di-acidic E483/484 motif in Kv1.3 and the di-basic R750/752 sequence in Sec24. These findings identify a previously unrecognized motif of Kv channels essential for their expression on the cell surface. Our results contribute to our understanding of how Kv1 channels target to the cell membrane, and provide new therapeutic strategies for the treatment of pathological conditions.
authors.affiliation: Molecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Diagonal 643, E-08028 Barcelona, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Martínez-Mármol
authors.forename: Mireia
authors.initials: M
authors.lastname: Pérez-Verdaguer
authors.forename: Sara R
authors.initials: SR
authors.lastname: Roig
authors.forename: Albert
authors.initials: A
authors.lastname: Vallejo-Gracia
authors.forename: Pelagia
authors.initials: P
authors.lastname: Gotsi
authors.forename: Antonio
authors.initials: A
authors.lastname: Serrano-Albarrás
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Bahamonde
authors.forename: Antonio
authors.initials: A
authors.lastname: Ferrer-Montiel
authors.forename: Gregorio
authors.initials: G
authors.lastname: Fernández-Ballester
authors.forename: Núria
authors.initials: N
authors.lastname: Comes
authors.forename: Antonio
authors.initials: A
authors.lastname: Felipe
mesh_terms: D020816:Amino Acid Motifs; D019943:Amino Acid Substitution; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D020756:Coatomer Protein / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051664:Kv1.3 Potassium Channel / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D016297:Mutagenesis, Site-Directed; D021382:Protein Sorting Signals; D021381:Protein Transport; D051381:Rats; D051637:Shaker Superfamily of Potassium Channels / Q000235:genetics / Q000378:metabolism
chemical_list: D020756:Coatomer Protein; D051664:Kv1.3 Potassium Channel; D021382:Protein Sorting Signals; D051637:Shaker Superfamily of Potassium Channels
keywords: Forward-traffic motifs; Lymphocytes; Neurons; Plasma membrane; Voltage-dependent K+ channels