title: The KCNQ1 (Kv7.1) COOH terminus, a multitiered scaffold for subunit assembly and protein interaction.
abstract: The Kv7 subfamily of voltage-dependent potassium channels, distinct from other subfamilies by dint of its large intracellular COOH terminus, acts to regulate excitability in cardiac and neuronal tissues. KCNQ1 (Kv7.1), the founding subfamily member, encodes a channel subunit directly implicated in genetic disorders, such as the long QT syndrome, a cardiac pathology responsible for arrhythmias. We have used a recombinant protein preparation of the COOH terminus to probe the structure and function of this domain and its individual modules. The COOH-terminal proximal half associates with one calmodulin constitutively bound to each subunit where calmodulin is critical for proper folding of the whole intracellular domain. The distal half directs tetramerization, employing tandem coiled-coils. The first coiled-coil complex is dimeric and undergoes concentration-dependent self-association to form a dimer of dimers. The outer coiled-coil is parallel tetrameric, the details of which have been elucidated based on 2.0 A crystallographic data. Both coiled-coils act in a coordinate fashion to mediate the formation and stabilization of the tetrameric distal half. Functional studies, including characterization of structure-based and long QT mutants, prove the requirement for both modules and point to complex roles for these modules, including folding, assembly, trafficking, and regulation.
authors.affiliation: Department of Biochemistry, The Daniella Rich Institute for Structural Biology, Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978, Israel.
authors.forename: Reuven
authors.initials: R
authors.lastname: Wiener
authors.forename: Yoni
authors.initials: Y
authors.lastname: Haitin
authors.forename: Liora
authors.initials: L
authors.lastname: Shamgar
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Fernández-Alonso
authors.forename: Ariadna
authors.initials: A
authors.lastname: Martos
authors.forename: Orna
authors.initials: O
authors.lastname: Chomsky-Hecht
authors.forename: Germán
authors.initials: G
authors.lastname: Rivas
authors.forename: Bernard
authors.initials: B
authors.lastname: Attali
authors.forename: Joel A
authors.initials: JA
authors.lastname: Hirsch
mesh_terms: D000818:Animals; D002147:Calmodulin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D019281:Dimerization; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008133:Long QT Syndrome / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary / Q000502:physiology; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D002147:Calmodulin; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D021122:Protein Subunits; D011994:Recombinant Proteins