Structural insight into KCNQ (Kv7) channel assembly and channelopathy.
Kv7.x (KCNQ) voltage-gated potassium channels form the cardiac and auditory I(Ks) current and the neuronal M-current. The five Kv7 subtypes have distinct assembly preferences encoded by a C-terminal cytoplasmic assembly domain, the A-domain Tail. Here, we present the high-resolution structure of the Kv7.4 A-domain Tail together with biochemical experiments that show that the domain is a self-assembling, parallel, four-stranded coiled coil. Structural analysis and biochemical studies indicate conservation of the coiled coil in all Kv7 subtypes and that a limited set of interactions encode assembly specificity determinants. Kv7 mutations have prominent roles in arrhythmias, deafness, and epilepsy. The structure together with biochemical data indicate that A-domain Tail arrhythmia mutations cluster on the solvent-accessible surface of the subunit interface at a likely site of action for modulatory proteins. Together, the data provide a framework for understanding Kv7 assembly specificity and the molecular basis of a distinct set of Kv7 channelopathies.
Howard
Rebecca J
RJ
Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, CA 94158-2330, USA.
Clark
Kimberly A
KA
Holton
James M
JM
Minor
Daniel L
DL
D000595:Amino Acid Sequence; D003461:Crystallography; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051656:KCNQ Potassium Channels / Q000737:chemistry* / Q000235:genetics*; D051657:KCNQ1 Potassium Channel / Q000737:chemistry / Q000235:genetics; D008133:Long QT Syndrome / Q000235:genetics* / Q000503:physiopathology; D008969:Molecular Sequence Data; D009154:Mutation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; C117367:KCNQ4 protein, human