5j03
Crystal Structure of a chimeric Kv7.2 - Kv7.3 proximal C-terminal Domain in Complex with Calmodulin
Structural highlights
DiseaseKCNQ3_HUMAN Benign familial infantile epilepsy;Benign familial neonatal seizures;Juvenile myoclonic epilepsy. The disease is caused by mutations affecting the gene represented in this entry. Defects in KCNQ3 may be involved in epileptic disorders. These are characterized by paroxysmal transient disturbances of the electrical activity of the brain that may be manifested as episodic impairment or loss of consciousness, abnormal motor phenomena, psychic or sensory disturbances, or perturbation of the autonomic nervous system.[1] FunctionKCNQ2_HUMAN KCNQ3_HUMAN Probably important in the regulation of neuronal excitability. Associates with KCNQ2 or KCNQ5 to form a potassium channel with essentially identical properties to the channel underlying the native M-current, a slowly activating and deactivating potassium conductance which plays a critical role in determining the subthreshold electrical excitability of neurons as well as the responsiveness to synaptic inputs. Publication Abstract from PubMedThe Kv7 channel family, comprising voltage-gated potassium channels, plays major roles in fine-tuning cellular excitability by reducing firing frequency and controlling repolarization. Kv7 channels have a unique intracellular C-terminal (CT) domain bound constitutively by calmodulin (CaM). This domain plays key functions in channel tetramerization, trafficking and gating. CaM binds to the proximal CT, comprised of helices A and B. Kv7.2 and Kv7.3 are expressed in neural tissues. Together they form the hetero-tetrameric M channel. We characterized Kv7.2, Kv7.3 and chimeric Kv7.3 helix A-Kv7.2 helix B (Q3A-Q2B) proximal CT/CaM complexes by solution methods at various Ca2+ concentrations and determined them all to have a 1:1 stoichiometry. We then determined the crystal structure of the Q3A-Q2B/CaM complex at high Ca2+ concentration to 2.0 A resolution. CaM hugs the anti-parallel coiled coil of helices A and B, braced together by an additional helix. The structure displays a hybrid apo-Ca2+ CaM conformation even though four Ca2+ ions are bound. Our results pinpoint unique interactions enabling the possible inter-subunit pairing of Kv7.3 helix A and Kv7.2 helix B while underlining the importance of Kv7.3 helix A's role in stabilizing channel oligomerization. Also, the structure can be used to rationalize various channelopathic mutants. Functionally testing of the chimeric channel found it to have a voltage-dependence similar to the M channel, thereby demonstrating helix A's importance in imparting gating properties. Structural Insights into the M-channel Proximal C-terminus/Calmodulin Complex.,Strulovich R, Tobelaim WS, Attali B, Hirsch JA Biochemistry. 2016 Aug 26. PMID:27564677[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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