8sik
From Proteopedia
KCNQ1 with voltage sensor in the up conformation
Structural highlights
DiseaseCALM1_HUMAN The disease is caused by mutations affecting the gene represented in this entry. Mutations in CALM1 are the cause of CPVT4. The disease is caused by mutations affecting the gene represented in this entry. Mutations in CALM1 are the cause of LQT14. FunctionCALM1_HUMAN Calmodulin mediates the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding. Among the enzymes to be stimulated by the calmodulin-calcium complex are a number of protein kinases and phosphatases. Together with CCP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis (PubMed:16760425). Mediates calcium-dependent inactivation of CACNA1C (PubMed:26969752). Positively regulates calcium-activated potassium channel activity of KCNN2 (PubMed:27165696).[1] [2] [3] [4] Publication Abstract from PubMedVoltage-dependent ion channels underlie the propagation of action potentials and other forms of electrical activity in cells. In these proteins, voltage sensor domains (VSDs) regulate opening and closing of the pore through the displacement of their positive-charged S4 helix in response to the membrane voltage. The movement of S4 at hyperpolarizing membrane voltages in some channels is thought to directly clamp the pore shut through the S4-S5 linker helix. The KCNQ1 channel (also known as K(v)7.1), which is important for heart rhythm, is regulated not only by membrane voltage but also by the signaling lipid phosphatidylinositol 4,5-bisphosphate (PIP(2)). KCNQ1 requires PIP(2) to open and to couple the movement of S4 in the VSD to the pore. To understand the mechanism of this voltage regulation, we use cryogenic electron microscopy to visualize the movement of S4 in the human KCNQ1 channel in lipid membrane vesicles with a voltage difference across the membrane, i.e., an applied electric field in the membrane. Hyperpolarizing voltages displace S4 in such a manner as to sterically occlude the PIP(2)-binding site. Thus, in KCNQ1, the voltage sensor acts primarily as a regulator of PIP(2) binding. The voltage sensors' influence on the channel's gate is indirect through the reaction sequence: voltage sensor movement --> alter PIP(2) ligand affinity --> alter pore opening. The membrane electric field regulates the PIP(2)-binding site to gate the KCNQ1 channel.,Mandala VS, MacKinnon R Proc Natl Acad Sci U S A. 2023 May 23;120(21):e2301985120. doi: , 10.1073/pnas.2301985120. Epub 2023 May 16. PMID:37192161[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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