6n5w

Crystal structure of the Ca2+/CaM complex with independent peptides of Kv7.4 (KCNQ4) A & B domains

spinqualitylabelsall models 6n5w, resolution 2.15Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6n5w is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.15Å Ligands: CA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease KCNQ4_HUMAN Defects in KCNQ4 are the cause of deafness autosomal dominant type 2A (DFNA2A) [MIM:600101. DFNA2A is a form of sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. Function KCNQ4_HUMAN Probably important in the regulation of neuronal excitability. May underlie a potassium current involved in regulating the excitability of sensory cells of the cochlea. KCNQ4 channels are blocked by linopirdin, XE991 and bepridil, whereas clofilium is without significant effect. Muscarinic agonist oxotremorine-M strongly suppress KCNQ4 current in CHO cells in which cloned KCNQ4 channels were coexpressed with M1 muscarinic receptors. Publication Abstract from PubMed Calmodulin (CaM) conveys intracellular Ca(2+) signals to KCNQ (Kv7, "M-type") K(+) channels and many other ion channels. Whether this "calmodulation" involves a dramatic structural rearrangement or only slight perturbations of the CaM-KCNQ complex is as yet unclear. A consensus structural model of conformational shifts occurring between low-nM to physiologically high intracellular [Ca(2+)] is still under debate. Here, we used various techniques of biophysical chemical analyses to investigate the interactions between CaM and synthetic peptides corresponding to the A and B domains of the KCNQ4 subtype. We found that in the absence of CaM, the peptides are disordered, whereas Ca(2+)/CaM imposed helical structure on both KCNQ A and B domains. Isothermal titration calorimetry revealed that Ca(2+)/CaM has higher affinity for the B domain than for the A domain of KCNQ2-4 and much higher affinity for the B domain when prebound with the A domain. X-ray crystallography confirmed these discrete peptides spontaneously bind Ca(2+)/CaM, similar to previous reports of CaM binding KCNQ-AB domains that are linked together. Microscale thermophoresis and HSQC-NMR indicated the C-lobe of Ca(2+)-free CaM to interact with the KCNQ4 B domain (Kd ~10-20 microM), with increasing Ca(2+) molar ratios shifting the CaM-B domain interactions via only the CaM C-lobe to also include the N-lobe. Our findings suggest that in response to increased Ca(2+), CaM undergoes lobe-switching that imposes a dramatic mutually induced conformational fit to both the proximal C-terminus of KCNQ4 channels and CaM, likely underlying Ca(2+)-dependent regulation of KCNQ gating. A mutually-induced conformational fit underlies Ca(2+)-directed interactions between calmodulin and the proximal C terminus of KCNQ4 K(+) channels.,Archer CR, Enslow BT, Taylor AB, De la Rosa V, Bhattacharya A, Shapiro MS J Biol Chem. 2019 Feb 26. pii: RA118.006857. doi: 10.1074/jbc.RA118.006857. PMID:30808708 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Calmodulin 3D structures Potassium channel 3D structures

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