{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Archer CR"],"funding":["HHS | National Institutes of Health","University of Texas Health Science Center at San Antonio","NCATS NIH HHS","Morrison Trust","NIAID NIH HHS","NHLBI NIH HHS","NINDS NIH HHS","NCI NIH HHS","NIGMS NIH HHS","NIH HHS"],"pagination":["6094-6112"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC6463706"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["294(15)"],"pubmed_abstract":["Calmodulin (CaM) conveys intracellular Ca2+ 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 nanomolar and physiologically high intracellular [Ca2+] 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 Ca2+/CaM imposed helical structure on both KCNQ A and B domains. Isothermal titration calorimetry revealed that Ca2+/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 that these discrete peptides spontaneously form a complex with Ca2+/CaM, similar to previous reports of CaM binding KCNQ-AB domains that are linked together. Microscale thermophoresis and heteronuclear single-quantum coherence NMR spectroscopy indicated the C-lobe of Ca2+-free CaM to interact with the KCNQ4 B domain (Kd ∼10-20 μm), with increasing Ca2+ 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 Ca2+, 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 Ca2+-dependent regulation of KCNQ gating."],"journal":["The Journal of biological chemistry"],"pubmed_title":["A mutually induced conformational fit underlies Ca2+-directed interactions between calmodulin and the proximal C terminus of KCNQ4 K+ channels."],"pmcid":["PMC6463706"],"funding_grant_id":["R01 AI104476","UL1 TR001120","T32 HL007446","P30 GM124165","P30 CA054174","Research Award","R01 NS043394","F31 NS090887","K12 GM111726","Faculty Scholar Award","S10 OD021527","R01 NS065138","R01 NS094461","R56 NS065138"],"pubmed_authors":["Enslow BT","Bhattacharya A","Archer CR","Taylor AB","Shapiro MS","De la Rosa V"],"additional_accession":[]},"is_claimable":false,"name":"A mutually induced conformational fit underlies Ca2+-directed interactions between calmodulin and the proximal C terminus of KCNQ4 K+ channels.","description":"Calmodulin (CaM) conveys intracellular Ca2+ 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 nanomolar and physiologically high intracellular [Ca2+] 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 Ca2+/CaM imposed helical structure on both KCNQ A and B domains. Isothermal titration calorimetry revealed that Ca2+/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 that these discrete peptides spontaneously form a complex with Ca2+/CaM, similar to previous reports of CaM binding KCNQ-AB domains that are linked together. Microscale thermophoresis and heteronuclear single-quantum coherence NMR spectroscopy indicated the C-lobe of Ca2+-free CaM to interact with the KCNQ4 B domain (Kd ∼10-20 μm), with increasing Ca2+ 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 Ca2+, 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 Ca2+-dependent regulation of KCNQ gating.","dates":{"release":"2019-01-01T00:00:00Z","publication":"2019 Apr","modification":"2026-04-29T22:54:40.419Z","creation":"2025-04-04T09:44:08.358Z"},"accession":"S-EPMC6463706","cross_references":{"pubmed":["30808708"],"doi":["10.1074/jbc.ra118.006857","10.1074/jbc.RA118.006857"]}}