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6n5w

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

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:
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.^[1] ^[2] ^[3] ^[4] ^[5]

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.^[6]

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^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Kubisch C, Schroeder BC, Friedrich T, Lutjohann B, El-Amraoui A, Marlin S, Petit C, Jentsch TJ. KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness. Cell. 1999 Feb 5;96(3):437-46. PMID:10025409
↑ Coucke PJ, Van Hauwe P, Kelley PM, Kunst H, Schatteman I, Van Velzen D, Meyers J, Ensink RJ, Verstreken M, Declau F, Marres H, Kastury K, Bhasin S, McGuirt WT, Smith RJ, Cremers CW, Van de Heyning P, Willems PJ, Smith SD, Van Camp G. Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families. Hum Mol Genet. 1999 Jul;8(7):1321-8. PMID:10369879
↑ Talebizadeh Z, Kelley PM, Askew JW, Beisel KW, Smith SD. Novel mutation in the KCNQ4 gene in a large kindred with dominant progressive hearing loss. Hum Mutat. 1999;14(6):493-501. PMID:10571947 doi:<493::AID-HUMU8>3.0.CO;2-P 10.1002/(SICI)1098-1004(199912)14:6<493::AID-HUMU8>3.0.CO;2-P
↑ Van Hauwe P, Coucke PJ, Ensink RJ, Huygen P, Cremers CW, Van Camp G. Mutations in the KCNQ4 K+ channel gene, responsible for autosomal dominant hearing loss, cluster in the channel pore region. Am J Med Genet. 2000 Jul 31;93(3):184-7. PMID:10925378
↑ Arnett J, Emery SB, Kim TB, Boerst AK, Lee K, Leal SM, Lesperance MM. Autosomal dominant progressive sensorineural hearing loss due to a novel mutation in the KCNQ4 gene. Arch Otolaryngol Head Neck Surg. 2011 Jan;137(1):54-9. doi:, 10.1001/archoto.2010.234. PMID:21242547 doi:10.1001/archoto.2010.234
↑ Sogaard R, Ljungstrom T, Pedersen KA, Olesen SP, Jensen BS. KCNQ4 channels expressed in mammalian cells: functional characteristics and pharmacology. Am J Physiol Cell Physiol. 2001 Apr;280(4):C859-66. PMID:11245603
↑ Archer CR, Enslow BT, Taylor AB, De la Rosa V, Bhattacharya A, Shapiro MS. A mutually-induced conformational fit underlies Ca(2+)-directed interactions between calmodulin and the proximal C terminus of KCNQ4 K(+) channels. J Biol Chem. 2019 Feb 26. pii: RA118.006857. doi: 10.1074/jbc.RA118.006857. PMID:30808708 doi:http://dx.doi.org/10.1074/jbc.RA118.006857

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6n5w"

Categories: Homo sapiens | Large Structures | Archer CR | Shapiro MS | Taylor AB

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6n5w is ON HOLD
+==Crystal structure of the Ca2+/CaM complex with independent peptides of Kv7.4 (KCNQ4) A & B domains==
+<StructureSection load='6n5w' size='340' side='right'caption='[[6n5w]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6n5w]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6N5W OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6N5W FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.15&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6n5w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6n5w OCA], [https://pdbe.org/6n5w PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6n5w RCSB], [https://www.ebi.ac.uk/pdbsum/6n5w PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6n5w ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/KCNQ4_HUMAN KCNQ4_HUMAN] Defects in KCNQ4 are the cause of deafness autosomal dominant type 2A (DFNA2A) [MIM:[https://omim.org/entry/600101 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.<ref>PMID:10025409</ref> <ref>PMID:10369879</ref> <ref>PMID:10571947</ref> <ref>PMID:10925378</ref> <ref>PMID:21242547</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/KCNQ4_HUMAN 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.<ref>PMID:11245603</ref>
+<div style="background-color:#fffaf0;">
+== 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.
-Authors: Taylor, A.B., Archer, C.R., Shapiro, M.S.
+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<ref>PMID:30808708</ref>
-Description: Crystal structure of the Ca2+/CaM complex with independent peptides of Kv7.4 (KCNQ4) A & B domains
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Shapiro, M.S]]
+<div class="pdbe-citations 6n5w" style="background-color:#fffaf0;"></div>
-[[Category: Archer, C.R]]
-[[Category: Taylor, A.B]]
+==See Also==
+*[[Calmodulin 3D structures|Calmodulin 3D structures]]
+*[[Potassium channel 3D structures|Potassium channel 3D structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Archer CR]]
+[[Category: Shapiro MS]]
+[[Category: Taylor AB]]

6n5w

From Proteopedia

Current revision

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

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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