4gow

From Proteopedia

(Difference between revisions)

Revision as of 11:20, 21 December 2014

Crystal Structure of Ca2+/CaM:Kv7.4 (KCNQ4) B helix complex

Structural highlights

4gow is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	CALM1, CALM, CAM, CAM1, CALM2, CAM2, CAMB, CALM3, CALML2, CAM3, CAMC, CAMIII (Homo sapiens), KCNQ4 (Homo sapiens)
Resources:	FirstGlance, OCA, RCSB, PDBsum

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) is an important regulator of Kv7.x (KCNQx) voltage-gated potassium channels. Channels from this family produce neuronal M currents and cardiac and auditory I(KS) currents and harbor mutations that cause arrhythmias, epilepsy, and deafness. Despite extensive functional characterization, biochemical and structural details of the interaction between CaM and the channel have remained elusive. Here, we show that both apo-CaM and Ca(2+)/CaM bind to the C-terminal tail of the neuronal channel Kv7.4 (KCNQ4), which is involved in both hearing and mechanosensation. Interactions between apo-CaM and the Kv7.4 tail involve two C-terminal tail segments, known as the A and B segments, whereas the interaction between Ca(2+)/CaM and the Kv7.4 C-terminal tail requires only the B segment. Biochemical studies show that the calcium dependence of the CaM:B segment interaction is conserved in all Kv7 subtypes. X-ray crystallographic determination of the structure of the Ca(2+)/CaM:Kv7.4 B segment complex shows that Ca(2+)/CaM wraps around the Kv7.4 B segment, which forms an alpha-helix, in an antiparallel orientation that embodies a variation of the classic 1-14 Ca(2+)/CaM interaction motif. Taken together with the context of prior studies, our data suggest a model for modulation of neuronal Kv7 channels involving a calcium-dependent conformational switch from an apo-CaM form that bridges the A and B segments to a Ca(2+)/CaM form bound to the B-helix. The structure presented here also provides a context for a number of disease-causing mutations and for further dissection of the mechanisms by which CaM controls Kv7 function.

Structure of a Ca(2+)/CaM:Kv7.4 (KCNQ4) B-Helix Complex Provides Insight into M Current Modulation.,Xu Q, Chang A, Tolia A, Minor DL Jr J Mol Biol. 2012 Nov 23. pii: S0022-2836(12)00895-9. doi:, 10.1016/j.jmb.2012.11.023. PMID:23178170^[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
↑ Xu Q, Chang A, Tolia A, Minor DL Jr. Structure of a Ca(2+)/CaM:Kv7.4 (KCNQ4) B-Helix Complex Provides Insight into M Current Modulation. J Mol Biol. 2012 Nov 23. pii: S0022-2836(12)00895-9. doi:, 10.1016/j.jmb.2012.11.023. PMID:23178170 doi:10.1016/j.jmb.2012.11.023

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/4gow"

@@ Line 1: / Line 1: @@
-{{STRUCTURE_4gow|  PDB=4gow  |  SCENE=  }}
+==Crystal Structure of Ca2+/CaM:Kv7.4 (KCNQ4) B helix complex==
-===Crystal Structure of Ca2+/CaM:Kv7.4 (KCNQ4) B helix complex===
+<StructureSection load='4gow' size='340' side='right' caption='[[4gow]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
-{{ABSTRACT_PUBMED_23178170}}
+== Structural highlights ==
+<table><tr><td colspan='2'>[[4gow]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GOW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GOW FirstGlance]. <br>
-==Disease==
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CALM1, CALM, CAM, CAM1, CALM2, CAM2, CAMB, CALM3, CALML2, CAM3, CAMC, CAMIII ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]), KCNQ4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4gow FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gow OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4gow RCSB], [http://www.ebi.ac.uk/pdbsum/4gow PDBsum]</span></td></tr>
+</table>
+== Disease ==
 [[http://www.uniprot.org/uniprot/KCNQ4_HUMAN KCNQ4_HUMAN]] Defects in KCNQ4 are the cause of deafness autosomal dominant type 2A (DFNA2A) [MIM:[http://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 ==
+[[http://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) is an important regulator of Kv7.x (KCNQx) voltage-gated potassium channels. Channels from this family produce neuronal M currents and cardiac and auditory I(KS) currents and harbor mutations that cause arrhythmias, epilepsy, and deafness. Despite extensive functional characterization, biochemical and structural details of the interaction between CaM and the channel have remained elusive. Here, we show that both apo-CaM and Ca(2+)/CaM bind to the C-terminal tail of the neuronal channel Kv7.4 (KCNQ4), which is involved in both hearing and mechanosensation. Interactions between apo-CaM and the Kv7.4 tail involve two C-terminal tail segments, known as the A and B segments, whereas the interaction between Ca(2+)/CaM and the Kv7.4 C-terminal tail requires only the B segment. Biochemical studies show that the calcium dependence of the CaM:B segment interaction is conserved in all Kv7 subtypes. X-ray crystallographic determination of the structure of the Ca(2+)/CaM:Kv7.4 B segment complex shows that Ca(2+)/CaM wraps around the Kv7.4 B segment, which forms an alpha-helix, in an antiparallel orientation that embodies a variation of the classic 1-14 Ca(2+)/CaM interaction motif. Taken together with the context of prior studies, our data suggest a model for modulation of neuronal Kv7 channels involving a calcium-dependent conformational switch from an apo-CaM form that bridges the A and B segments to a Ca(2+)/CaM form bound to the B-helix. The structure presented here also provides a context for a number of disease-causing mutations and for further dissection of the mechanisms by which CaM controls Kv7 function.
-==Function==
+Structure of a Ca(2+)/CaM:Kv7.4 (KCNQ4) B-Helix Complex Provides Insight into M Current Modulation.,Xu Q, Chang A, Tolia A, Minor DL Jr J Mol Biol. 2012 Nov 23. pii: S0022-2836(12)00895-9. doi:, 10.1016/j.jmb.2012.11.023. PMID:23178170<ref>PMID:23178170</ref>
-[[http://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>
-==About this Structure==
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[4gow]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GOW OCA].
+</div>
-==Reference==
+==See Also==
-<ref group="xtra">PMID:023178170</ref><references group="xtra"/><references/>
+*[[Calmodulin|Calmodulin]]
+*[[Galactosidase|Galactosidase]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Chang, A.]]
+[[Category: Chang, A]]
-[[Category: Minor, D L.]]
+[[Category: Minor, D L]]
-[[Category: Tolia, A.]]
+[[Category: Tolia, A]]
-[[Category: Xu, Q.]]
+[[Category: Xu, Q]]
 [[Category: Calmodulin]]
 [[Category: Ion channel]]

4gow

From Proteopedia

Revision as of 11:20, 21 December 2014

Crystal Structure of Ca2+/CaM:Kv7.4 (KCNQ4) B helix complex

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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