View source for 5kjg


==Connexin 26 G12R mutant NMR structure==
<StructureSection load='5kjg' size='340' side='right'caption='[[5kjg]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5kjg]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KJG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5KJG FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 20 models</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</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=5kjg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kjg OCA], [https://pdbe.org/5kjg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5kjg RCSB], [https://www.ebi.ac.uk/pdbsum/5kjg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5kjg ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/CXB2_HUMAN CXB2_HUMAN] KID syndrome;Knuckle pads - leuconychia - sensorineural deafness;Autosomal dominant nonsyndromic sensorineural deafness type DFNA;Autosomal recessive nonsyndromic sensorineural deafness type DFNB;Palmoplantar keratoderma - deafness;Keratoderma hereditarium mutilans. Defects in GJB2 are the cause of deafness autosomal recessive type 1A (DFNB1A) [MIM:[https://omim.org/entry/220290 220290]. DFNB1A 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:11439000</ref> <ref>PMID:14722929</ref> <ref>PMID:15666300</ref> <ref>PMID:15994881</ref> <ref>PMID:9328482</ref> <ref>PMID:9336442</ref> <ref>PMID:9529365</ref> <ref>PMID:9471561</ref> <ref>PMID:10830906</ref> <ref>PMID:11313763</ref> <ref>PMID:12239718</ref> <ref>PMID:12121355</ref> <ref>PMID:12786758</ref> <ref>PMID:15592461</ref> <ref>PMID:17660464</ref> <ref>PMID:19384972</ref>   Defects in GJB2 are the cause of deafness autosomal dominant type 3A (DFNA3A) [MIM:[https://omim.org/entry/601544 601544].  Defects in GJB2 are a cause of Vohwinkel syndrome (VS) [MIM:[https://omim.org/entry/124500 124500]. VS is an autosomal dominant disease characterized by hyperkeratosis, constriction on finger and toes and congenital deafness.<ref>PMID:12668604</ref> <ref>PMID:10369869</ref>   Defects in GJB2 are a cause of palmoplantar keratoderma with deafness (PPKDFN) [MIM:[https://omim.org/entry/148350 148350]. PPKDFN is an autosomal dominant disorder characterized by the association of palmoplantar hyperkeratosis with progressive, bilateral, high-frequency, sensorineural deafness.<ref>PMID:12668604</ref> <ref>PMID:9856479</ref> <ref>PMID:10757647</ref> <ref>PMID:10633135</ref> <ref>PMID:12372058</ref> <ref>PMID:15996214</ref> <ref>PMID:17993581</ref>   Defects in GJB2 are a cause of keratitis-ichthyosis-deafness syndrome (KID syndrome) [MIM:[https://omim.org/entry/148210 148210]; an autosomal dominant form of ectodermal dysplasia. Ectodermal dysplasias (EDs) constitute a heterogeneous group of developmental disorders affecting tissues of ectodermal origin. EDs are characterized by abnormal development of two or more ectodermal structures such as hair, teeth, nails and sweat glands, with or without any additional clinical sign. Each combination of clinical features represents a different type of ectodermal dysplasia. KID syndrome is characterized by the association of hyperkeratotic skin lesions with vascularizing keratitis and profound sensorineural hearing loss. Clinical features include deafness, ichthyosis, photobia, absent or decreased eyebrows, sparse or absent scalp hair, decreased sweating and dysplastic finger and toenails.  Defects in GJB2 are the cause of Bart-Pumphrey syndrome (BPS) [MIM:[https://omim.org/entry/149200 149200]. BPS is an autosomal dominant disorder characterized by sensorineural hearing loss, palmoplantar keratoderma, knuckle pads, and leukonychia, It shows considerable phenotypic variability.<ref>PMID:15482471</ref> <ref>PMID:15952212</ref>   Defects in GJB2 are the cause of ichthyosis hystrix-like with deafness syndrome (HID syndrome) [MIM:[https://omim.org/entry/602540 602540]. HID syndrome is an autosomal-dominant inherited keratinizing disorder characterized by sensorineural deafness and spiky hyperkeratosis affecting the entire skin. HID syndrome is considered to differ from the similar KID syndrome in the extent and time of occurrence of skin symptoms and the severity of the associated keratitis.
== Function ==
[https://www.uniprot.org/uniprot/CXB2_HUMAN CXB2_HUMAN] One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Alterations in gap junctions underlie the etiologies of syndromic deafness (KID) and Charcot-Marie Tooth disease (CMTX). Functional gap junctions are composed of connexin molecules with N-termini containing a flexible turn around G12, inserting the N-termini into the channel pore allowing voltage gating. The loss of this turn correlates with loss of Connexin 32 (Cx32) function by impaired trafficking to the cell membrane. Using (1)H NMR we show the N-terminus of a syndromic deafness mutation Cx26G12R, producing "leaky channels", contains a turn around G12 which is less structured and more flexible than wild-type. In contrast, the N-terminal structure of the same mutation in Cx32 chimera, Cx32*43E1G12R shows a larger constricted turn and no membrane current expression but forms membrane inserted hemichannels. Their function was rescued by formation of heteromeric channels with wild type subunits. We suggest the inflexible Cx32G12R N-terminus blocks ion conduction in homomeric channels and this channel block is relieved by incorporation of wild type subunits. In contrast, the increased open probability of Cx26G12R hemichannels is likely due to the addition of positive charge in the channel pore changing pore electrostatics and impairing hemichannel regulation by Ca(2+). These results provide mechanistic information on aberrant channel activity observed in disease.

Structural studies of N-terminal mutants of Connexin 26 and Connexin 32 using (1)H NMR spectroscopy.,Batir Y, Bargiello TA, Dowd TL Arch Biochem Biophys. 2016 Oct 15;608:8-19. doi: 10.1016/j.abb.2016.06.019. Epub , 2016 Jul 1. PMID:27378082<ref>PMID:27378082</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 5kjg" style="background-color:#fffaf0;"></div>

==See Also==
*[[Connexin 3D structure|Connexin 3D structure]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Bargiello TA]]
[[Category: Dowd TL]]