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1.A.24.1.3
Heteromeric connexin (Cx)32/Cx26) (transports cAMP, cGMP and all inositol phosphates with 1-4 esterified phosphate groups (homomeric Cx26(β2) or homomeric Cx32 do not transport the inositol phosphates as well) (Ayad et al., 2006). The GJB2 gene encodes connexin 26, the protein involved in cell-cell attachment in many tissues. GJB2 mutations cause autosomal recessive (DFNB1) and sometimes dominant (DFNA3) non-syndromic sensorineural hearing loss as well as various skin disease phenotypes (Iossa et al., 2011). TMS1 regulates oligomerization and function (Jara et al., 2012).  The carboxyl tail pg Cx32 regulates gap junction assembly (Katoch et al. 2015).  In Cx46, neutralization of negative charges or addition of positive charge in the Cx26 equivalent region reduced the slow gate voltage dependence. In Cx50 the addition of a glutamate in the same region decreased the voltage dependence and the neutralization of a negative charge increased it. Thus, the charges at the end of TMS1 are part of the slow gate voltage sensor in Cxs. The fact that Cx42, which has no charge in this region, still presents voltage dependent slow gating suggests that charges still unidentified also contribute to the slow gate voltage sensitivity (Pinto et al. 2016).  Syndromic deafness mutations at Asn14 alter the open stability of Cx26 hemichannels (Sanchez et al. 2016). The Leu89Pro substitution in the second TMS of CX32 disrupts the trafficking of the protein, inhibiting the assembly of CX32 gap junctions, which in turn may result in peripheral neuropathy (Da et al. 2016).  Cx26 mutants that promote cell death or exert transdominant effects on other connexins in keratinocytes lead to skin diseases and hearing loss, whereas mutants having reduced channel function without aberrant effects on coexpressed connexins cause only hearing loss (Press et al. 2017). When challenged by a field of 0.06 V/nm, the Cx26 hemichannel relaxed toward a novel configuration characterized by a widened pore and an increased bending of the second TMS at the level of the conserved Pro87. A point mutation that inhibited such a transition impeded hemichannel opening in electrophysiology and dye uptake experiments.  Thus, the Cx26 hemichannel uses a global degree of freedom to transit between different configuration states, which may be shared among all connexins (Zonta et al. 2018). A group of human mutations within the N-terminal (NT) domain of connexin 26 hemichannels produce aberrant channel activity, which gives rise to deafness and skin disorders, including keratitis-ichthyosis-deafness (KID) syndrome. Structural and functional studies indicate that the NT domain of connexin hemichannels is folded into the pore, where it plays important roles in permeability and gating. The mutation, N14K disrupts cytosolic intersubunit interactions and promotes channel opening (Valdez Capuccino et al. 2018). A missense mutation in the Connexin 26 gene is associated with autosomal recessive sensorineural deafness (Leshinsky-Silver et al. 2005).

Accession Number:P08034
Protein Name:Cx32 aka Gap junction beta-1 protein
Length:283
Molecular Weight:32025.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:4
Location1 / Topology2 / Orientation3: Cell membrane1 / Multi-pass membrane protein2
Substrate cAMP, cGMP, Inositol phosphates, small molecules

Cross database links:

Genevestigator: P08034
eggNOG: prNOG16944
HEGENOM: HBG717760
RefSeq: NP_000157.1    NP_001091111.1   
Entrez Gene ID: 2705   
Pfam: PF00029    PF10582   
OMIM: 145900  phenotype
302800  phenotype
304040  gene
KEGG: hsa:2705   

Gene Ontology

GO:0005922 C:connexon complex
GO:0005789 C:endoplasmic reticulum membrane
GO:0016021 C:integral to membrane
GO:0005243 F:gap junction channel activity
GO:0007267 P:cell-cell signaling
GO:0007399 P:nervous system development

References (66)

[1] “Cloning and characterization of human and rat liver cDNAs coding for a gap junction protein.”  Kumar N.M.et.al.   2875078
[2] “Complete sequencing and characterization of 21,243 full-length human cDNAs.”  Ota T.et.al.   14702039
[3] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[4] “Topology of the 32-kd liver gap junction protein determined by site-directed antibody localizations.”  Milks L.C.et.al.   2460334
[5] “A Calpha model for the transmembrane alpha helices of gap junction intercellular channels.”  Fleishman S.J.et.al.   15383278
[6] “Mutations in the peripheral myelin genes and associated genes in inherited peripheral neuropathies.”  Nelis E.et.al.   9888385
[7] “Connexin mutations in X-linked Charcot-Marie-Tooth disease.”  Bergoffen J.et.al.   8266101
[8] “Mutations in the connexin 32 gene in X-linked dominant Charcot-Marie-Tooth disease (CMTX1).”  Fairweather N.et.al.   8162049
[9] “Point mutations of the connexin32 (GJB1) gene in X-linked dominant Charcot-Marie-Tooth neuropathy.”  Ionasescu V.et.al.   8004109
[10] “X-linked dominant Charcot-Marie-Tooth neuropathy: valine-38-methionine substitution of connexin32.”  Orth U.et.al.   7833935
[11] “New connexin32 mutations associated with X-linked Charcot-Marie-Tooth disease.”  Bone L.J.et.al.   7477983
[12] “Correlation between connexin 32 gene mutations and clinical phenotype in X-linked dominant Charcot-Marie-Tooth neuropathy.”  Ionasescu V.et.al.   8737658
[13] “X-linked dominant Charcot-Marie-Tooth neuropathy (CMTX): new mutations in the connexin32 gene.”  Ressot C.et.al.   8698335
[14] “Novel mutations in the connexin 32 gene associated with X-linked Charcot-Marie tooth disease.”  Tan C.C.et.al.   8829637
[15] “Novel missense mutation of the connexin32 (GJB1) gene in X-linked dominant Charcot-Marie-Tooth neuropathy.”  Schiavon F.et.al.   8807343
[16] “Two novel mutations (C53S, S26L) in the connexin32 of Charcot-Marie-Tooth disease type X families.”  Yoshimura T.et.al.   8889588
[17] “A point mutation in codon 3 of connexin-32 is associated with X-linked Charcot-Marie-Tooth neuropathy.”  Gupta S.et.al.   8956046
[18] “Arginine-164-tryptophan substitution in connexin32 associated with X linked dominant Charcot-Marie-Tooth disease.”  Oterino A.et.al.   8733054
[19] “Linkage and mutation analysis of Charcot-Marie-Tooth neuropathy type 2 families with chromosomes 1p35-p36 and Xq13.”  Timmerman V.et.al.   8628473
[20] “New mutations in the X-linked form of Charcot-Marie-Tooth disease.”  Latour P.et.al.   9018031
[21] “Connexin32 gene mutations in X-linked dominant Charcot-Marie-Tooth disease (CMTX1).”  Janssen E.A.M.et.al.   9099841
[22] “Mutational analysis of the MPZ, PMP22 and Cx32 genes in patients of Spanish ancestry with Charcot-Marie-Tooth disease and hereditary neuropathy with liability to pressure palsies.”  Bort S.et.al.   9187667
[23] “Screening for connexin 32 mutations in Charcot-Marie-Tooth disease families with possible X-linked inheritance.”  Silander K.et.al.   9272161
[24] “Mutation analysis of the connexin 32 (Cx32) gene in Charcot-Marie-Tooth neuropathy type 1: identification of five new mutations.”  Nelis E.et.al.   8990008
[25] “Charcot-Marie-Tooth disease with intermediate motor nerve conduction velocities: characterization of 14 Cx32 mutations in 35 families.”  Rouger H.et.al.   9401007
[26] “Connexin32 and X-linked Charcot-Marie-Tooth disease.”  Bone L.J.et.al.   9361298
[27] “Mutations in the X-linked form of Charcot-Marie-Tooth disease in the French population.”  Latour P.et.al.   10732813
[28] “Four novel mutations of the connexin 32 gene in four Japanese families with Charcot-Marie-Tooth disease type 1.”  Ikegami T.et.al.   9856562
[29] “X-linked Charcot-Marie-Tooth disease and connexin32.”  Ionasescu V.V.et.al.   10873293
[30] “A novel mutation (C201R) in the transmembrane domain of connexin 32 in severe X-linked Charcot-Marie-Tooth disease.”  Sillen A.et.al.   9452025
[31] “Mutation analysis in Charcot-Marie-Tooth disease type 1 (CMT1).”  Sorour E.et.al.   9452099
[32] “Spectrum of mutations in Finnish patients with Charcot-Marie-Tooth disease and related neuropathies.”  Silander K.et.al.   9633821
[33] “Mutations of connexin32 in Charcot-Marie-Tooth disease type X interfere with cell-to-cell communication but not cell proliferation and myelin-specific gene expression.”  Yoshimura T.et.al.   9469569
[34] “Efficient neurophysiologic selection of X-linked Charcot-Marie-Tooth families: ten novel mutations.”  Nicholson G.A.et.al.   9818870
[35] “HMSN and HNPP. Laboratory service provision in the south west of England -- two years' experience.”  Williams M.M.et.al.   10586284
[36] “Three novel mutations in the gap junction beta 1 (GJB1) gene coding region identified in Charcot-Marie-Tooth patients of Greek origin: T55I, R164Q, V120E.”  Karadimas C.et.al.   10220155
[37] “Central visual, acoustic, and motor pathway involvement in a Charcot-Marie-Tooth family with an Asn205Ser mutation in the connexin 32 gene.”  Baehr M.et.al.   10071100
[38] “Altered formation of hemichannels and gap junction channels caused by C-terminal connexin-32 mutations.”  Castro C.et.al.   10234007
[39] “Mutational analysis and genotype/phenotype correlation in Turkish Charcot-Marie-Tooth type 1 and HNPP patients.”  Bissar-Tadmouri N.et.al.   11140841
[40] “A family with X-linked dominant Charcot-Marie-Tooth caused by a connexin32 mutation.”  Verhelst H.E.et.al.   11030070
[41] “Severe X-linked Charcot-Marie-Tooth neuropathy due to new mutations [G59R(G-->C), W44X(G-->A)] in the connexin 32 gene.”  Felice K.J.et.al.   10894999
[42] “Screening for mutations in the peripheral myelin genes PMP22, MPZ and Cx32 (GJB1) in Russian Charcot-Marie-Tooth neuropathy patients.”  Mersiyanova I.V.et.al.   10737979
[43] “Mutations in the peripheral myelin protein zero and connexin32 genes detected by non-isotopic RNase cleavage assay and their phenotypes in Japanese patients with Charcot-Marie-Tooth disease.”  Yoshihara T.et.al.   10923043
[44] “A new de novo mutation of the connexin-32 gene in a patient with X-linked Charcot-Marie-Tooth type 1 disease.”  Di Iorio G.et.al.   10938190
[45] “Clinical, electrophysiological and molecular genetic characteristics of 93 patients with X-linked Charcot-Marie-Tooth disease.”  Dubourg O.et.al.   11571214
[46] “A novel connexin 32 missense mutation (E208G) causing Charcot-Marie-Tooth disease.”  Kochanski A.et.al.   11180613
[47] “Charcot-Marie-Tooth disease type I and related demyelinating neuropathies: mutation analysis in a large cohort of Italian families.”  Mostacciuolo M.L.et.al.   11438991
[48] “Charcot-Marie-Tooth type X: a novel mutation in the Cx32 gene with central conduction slowing.”  Seeman P.et.al.   11562788
[49] “Mutation analysis in Chariot-Marie Tooth disease type 1: point mutations in the MPZ gene and the GJB1 gene cause comparable phenotypic heterogeneity.”  Young P.et.al.   11437164
[50] “Episodes of generalized weakness in two sibs with the C164T mutation of the connexin 32 gene.”  Panas M.et.al.   11723288
[51] “Charcot-Marie-Tooth disease and related neuropathies: mutation distribution and genotype-phenotype correlation.”  Boerkoel C.F.et.al.   11835375
[52] “Transient central nervous system white matter abnormality in X-linked Charcot-Marie-Tooth disease.”  Paulson H.L.et.al.   12325071
[53] “Molecular analysis in Japanese patients with Charcot-Marie-Tooth disease: DGGE analysis for PMP22, MPZ, and Cx32/GJB1 mutations.”  Numakura C.et.al.   12402337
[54] “Six novel connexin32 (GJB1) mutations in X-linked Charcot-Marie-Tooth disease.”  Lee M.-J.et.al.   12185164
[55] “Diverse trafficking abnormalities of connexin32 mutants causing CMTX.”  Yum S.W.et.al.   12460545
[56] “X-linked Charcot-Marie-Tooth disease caused by a novel point mutation in the connexin-32 gene.”  Ma W.et.al.   12536289
[57] “Charcot-Marie-Tooth neuropathy: clinical phenotypes of four novel mutations in the MPZ and Cx 32 genes.”  Street V.A.et.al.   12207932
[58] “Voltage opens unopposed gap junction hemichannels formed by a connexin 32 mutant associated with X-linked Charcot-Marie-Tooth disease.”  Abrams C.K.et.al.   11891346
[59] “Transient, recurrent, white matter lesions in X-linked Charcot-Marie-Tooth disease with novel connexin 32 mutation.”  Hanemann C.O.et.al.   12707076
[60] “Demyelinating and axonal features of Charcot-Marie-Tooth disease with mutations of myelin-related proteins (PMP22, MPZ and Cx32): a clinicopathological study of 205 Japanese patients.”  Hattori N.et.al.   12477701
[61] “Novel mutations in the Charcot-Marie-Tooth disease genes PMP22, MPZ, and GJB1.”  Huehne K.et.al.   12497641
[62] “Pathogenesis of X-linked Charcot-Marie-Tooth disease: differential effects of two mutations in connexin 32.”  Abrams C.K.et.al.   14627639
[63] “Mutational analysis of PMP22, MPZ, GJB1, EGR2 and NEFL in Korean Charcot-Marie-Tooth neuropathy patients.”  Choi B.-O.et.al.   15241803
[64] “Severe neuropathy with leaky connexin32 hemichannels.”  Liang G.S.L.et.al.   15852376
[65] “X-linked Charcot-Marie-Tooth disease: phenotypic expression of a novel mutation Ile127Ser in the GJB1 (connexin 32) gene.”  Vondracek P.et.al.   15468313
[66] “Two missense mutations of EGR2 R359W and GJB1 V136A in a Charcot-Marie-Tooth disease family.”  Chung K.W.et.al.   15947997
Structure:
1TXH     

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FASTA formatted sequence
1:	MNWTGLYTLL SGVNRHSTAI GRVWLSVIFI FRIMVLVVAA ESVWGDEKSS FICNTLQPGC 
61:	NSVCYDQFFP ISHVRLWSLQ LILVSTPALL VAMHVAHQQH IEKKMLRLEG HGDPLHLEEV 
121:	KRHKVHISGT LWWTYVISVV FRLLFEAVFM YVFYLLYPGY AMVRLVKCDV YPCPNTVDCF 
181:	VSRPTEKTVF TVFMLAASGI CIILNVAEVV YLIIRACARR AQRRSNPPSR KGSGFGHRLS 
241:	PEYKQNEINK LLSEQDGSLK DILRRSPGTG AGLAEKSDRC SAC