P08050 (CXA1_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Gap junction alpha-1 protein

Alternative name(s):
Connexin-43
Short name=Cx43
Gap junction 43 kDa heart protein

Gene names

Name:	Gja1
Synonyms:	Cxn-43

Organism

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	382 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Gap junction protein that acts as a regulator of bladder capacity. A 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. Negative regulator of bladder functional capacity: acts by enhancing intercellular electrical and chemical transmission, thus sensitizing bladder muscles to cholinergic neural stimuli and causing them to contract By similarity.
Subunit structure	A connexon is composed of a hexamer of connexins. Interacts with SGSM3. Interacts with KIAA1432/CIP150. Interacts with CNST and CSNK1D By similarity. Interacts (via C-terminus) with TJP1. Interacts (via C-terminus) with SRC (via SH3 domain). Interacts with UBQLN4. Ref.10 Ref.12 Ref.13
Subcellular location	Cell membrane; Multi-pass membrane protein. Cell junction › gap junction Ref.13.
Induction	In bladder smooth muscle cells, exhibits night/day variations with low levels during the sleep phase, at circadian time (CT) 4-8 (at protein level). Expression starts to increase around CT12 and forms a plateau during the active phase (CT16-24) (at protein level). Ref.11
Post-translational modification	Contains at least one intramolecular disulfide bond. Phosphorylation at Ser-325, Ser-328 and Ser-330 by CK1 modulates gap junction assembly. Phosphorylated at Ser-368 by PRKCG; phosphorylation induces disassembly of gap junction plaques and inhibition of gap junction activity By similarity. Ref.9 Sumoylated with SUMO1, SUMO2 and SUMO3, which may regulate the level of functional Cx43 gap junctions at the plasma membrane. May be desumoylated by SENP1 or SENP2 By similarity. S-nitrosylation at Cys-271 is enriched at the muscle endothelial gap junction in arteries, it augments channel permeability and may regulate of smooth muscle cell to endothelial cell communication.
Sequence similarities	Belongs to the connexin family. Alpha-type (group II) subfamily.

Ontologies

Keywords
Cellular component	Cell junction Cell membrane Gap junction Membrane
Domain	Transmembrane Transmembrane helix
PTM	Disulfide bond Isopeptide bond Phosphoprotein S-nitrosylation Ubl conjugation
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	ATP transport Inferred from mutant phenotype PubMed 16731531. Source: RGD adult heart development Inferred from electronic annotation. Source: Compara apoptotic process Inferred from mutant phenotype PubMed 17107662. Source: RGD atrial ventricular junction remodeling Inferred from electronic annotation. Source: Compara blood vessel morphogenesis Inferred from electronic annotation. Source: Compara cardiac conduction Inferred from electronic annotation. Source: Compara cell communication by chemical coupling Inferred from electronic annotation. Source: Compara cell communication by electrical coupling Inferred from electronic annotation. Source: Compara cell-cell signaling Inferred from direct assay PubMed 15048573. Source: RGD cellular response to mechanical stimulus Inferred from expression pattern PubMed 10631100. Source: RGD chronic inflammatory response Inferred from mutant phenotype PubMed 23165424. Source: RGD elevation of cytosolic calcium ion concentration Inferred from mutant phenotype PubMed 22577485. Source: RGD endothelium development Inferred from expression pattern PubMed 10990491. Source: RGD epithelial cell maturation Inferred from electronic annotation. Source: Compara gap junction assembly Traceable author statement PubMed 15709751. Source: UniProtKB heart development Inferred from expression pattern PubMed 8944820. Source: RGD heart looping Inferred from electronic annotation. Source: Compara in utero embryonic development Inferred from electronic annotation. Source: Compara lens development in camera-type eye Inferred from electronic annotation. Source: Compara limb bud formation Inferred from electronic annotation. Source: Compara milk ejection Inferred from electronic annotation. Source: Compara negative regulation of cardiac muscle cell proliferation Inferred from mutant phenotype PubMed 19377854. Source: RGD negative regulation of gene expression Inferred from electronic annotation. Source: Compara neuron migration Inferred from electronic annotation. Source: Compara neuron projection morphogenesis Inferred from mutant phenotype PubMed 16731531. Source: RGD osteoblast differentiation Inferred from electronic annotation. Source: Compara positive regulation of I-kappaB kinase/NF-kappaB cascade Inferred from electronic annotation. Source: Compara positive regulation of behavioral fear response Inferred from mutant phenotype PubMed 22665389. Source: RGD positive regulation of cell communication by chemical coupling Inferred from mutant phenotype PubMed 15678088. Source: RGD positive regulation of gene expression Inferred from electronic annotation. Source: Compara positive regulation of glomerular filtration Inferred from mutant phenotype PubMed 18046320. Source: RGD positive regulation of protein catabolic process Inferred from direct assay PubMed 12952975. Source: RGD positive regulation of striated muscle tissue development Inferred from electronic annotation. Source: Compara positive regulation of vasoconstriction Inferred from mutant phenotype PubMed 21414209. Source: RGD positive regulation of vasodilation Inferred from mutant phenotype PubMed 15301736. Source: RGD protein oligomerization Inferred from direct assay PubMed 11557558PubMed 15817491. Source: RGD regulation of atrial cardiac muscle cell membrane depolarization Inferred from electronic annotation. Source: Compara regulation of bone mineralization Inferred from electronic annotation. Source: Compara regulation of bone remodeling Inferred from electronic annotation. Source: Compara regulation of calcium ion transport Inferred from mutant phenotype PubMed 16878174. Source: RGD regulation of tight junction assembly Inferred from mutant phenotype PubMed 19509333. Source: RGD regulation of ventricular cardiac muscle cell membrane depolarization Inferred from electronic annotation. Source: Compara regulation of ventricular cardiac muscle cell membrane repolarization Inferred from electronic annotation. Source: Compara response to fluid shear stress Inferred from expression pattern PubMed 15558296. Source: RGD response to pH Inferred from direct assay PubMed 14699011. Source: RGD response to peptide hormone stimulus Inferred from expression pattern PubMed 12700188. Source: RGD skeletal muscle tissue regeneration Inferred from electronic annotation. Source: Compara vascular transport Inferred from mutant phenotype PubMed 16878174. Source: RGD
Cellular_component	Golgi-associated vesicle membrane Traceable author statement. Source: Reactome apical plasma membrane Inferred from electronic annotation. Source: Compara connexon complex Inferred from direct assay PubMed 15048573PubMed 16731531PubMed 9851942. Source: RGD contractile fiber Inferred from electronic annotation. Source: Compara cytosol Inferred from electronic annotation. Source: Compara early endosome Inferred from direct assay PubMed 16162097. Source: RGD endoplasmic reticulum membrane Traceable author statement. Source: Reactome fascia adherens Inferred from direct assay PubMed 16515795PubMed 9851942. Source: RGD integral to plasma membrane Traceable author statement PubMed 15709751. Source: UniProtKB intermediate filament Inferred from electronic annotation. Source: Compara lateral plasma membrane Inferred from electronic annotation. Source: Compara lysosome Inferred from direct assay PubMed 16162097. Source: RGD membrane raft Inferred from direct assay PubMed 18162583. Source: BHF-UCL mitochondrial outer membrane Inferred from direct assay PubMed 17107662. Source: RGD multivesicular body Inferred from direct assay PubMed 16162097. Source: RGD
Molecular_function	gap junction channel activity Inferred from direct assay PubMed 15048573PubMed 16731531. Source: RGD protein domain specific binding Inferred from direct assay PubMed 17008717. Source: RGD signal transducer activity Inferred from electronic annotation. Source: Compara
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Sgsm3	Q8VCZ6	4	EBI-476947,EBI-525155	From a different organism.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed Ref.5 Ref.6

Chain

2 – 382

381

Gap junction alpha-1 protein

PRO_0000057804

Regions

Topological domain

2 – 13

12

Cytoplasmic Probable

Transmembrane

14 – 36

23

Helical; Probable

Topological domain

37 – 76

40

Extracellular Probable

Transmembrane

77 – 99

23

Helical; Probable

Topological domain

100 – 154

55

Cytoplasmic Probable

Transmembrane

155 – 177

23

Helical; Probable

Topological domain

178 – 208

31

Extracellular Probable

Transmembrane

209 – 231

23

Helical; Probable

Topological domain

232 – 382

151

Cytoplasmic Probable

Amino acid modifications

Modified residue

247

1

Phosphotyrosine By similarity

Modified residue

255

1

Phosphoserine By similarity

Modified residue

262

1

Phosphoserine By similarity

Modified residue

271

1

S-nitrosocysteine By similarity

Modified residue

306

1

Phosphoserine By similarity

Modified residue

313

1

Phosphotyrosine By similarity

Modified residue

314

1

Phosphoserine By similarity

Modified residue

325

1

Phosphoserine; by CK1 By similarity

Modified residue

326

1

Phosphothreonine By similarity

Modified residue

328

1

Phosphoserine; by CK1 By similarity

Modified residue

330

1

Phosphoserine; by CK1 By similarity

Modified residue

365

1

Phosphoserine Ref.9

Modified residue

368

1

Phosphoserine; by PKC/PRKCG Probable

Modified residue

369

1

Phosphoserine Ref.9

Modified residue

373

1

Phosphoserine Ref.9

Disulfide bond

54 ↔ 192

By similarity

Disulfide bond

187 ↔ 198

By similarity

Cross-link

144

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) By similarity

Cross-link

237

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) By similarity

Experimental info

Sequence conflict

2

1

G → A AA sequence Ref.5

Sequence conflict

16

1

A → T no nucleotide entry Ref.2

Sequence conflict

28

1

V → I AA sequence Ref.5

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

382

Helix Strand Turn

Details...

Turn

256 – 259

4

Beta strand

263 – 265

3

Beta strand

297 – 300

4

Helix

317 – 325

9

Helix

342 – 348

7

Turn

349 – 352

4

Beta strand

360 – 362

3

Turn

366 – 370

5

Beta strand

379 – 381

3

Sequences

	Sequence		Length	Mass (Da)
	P08050 [UniParc]. Last modified January 23, 2007. Version 2. Checksum: 0196416EA6A69490	FASTA	382	43,031
	10 20 30 40 50 60 MGDWSALGKL LDKVQAYSTA GGKVWLSVLF IFRILLLGTA VESAWGDEQS AFRCNTQQPG 70 80 90 100 110 120 CENVCYDKSF PISHVRFWVL QIIFVSVPTL LYLAHVFYVM RKEEKLNKKE EELKVAQTDG 130 140 150 160 170 180 VNVEMHLKQI EIKKFKYGIE EHGKVKMRGG LLRTYIISIL FKSVFEVAFL LIQWYIYGFS 190 200 210 220 230 240 LSAVYTCKRD PCPHQVDCFL SRPTEKTIFI IFMLVVSLVS LALNIIELFY VFFKGVKDRV 250 260 270 280 290 300 KGRSDPYHAT TGPLSPSKDC GSPKYAYFNG CSSPTAPLSP MSPPGYKLVT GDRNNSSCRN 310 320 330 340 350 360 YNKQASEQNW ANYSAEQNRM GQAGSTISNS HAQPFDFPDD NQNAKKVAAG HELQPLAIVD 370 380 QRPSSRASSR ASSRPRPDDL EI

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Connexin43: a protein from rat heart homologous to a gap junction protein from liver." Beyer E.C., Paul D.L., Goodenough D.A. J. Cell Biol. 105:2621-2629(1987) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Molecular cloning of a rat uterine gap junction protein and analysis of gene expression during gestation." Lang L.M., Beyer E.C., Schwartz A.L., Gitlin J.D. Am. J. Physiol. 260:E787-E793(1991) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Uterus.
[3]	Ma L.X., Peng Y.W. Submitted (JUN-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Strain: Sprague-Dawley.
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Heart.
[5]	"The Mr 28,000 gap junction proteins from rat heart and liver are different but related." Nicholson B.J., Gros D.B., Kent S.B.H., Hood L.E., Revel J.-P. J. Biol. Chem. 260:6514-6517(1985) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 2-33. Tissue: Heart.
[6]	"Affinity purification of a rat-brain junctional protein, connexin 43." Dupont E., el Aoumari A., Fromaget C., Briand J.-C., Gros D. Eur. J. Biochem. 200:263-270(1991) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 2-16. Tissue: Brain.
[7]	"Connexon integrity is maintained by non-covalent bonds: intramolecular disulfide bonds link the extracellular domains in rat connexin-43." John S.A., Revel J.-P. Biochem. Biophys. Res. Commun. 178:1312-1318(1991) [PubMed] [Europe PMC] [Abstract] Cited for: DISULFIDE BONDS.
[8]	"Membrane topology and quaternary structure of cardiac gap junction ion channels." Yeager M., Gilula N.B. J. Mol. Biol. 223:929-948(1992) [PubMed] [Europe PMC] [Abstract] Cited for: TOPOLOGY.
[9]	"Identification and functional analysis of novel phosphorylation sites in Cx43 in rat primary granulosa cells." Yogo K., Ogawa T., Akiyama M., Ishida N., Takeya T. FEBS Lett. 531:132-136(2002) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-365; SER-368; SER-369 AND SER-373.
[10]	"NMR structure note: UBA domain of CIP75." Kieken F., Spagnol G., Su V., Lau A.F., Sorgen P.L. J. Biomol. NMR 46:245-250(2010) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH UBQLN4.
[11]	"Involvement of urinary bladder Connexin43 and the circadian clock in coordination of diurnal micturition rhythm." Negoro H., Kanematsu A., Doi M., Suadicani S.O., Matsuo M., Imamura M., Okinami T., Nishikawa N., Oura T., Matsui S., Seo K., Tainaka M., Urabe S., Kiyokage E., Todo T., Okamura H., Tabata Y., Ogawa O. Nat. Commun. 3:809-809(2012) [PubMed] [Europe PMC] [Abstract] Cited for: INDUCTION.
[12]	"Structural changes in the carboxyl terminus of the gap junction protein connexin43 indicates signaling between binding domains for c-Src and zonula occludens-1." Sorgen P.L., Duffy H.S., Sahoo P., Coombs W., Delmar M., Spray D.C. J. Biol. Chem. 279:54695-54701(2004) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 255-381, INTERACTION WITH TJP1 AND SRC.
[13]	"Domain-swapped dimerization of ZO-1 PDZ2 generates specific and regulatory connexin43-binding sites." Chen J., Pan L., Wei Z., Zhao Y., Zhang M. EMBO J. 27:2113-2123(2008) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 374-382 IN COMPLEX WITH TJP1, SUBCELLULAR LOCATION, INTERACTION WITH TJP1.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X06656 mRNA. Translation: CAA29855.1.
AY324140 mRNA. Translation: AAP88589.1.
BC081842 mRNA. Translation: AAH81842.1.

IPI

IPI00231746.

PIR

A24047.
S00532.

RefSeq

NP_036699.1. NM_012567.2.

UniGene

Rn.10346.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1R5S	NMR	-	A	255-381	[»]
3CYY	X-ray	2.40	C/D	374-382	[»]

DisProt

DP00278.

ProteinModelPortal

P08050.

SMR

P08050. Positions 252-382.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-34793N.

IntAct

P08050. 5 interactions.

Protein family/group databases

TCDB

1.A.24.1.1. gap junction-forming connexin family.

PTM databases

PhosphoSite

P08050.

Proteomic databases

PaxDb

P08050.

PRIDE

P08050.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENSRNOT00000001054; ENSRNOP00000001054; ENSRNOG00000000805.

GeneID

24392.

KEGG

rno:24392.

UCSC

RGD:2690. rat.

Organism-specific databases

CTD

2697.

RGD

2690. Gja1.

Phylogenomic databases

eggNOG

NOG45368.

GeneTree

ENSGT00700000104079.

HOGENOM

HOG000231127.

HOVERGEN

HBG009576.

InParanoid

P08050.

KO

K07372.

OMA

GANVDMH.

OrthoDB

EOG402WSC.

Enzyme and pathway databases

Reactome

REACT_12587. Transport of connexins along the secretory pathway.
REACT_97881. Membrane Trafficking.

Gene expression databases

ArrayExpress

P08050.

Genevestigator

P08050.

GermOnline

ENSRNOG00000000805. Rattus norvegicus.

Family and domain databases

InterPro

IPR000500. Connexin.
IPR002261. Connexin43.
IPR013124. Connexin43_C.
IPR019570. Connexin_CCC.
IPR017990. Connexin_CS.
IPR013092. Connexin_N.
[Graphical view]

PANTHER

PTHR11984. PTHR11984. 1 hit.

Pfam

PF00029. Connexin. 1 hit.
PF03508. Connexin43. 1 hit.
PF10582. Connexin_CCC. 1 hit.
[Graphical view]

PRINTS

PR00206. CONNEXIN.
PR01132. CONNEXINA1.

SMART

SM00037. CNX. 1 hit.
SM01089. Connexin_CCC. 1 hit.
[Graphical view]

PROSITE

PS00407. CONNEXINS_1. 1 hit.
PS00408. CONNEXINS_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

P08050.

NextBio

603181.

Entry information

Entry name

CXA1_RAT

Accession

Primary (citable) accession number: P08050
Secondary accession number(s): Q53ZE1

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 1, 1988
Last sequence update:	January 23, 2007
Last modified:	May 1, 2013
This is version 136 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program