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20  structures 123  species 1  interaction 2797  sequences 25  architectures

Family: Connexin (PF00029)

Summary: Connexin

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This is the Wikipedia entry entitled "Connexin". More...

Connexin Edit Wikipedia article

An open gap junction, composed of six identical connexin proteins. Each of these six units is a single polypeptide which passes the membrane four times (referred to as four-pass transmembrane proteins).
Symbol Connexin
Pfam PF00029
InterPro IPR013092
TCDB 1.A.24
OPM superfamily 215
OPM protein 2zw3

Connexins (Cx) (TC# 1.A.24), or gap junction proteins, are structurally related transmembrane proteins that assemble to form vertebrate gap junctions. An entirely different family of proteins, the innexins, form gap junctions in invertebrates.[1] Each gap junction is composed of two hemichannels, or connexons, which consist of homo- or heterohexameric arrays of connexins, and the connexon in one plasma membrane docks end-to-end with a connexon in the membrane of a closely opposed cell. The hemichannel is made of six connexin subunits, each of which consist of four transmembrane segments. Gap junctions are essential for many physiological processes, such as the coordinated depolarization of cardiac muscle, proper embryonic development, and the conducted response in microvasculature. For this reason, mutations in connexin-encoding genes can lead to functional and developmental abnormalities.


Connexins are commonly named according to their molecular weights, e.g. Cx26 is the connexin protein of 26 kDa. A competing nomenclature is the gap junction protein system, where connexins are sorted by their α (GJA) and β (GJB) forms, with additional connexins grouped into the C, D and E groupings, followed by an identifying number, e.g. GJA1 corresponds to Cx43. Following a vote at the Gap Junction Conference (2007) in Elsinore the community agreed to use the GJ nomenclature system for the genes that encode connexins, but wished to retain the connexin nomenclature for the encoded proteins using the weight of the human protein for the numbering of orthologous proteins.


Connexon and connexin structure.svg

Connexins contain four highly ordered transmembrane segments (TMSs), primarily unstructured C and N cytoplasmic termini, a cytoplasmic loop (CL) and two extra-cellular loops, (EL-1) and (EL-2). Connexins are assembled in groups of six to form hemichannels, or connexons, and two hemichannels then combine to form a gap junction.

The crystal structure of the gap junction channel formed by human Cx26 (also known as GJB2) at 3.5 Å resolution is available.[2] The density map showed the two membrane-spanning hemichannels and the arrangement of the four TMSs of the six protomers forming each hemichannel. The hemichannels feature a positively charged cytoplasmic entrance, a funnel, a negatively charged transmembrane pathway, and an extracellular cavity. The pore is narrowed at the funnel, which is formed by the six amino-terminal helices lining the wall of the channel, which thus determines the molecular size restriction at the channel entrance.

The connexin gene family is diverse, with twenty-one identified members in the sequenced human genome, and twenty in the mouse (nineteen of which are orthologous pairs). They usually weigh between 25 and 60 kDa, and have an average length of 380 amino acids. The various connexins have been observed to combine into both homomeric and heteromeric gap junctions, each of which may exhibit different functional properties including pore conductance, size selectivity, charge selectivity, voltage gating, and chemical gating.[3]

Biosynthesis and Internalization

A remarkable aspect of connexins is that they have a relatively short half life of only a few hours.[4] The result is the presence of a dynamic cycle by which connexins are synthesized and replaced. It has been suggested that this short life span allows for more finely regulated physiological processes to take place, such as in the myometrium.

From the Nucleus to the Membrane

As they are being translated by ribosomes, connexins are inserted into the membrane of the endoplasmic reticulum (ER).[5] It is in the ER that connexins are properly folded, yielding two extracellular loops, EL-1 and EL-2. It is also in the ER that the oligomerization of connexin molecules into hemichannels begins, a process which may continue in the UR-Golgi intermediate compartment as well.[4] The arrangements of these hemichannels can be homotypic, heterotypic, and combined heterotypic/heteromeric. After exiting the ER and passing through the ERGIC, the folded connexins will usually enter the cis-Golgi network.[6] However, some connexins, such as Cx26 may be transported independent of the Golgi.[7][8][9][10][11]

Gap Junction Assembly

After being inserted into the plasma membrane of the cell, the hemichannels freely diffuse within the lipid bilayer.[12] Through the aid of specific proteins, mainly cadherins, the hemichannels are able to dock with hemichannels of adjacent cells forming gap junctions.[13] Recent studies have shown the existence of communication between adherens junctions and gap junctions,[14] suggesting a higher level of coordination than previously thought.

Life cycle and protein associations of connexins. Connexins are synthesized on ER-bound ribosomes and inserted into the ER cotranslationally. This is followed by oligomerization between the ER and trans-Golgi network (depending on the connexin type) into connexons, which are then delivered to the membrane via the actin or microtubule networks. Connexons may also be delivered to the plasma membrane by direct transfer from the rough ER. Upon insertion into the membrane, connexons may remain as hemichannels or they dock with compatible connexons on adjacent cells to form gap junctions. Newly delivered connexons are added to the periphery of pre-formed gap junctions, while the central "older" gap junction fragment are degraded by internalization of a double-membrane structure called an annular junction into one of the two cells, where subsequent lysosomal or proteasomal degradation occurs, or in some cases the connexons are recycled to the membrane (indicated by dashed arrow). During their life cycle, connexins associate with different proteins, including (1) cytoskeletal components as microtubules, actin, and actin-binding proteins α-spectrin and drebrin, (2) junctional molecules including adherens junction components such as cadherins, α-catenin, and β-catenin, as well as tight junction components such as ZO-1 and ZO-2, (3) enzymes such as kinases and phosphatases which regulate the assembly, function, and degradation, and (4) other proteins such as caveolin. Dbouk et al., 2009.[15]


Connexin gap junctions are found only in vertebrates, while a functionally analogous (but genetically unrelated) group of proteins, the innexins, are responsible for gap junctions in invertebrate species. Innexin orthologs have also been identified in Chordates, but they are no longer capable of forming gap junctions. Instead, the channels formed by these proteins (called pannexins) act as very large transmembrane pores that connect the intra- and extracellular compartments.

Within the CNS, gap junctions provide electrical coupling between progenitor cells, neurons, and glial cells. By using specific connexin knockout mice, studies revealed that cell coupling is essential for visual signaling. In the retina, ambient light levels influence cell coupling provided by gap junction channels, adapting the visual function for various lighting conditions. Cell coupling is governed by several mechanisms, including connexin expression.[16]

Decrock et al. have discussed a multilevel platform via which connexins and pannexins can influence the following cellular functions within a tissue: (1) connexin gap junctional channels (GJCs) enable direct cell-cell communication of small molecules, (2) connexin hemichannels and pannexin channels can contribute to autocrine/paracrine signaling pathways, and (3) different structural domains of these proteins allow for channel-independent functions, such as cell-cell adhesion, interactions with the cytoskeleton, and the activation of intracellular signaling pathways.[17] Thus, connexins and pannexins have multifaceted contributions to brain development and specific processes in the neuro-glio-vascular unit, including synaptic transmission and plasticity, glial signaling, vasomotor control, and blood-brain barrier integrity in the mature CNS.[17]

Substrate Specificity

Different connexins may exhibit differing specificities for solutes. For example, adenosine passed about 12-fold better through channels formed by Cx32 while AMP and ADP passed about 8-fold better, and ATP greater than 300-fold better, through channels formed by Cx43. Thus, addition of phosphate to adenosine appears to shift its relative permeability from channels formed by Cx32 to channels formed by Cx43. This may have functional consequence because the energy status of a cell could be controlled via connexin expression and channel formation.[18]

Transport Reaction

The transport reaction catalyzed by connexin gap junctions is:

Small molecules (cell 1 cytoplasm) ⇌ small molecules (cell 2 cytoplasm)

Human connexins and implications in disease

Connexin Gene Location and Function
Cx43 GJA1 Expressed at the surface of vasculature with atherosclerotic plaque, and up-regulated during atherosclerosis in mice. May have pathological effects. Also expressed between granulosa cells, which is required for proliferation. Normally expressed in astrocytes, also detected in most of the human astrocytomas and in the astroglial component of glioneuronal tumors.[19] It is also the main cardiac connexin, found mainly in ventricular myocardium.[20] Associated with oculodentodigital dysplasia.
Cx46 GJA3
Cx37 GJA4 Induced in vascular smooth muscle during coronary arteriogenesis. Cx37 mutations are not lethal. Forms gap junctions between oocytes and granulosa cells, and are required for oocyte survival.
Cx40 GJA5 Expressed selectively in atrial myocytes. Responsible for mediating the coordinated electrical activation of atria.[21]
Cx33 GJA6
Pseudogene in humans
Cx50 GJA8 Gap Junctions between A-typ Horizontal cells in Mouse and Rabbit Retina[22]
Cx59 GJA10
Cx62 GJA10 Human Cx62 complies Cx57 (Mouse). Location in axon-bearing B-typ Horizontal Cell in Rabbit Retina[23]
Cx32 GJB1 Major component of the peripheral myelin. Mutations in the human gene cause X-linked Charcot-Marie-Tooth disease, a hereditary neuropathy. In human normal brain CX32 expressed in neurons and oligodendrocytes.[19]
Cx26 GJB2 Mutated in Vohwinkel syndrome as well as Keratitis-Icthyosis-Deafness (KID) Syndrome.
Cx31 GJB3 Can be associated with Erythrokeratodermia variabilis.
Cx30.3 GJB4 Fonseca et al. confirmed Cx30.3 expression in thymocytes.[24] Can be associated with Erythrokeratodermia variabilis.
Cx31.1 GJB5
Cx30 GJB6 Mutated in Clouston syndrome (hidrotic ectodermal dysplasia)
Cx25 GJB7
Cx45 GJC1/GJA7 Human pancreatic ductal epithelial cells.[25] Atrio-ventricular node.
Cx47 GJC2/GJA12 Expressed in oligodentrocyte gap junctions[26]
Cx31.3 GJC3 Human ortholog of murine Cx29. Not known to form gap junctions.[27]
Cx36 GJD2/GJA9 Pancreatic beta cell function, mediating the release of insulin. Neurons throughout the Central Nervous System where they synchronize neural activity.[28]
Cx31.9 GJD3/GJC1
Cx39 GJD4
Cx40.1 GJD4
Cx23 GJE1

Gap junctions are essential for many physiological processes, such as the coordinated depolarization of cardiac muscle, proper embryonic development, and the conducted response in microvasculature. For this reason, deletion or mutation of the various connexin isoforms produces distinctive phenotypes and pathologies.[29] While mutations in Cx43 are mostly linked to oculodentodigital dysplasia, Cx47 mutations are associated with Pelizaeus-Merzbacher-like disease and lymphedema. Cx40 mutations are principally linked to atrial fibrillation. Mutations in Cx37 have not yet been described, but polymorphisms in the Cx37 gene have been implicated in the development of arterial disease.[30]


  1. ^ Lodish, Harvey F.; Arnold Berk; Paul Matsudaira; Chris A. Kaiser; Monty Krieger; Mathew P. Scott; S. Lawrence Zipursky; James Darnell (2004). Molecular Cell Biology (5th ed.). New York: W.H. Freeman and Company. pp. 230–1. ISBN 0-7167-4366-3. 
  2. ^ Maeda, Shoji; Nakagawa, So; Suga, Michihiro; Yamashita, Eiki; Oshima, Atsunori; Fujiyoshi, Yoshinori; Tsukihara, Tomitake (2009-04-02). "Structure of the connexin 26 gap junction channel at 3.5 A resolution". Nature. 458 (7238): 597–602. doi:10.1038/nature07869. ISSN 1476-4687. PMID 19340074. 
  3. ^ Ayad, Wafaa A.; Locke, Darren; Koreen, Irina V.; Harris, Andrew L. (2006-06-16). "Heteromeric, but not homomeric, connexin channels are selectively permeable to inositol phosphates". The Journal of Biological Chemistry. 281 (24): 16727–16739. doi:10.1074/jbc.M600136200. ISSN 0021-9258. PMID 16601118. 
  4. ^ a b Laird DW (March 2006). "Life cycle of connexins in health and disease". The Biochemical Journal. 394 (3): 527–43. doi:10.1042/BJ20051922. PMC 1383703Freely accessible. PMID 16492141. 
  5. ^ Bennett, Michael V. L.; Zukin, R. Suzanne (2004-02-19). "Electrical coupling and neuronal synchronization in the Mammalian brain". Neuron. 41 (4): 495–511. doi:10.1016/s0896-6273(04)00043-1. ISSN 0896-6273. PMID 14980200. 
  6. ^ Musil, LS; Goodenough DA (1993). "Multisubunit assembly of an integral plasma membrane channel protein, gap junction connexin43, occurs after exit from the ER". Cell. 74 (6): 1065–77. doi:10.1016/0092-8674(93)90728-9. PMID 7691412. 
  7. ^ Evans, W. H.; Ahmad, S.; Diez, J.; George, C. H.; Kendall, J. M.; Martin, P. E. (1999). "Trafficking pathways leading to the formation of gap junctions". Novartis Found. Symp. Novartis Foundation Symposia. 219: 44–54. doi:10.1002/9780470515587.ch4. ISBN 978-0-470-51558-7. PMID 10207897. 
  8. ^ George, C. H., Kendall, J. M. and Evans, W. H. (1999). "Intracellular trafficking pathways in the assembly of connexins into gap junctions". J. Biol. Chem. 274 (13): 8678–85. doi:10.1074/jbc.274.13.8678. PMID 10085106. 
  9. ^ George, C. H., Kendall, J. M., Campbell, A. K. and Evans, W. H. (1998). "Connexin–aequorin chimerae report cytoplasmic calcium environments along trafficking pathways leading to gap junction biogenesis in living COS-7 cells". J. Biol. Chem. 273 (45): 29822–9. doi:10.1074/jbc.273.45.29822. PMID 9792698. 
  10. ^ Martin, P. E., George, C. H., Castro, C., Kendall, J. M., Capel, J., Campbell, A. K., Revilla, A., Barrio, L. C. and Evans, W. H. (1998). "Assembly of chimeric connexin–aequorin proteins into functional gap junction channels. Reporting intracellular and plasma membrane calcium environments". J. Biol. Chem. 273 (3): 1719–26. doi:10.1074/jbc.273.3.1719. PMID 9430718. 
  11. ^ Martin, P. E., Errington, R. J. and Evans, W. H. (2001). "Gap junction assembly: multiple connexin fluorophores identify complex trafficking pathways". Cell Commun. Adhes. 8 (4–6): 243–8. doi:10.3109/15419060109080731. PMID 12064596. 
  12. ^ Thomas, T., Jordan, K., Simek, J., Shao, Q., Jedeszko, C., Walton, P. and Laird, D. W. (2005). "Mechanisms of Cx43 and Cx26 transport to the plasma membrane and gap junction regeneration". J Cell Sci. 118 (Pt 19): 4451–62. doi:10.1242/jcs.02569. PMID 16159960. 
  13. ^ Jongen, W. M., Fitzgerald, D. J., Asamoto, M., Piccoli, C., Slaga, T. J., Gros, D., Takeichi, M. and Yamasaki, H. (1991). "Regulation of connexin 43-mediated gap junctional intercellular communication by Ca2+ in mouse epidermal cells is controlled by E- cadherin". J. Cell Biol. 114 (3): 545–555. doi:10.1083/jcb.114.3.545. PMC 2289094Freely accessible. PMID 1650371. 
  14. ^ Wei, C. J., Francis, R., Xu, X. and Lo, C. W. (2005). "Connexin43 associated with an N-cadherin-containing multiprotein complex is required for gap junction formation in NIH3T3 cells". J. Biol. Chem. 280 (20): 19925–36. doi:10.1074/jbc.M412921200. PMID 15741167. 
  15. ^ Dbouk HA, Mroue RM, El-Sabban ME, Talhouk RS (2009). "Connexins: a myriad of functions extending beyond assembly of gap junction channels". Cell Commun. Signal. 7: 4. doi:10.1186/1478-811X-7-4. PMC 2660342Freely accessible. PMID 19284610. 
  16. ^ Kihara AH, de Castro LM, Moriscot AS, Hamassaki DE (May 2006). "Prolonged dark adaptation changes connexin expression in the mouse retina". J Neurosci Res. 83 (7): 1331–41. doi:10.1002/jnr.20815. PMID 16496335. 
  17. ^ a b Decrock, Elke; De Bock, Marijke; Wang, Nan; Bultynck, Geert; Giaume, Christian; Naus, Christian C.; Green, Colin R.; Leybaert, Luc (2015-08-01). "Connexin and pannexin signaling pathways, an architectural blueprint for CNS physiology and pathology?". Cellular and molecular life sciences: CMLS. 72 (15): 2823–2851. doi:10.1007/s00018-015-1962-7. ISSN 1420-9071. PMID 26118660. 
  18. ^ Goldberg, Gary S.; Moreno, Alonso P.; Lampe, Paul D. (2002-09-27). "Gap junctions between cells expressing connexin 43 or 32 show inverse permselectivity to adenosine and ATP". The Journal of Biological Chemistry. 277 (39): 36725–36730. doi:10.1074/jbc.M109797200. ISSN 0021-9258. PMID 12119284. 
  19. ^ a b Aronica E; Gorter J; Jansen G; et al. (2001). "Expression of connexin 43 and connexin 32 gap-junction proteins in epilepsy-associated brain tumors and in the perilesional epileptic cortex". Acta Neuropathol. 101 (5): 449–59. doi:10.1007/s004010000305. PMID 11484816. 
  20. ^ Verheule S, van Kempen MJ, te Welscher PH, Kwak BR, Jongsma HJ (May 1997). "Characterization of gap junction channels in adult rabbit atrial and ventricular myocardium". Circ. Res. 80 (5): 673–81. doi:10.1161/01.res.80.5.673. PMID 9130448. 
  21. ^ Gollob MH; et al. (June 22, 2006). "Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation". N Engl J Med. 354 (25): 2677–88. doi:10.1056/NEJMoa052800. PMID 16790700. 
  22. ^ Massey, Stephen (16 January 2009). Connexins: A Guide (1st ed.). Springer-Verlag Gmbh. pp. 3–?. ISBN 1-934115-46-0. 
  23. ^ Beyer, Eric C.; Berthound, Viviana M. (16 January 2009). Connexins: A Guide (1st ed.). Springer-Verlag Gmbh. pp. 387–417. ISBN 1-934115-46-0. 
  24. ^ Fonseca PC, Nihei OK, Urban-Maldonado M, Abreu S, de Carvalho AC, Spray DC, Savino W, Alves LA (June 2004). "Characterization of connexin 30.3 and 43 in thymocytes". Immunol. Lett. 94 (1–2): 65–75. doi:10.1016/j.imlet.2004.03.019. PMID 15234537. 
  25. ^ Tai M-H; Olson, LK; Madhukar, BV; Linning, KD; Van Camp, L; Tsao, MS; Trosko, JE (2003). "Characterization of Gap Junctional Intercellular Communication in Immortalized Human Pancreatic Ductal Epithelial Cells With Stem Cell Characteristics". Pancreas. 26 (1): e18–e26. doi:10.1097/00006676-200301000-00025. PMID 12499933. 
  26. ^ Kamasawa N, Sik A, Morita M, et al. (2005). "Connexin-47 and connexin-32 in gap junctions of oligodendrocyte somata, myelin sheaths, paranodal loops and Schmidt-Lanterman incisures: implications for ionic homeostasis and potassium siphoning". Neuroscience. 136 (1): 65–86. doi:10.1016/j.neuroscience.2005.08.027. PMC 1550704Freely accessible. PMID 16203097. 
  27. ^ Sargiannidou I, Ahn M, Enriquez AD, Peinado A, Reynolds R, Abrams C, Scherer SS, and Kleopa KA (2008). "Human oligodendrocytes express Cx31.3: function and interactions with Cx32 mutants". Neurobiol. Dis. 30: 221–233. doi:10.1016/j.nbd.2008.01.009. PMC 2704064Freely accessible. PMID 18353664. 
  28. ^ Connors BW, Long MA (2004). "Electrical synapses in the mammalian brain". Annu Rev Neurosci. 27: 393–418. doi:10.1146/annurev.neuro.26.041002.131128. PMID 15217338. 
  29. ^ Pfenniger, Anna; Wohlwend, Annelise; Kwak, Brenda R. (2011-01-01). "Mutations in connexin genes and disease". European Journal of Clinical Investigation. 41 (1): 103–116. doi:10.1111/j.1365-2362.2010.02378.x. ISSN 1365-2362. PMID 20840374. 
  30. ^ Molica, Filippo; Meens, Merlijn J. P.; Morel, Sandrine; Kwak, Brenda R. (2014-09-01). "Mutations in cardiovascular connexin genes". Biology of the Cell / Under the Auspices of the European Cell Biology Organization. 106 (9): 269–293. doi:10.1111/boc.201400038. ISSN 1768-322X. PMID 24966059. 

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As of this edit, this article uses content from "1.A.24 The Gap Junction-forming Connexin (Connexin) Family", which is licensed in a way that permits reuse under the Creative Commons Attribution-ShareAlike 3.0 Unported License, but not under the GFDL. All relevant terms must be followed.

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Connexin Provide feedback

Connexin proteins form gap-junctions between cells. They carry four transmembrane regions, hence why this family now includes Connexin_CCC, which represented the second pair of TMs.

Literature references

  1. Hua VB, Chang AB, Tchieu JH, Kumar NM, Nielsen PA, Saier MH Jr;, J Membr Biol. 2003;194:59-76.: Sequence and phylogenetic analyses of 4 TMS junctional proteins of animals: connexins, innexins, claudins and occludins. PUBMED:14502443 EPMC:14502443

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR013092

The connexins are a family of integral membrane proteins that oligomerise to form intercellular channels that are clustered at gap junctions. These channels are specialised sites of cell-cell contact that allow the passage of ions, intracellular metabolites and messenger molecules (with molecular weight less than 1-2kDa) from the cytoplasm of one cell to its opposing neighbours. They are found in almost all vertebrate cell types, and somewhat similar proteins have been cloned from plant species. Invertebrates utilise a different family of molecules, innexins, that share a similar predicted secondary structure to the vertebrate connexins, but have no sequence identity to them [PUBMED:9769729].

Vertebrate gap junction channels are thought to participate in diverse biological functions. For instance, in the heart they permit the rapid cell-cell transfer of action potentials, ensuring coordinated contraction of the cardiomyocytes. They are also responsible for neurotransmission at specialised 'electrical' synapses. In non-excitable tissues, such as the liver, they may allow metabolic cooperation between cells. In the brain, glial cells are extensively-coupled by gap junctions; this allows waves of intracellular Ca2+ to propagate through nervous tissue, and may contribute to their ability to spatially-buffer local changes in extracellular K+ concentration [PUBMED:7685944].

The connexin protein family is encoded by at least 13 genes in rodents, with many homologues cloned from other species. They show overlapping tissue expression patterns, most tissues expressing more than one connexin type. Their conductances, permeability to different molecules, phosphorylation and voltage-dependence of their gating, have been found to vary. Possible communication diversity is increased further by the fact that gap junctions may be formed by the association of different connexin isoforms from apposing cells. However, in vitro studies have shown that not all possible combinations of connexins produce active channels [PUBMED:8811187, PUBMED:8608591].

Hydropathy analysis predicts that all cloned connexins share a common transmembrane (TM) topology. Each connexin is thought to contain 4 TM domains, with two extracellular and three cytoplasmic regions. This model has been validated for several of the family members by in vitro biochemical analysis. Both N- and C-termini are thought to face the cytoplasm, and the third TM domain has an amphipathic character, suggesting that it contributes to the lining of the formed-channel. Amino acid sequence identity between the isoforms is ~50-80%, with the TM domains being well conserved. Both extracellular loops contain characteristically conserved cysteine residues, which likely form intramolecular disulphide bonds. By contrast, the single putative intracellular loop (between TM domains 2 and 3) and the cytoplasmic C terminus are highly variable among the family members. Six connexins are thought to associate to form a hemi-channel, or connexon. Two connexons then interact (likely via the extracellular loops of their connexins) to form the complete gap junction channel.

       NH2-***        ***        *************-COOH
             **     **   **      **
             **    **     **    **   Cytoplasmic
             **    **     **    **   Membrane
             **    **     **    **
             **    **     **    **   Extracellular
              **  **       **  **
                **           **

Two sets of nomenclature have been used to identify the connexins. The first, and most commonly used, classifies the connexin molecules according to molecular weight, such as connexin43 (abbreviated to Cx43), indicating a connexin of molecular weight close to 43kDa. However, studies have revealed cases where clear functional homologues exist across species that have quite different molecular masses; therefore, an alternative nomenclature was proposed based on evolutionary considerations, which divides the family into two major subclasses, alpha and beta, each with a number of members [PUBMED:1320430]. Due to their ubiquity and overlapping tissue distributions, it has proved difficult to elucidate the functions of individual connexin isoforms. To circumvent this problem, particular connexin-encoding genes have been subjected to targeted-disruption in mice, and the phenotype of the resulting animals investigated. Around half the connexin isoforms have been investigated in this manner [PUBMED:9861669]. Further insight into the functional roles of connexins has come from the discovery that a number of human diseases are caused by mutations in connexin genes. For instance, mutations in Cx32 give rise to a form of inherited peripheral neuropathy called X-linked dominant Charcot-Marie-Tooth disease [PUBMED:7570999]. Similarly, mutations in Cx26 are responsible for both autosomal recessive and dominant forms of nonsyndromic deafness, a disorder characterised by hearing loss, with no apparent effects on other organ systems.

This domain is found in the N-terminal region of these proteins.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan Transporter (CL0375), which has the following description:

The members of this superfamily are probably all transporter protein domains. All families normally carry four tansmembrane regions, which in many instances associate into hexameric structures. They are frequently involved in gap-junction formation between cells or in forming pores linking the cytosol with the extracellulare space 1,2]. The clan includes members of the TCDB superfamilies 1.A.24 and 1.A.25.

The clan contains the following 12 members:

Amastin Claudin_2 Claudin_3 Clc-like Connexin Fig1 GSG-1 Innexin L_HMGIC_fpl Pannexin_like PMP22_Claudin SUR7


We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...

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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

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Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Prosite
Previous IDs: connexin;
Type: Family
Sequence Ontology: SO:0100021
Author: Sonnhammer ELL
Number in seed: 234
Number in full: 2797
Average length of the domain: 199.90 aa
Average identity of full alignment: 40 %
Average coverage of the sequence by the domain: 68.85 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 31.3 31.3
Trusted cut-off 31.8 31.5
Noise cut-off 31.2 31.2
Model length: 234
Family (HMM) version: 19
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Species distribution

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Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

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The tree shows the occurrence of this domain across different species. More...


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There is 1 interaction for this family. More...



For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Connexin domain has been found. There are 20 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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