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PR01132

Identifier
CONNEXINA1  [View Relations]  [View Alignment]  
Accession
PR01132
No. of Motifs
5
Creation Date
20-APR-1999
Title
Gap junction alpha-1 protein (Cx43) signature
Database References
PRINTS; PR00206 CONNEXIN
PRODOM; PD008097; PD008184
INTERPRO; IPR002261
Literature References
1. PHELAN, P., BACON, J.P., DAVIES, J.A., STEBBINGS, L.A., TODMAN, M.G.,
AVERY, L., BAINES, R.A., BARNES, T.M., FORD, C., HEKIMI, S., LEE, R.,
SHAW, J.E., STARICH, T.A., CURTIN, K.D., SUN, Y. AND WYMAN, R.J.
Innexins: a family of invertebrate gap-junction proteins.
TRENDS GENET. 14 348-349 (1998).
 
2. DERMIETZEL, R. AND SPRAY, D.C.
Gap junctions in the brain: where, what type, how many and why?
TRENDS NEUROSCIENCE 16 186-192 (1993).
 
3. GOODENOUGH, D.A., GOLIGER, J.A. AND PAUL, D.L.
Connexins, connexons, and intercellular communication.
ANNU.REV.BIOCHEMISTRY 65 475-502 (1996).
 
4. KUMAR, N.M. AND GILULA, N.B.
The gap junction communication channel.
CELL 84 381-388 (1996).
 
5. KUMAR, N.M. AND GILULA, N.B.
Molecular biology and genetics of gap junction channels.
SEMIN.CELL BIOL. 3 3-16 (1992).
 
6. NICHOLSON, S.M. AND BRUZZONE, R.
Gap junctions: getting the message through.
CURR.BIOL. 7 340-344 (1997).
 
7. SIMON, A.M. AND GOODENOUGH, D.A.
Diverse functions of vertebrate gap junctions.
TRENDS CELL BIOL. 8 477-483 (1998).
 
8. SPRAY, D.C. AND DERMIETZEL, R.
X-linked dominant Charcot-Marie-Tooth disease and other potential gap-
junctions diseases of the nervous system.
TRENDS NEUROSCIENCE 18 256-262 (1995).

Documentation
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 <1-2 kDa) from the cytoplasm of one cell to its apposing 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 [1].
 
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 [2].
 
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 [3,4].
 
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.
 
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 43 kDa. 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 [5]. 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 [6,7]. 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
[8]. 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.
 
Gap junction alpha-1 protein (also called connexin43, or Cx43) is a connexin
of 381 amino acid residues (human isoform) that is widely expressed in
several organs and cell types, and is the principal gap junction protein of
the heart. Characterisation of genetically-engineered mice that lack Cx43,
and also of human patients that have spontaneously-occurring mutations in
the gene encoding it (GJA1), suggest Cx43 is essential for the development
of normal cardiac architecture and ventricular conduction. Mice lacking Cx43
survive to term but die shortly after birth. They have cardiac malformations
that lead to the obstruction of the pulmonary artery, leading to neonatal
cyanosis, and subsequent death. This phenotype is reminiscent of some forms
of stenosis of the pulmonary artery. Human subjects with visceroatrial
heterotaxia (a heart disorder characterised by arterial defects), have been
found to have points mutations in the Cx43-encoding gene, as a result of 
which a potential phosphorylation site within the C-terminus is disrupted. 
Consequently, although these mutant Cx43 molecules still form functional gap
junction channels, their response to protein kinase activation is impaired.
 
CONNEXINA1 is a 5-element fingerprint that provides a signature for the
gap junction alpha-1 protein. The fingerprint was derived from an initial
alignment of 3 sequences: the motifs were drawn from conserved regions
within the C-terminal quarter of the alignment, focusing on those sections
that characterise the gap junction alpha-1 isoform but distinguish it from
others - motifs 1-5 reside within the putative cytoplasmic C-terminus.
Two iterations on SPTR37_9f were required to reach convergence, at which
point a true set comprising 8 sequences was identified.
Summary Information
8 codes involving  5 elements
0 codes involving 4 elements
0 codes involving 3 elements
0 codes involving 2 elements
Composite Feature Index
588888
400000
300000
200000
12345
True Positives
CXA1_BOVIN    CXA1_CHICK    CXA1_HUMAN    CXA1_MOUSE    
CXA1_RAT CXA1_XENLA O57474 O73863
Sequence Titles
CXA1_BOVIN  GAP JUNCTION ALPHA-1 PROTEIN (CONNEXIN 43) (CX43) (VASCULAR SMOOTH MUSCLE CONNEXIN 43) - BOS TAURUS (BOVINE). 
CXA1_CHICK GAP JUNCTION ALPHA-1 PROTEIN (CONNEXIN 43) (CX43) - GALLUS GALLUS (CHICKEN).
CXA1_HUMAN GAP JUNCTION ALPHA-1 PROTEIN (CONNEXIN 43) (CX43) (GAP JUNCTION 43 KD HEART PROTEIN) - HOMO SAPIENS (HUMAN).
CXA1_MOUSE GAP JUNCTION ALPHA-1 PROTEIN (CONNEXIN 43) (CX43) (GAP JUNCTION 43 KD HEART PROTEIN) - MUS MUSCULUS (MOUSE).
CXA1_RAT GAP JUNCTION ALPHA-1 PROTEIN (CONNEXIN 43) (CX43) (GAP JUNCTION 43 KD HEART PROTEIN) - RATTUS NORVEGICUS (RAT).
CXA1_XENLA GAP JUNCTION ALPHA-1 PROTEIN (CONNEXIN 43) (CX43) - XENOPUS LAEVIS (AFRICAN CLAWED FROG).
O57474 GAP JUNCTION PROTEIN (CONNEXIN) - BRACHYDANIO RERIO (ZEBRAFISH) (ZEBRA DANIO).
O73863 GAP JUNCTION PROTEIN (CONNEXIN) - DANIO AEQUIPINNATUS (GIANT DANIO) (BRACHYDANIO AEQUIPINNATUS).
Scan History
SPTR37_9f  2  150  NSINGLE    
Initial Motifs
Motif 1  width=11
Element Seqn Id St Int Rpt
RNNSSCRNYNK CXA1_BOVIN 293 293 -
RNNSSCRNYNK CXA1_MOUSE 292 292 -
RNNSSCRNYNK CXA1_CHICK 291 291 -

Motif 2 width=10
Element Seqn Id St Int Rpt
QASEQNWANY CXA1_BOVIN 304 0 -
QASEQNWANY CXA1_MOUSE 303 0 -
QASEQNWANY CXA1_CHICK 302 0 -

Motif 3 width=11
Element Seqn Id St Int Rpt
STISNSHAQPF CXA1_BOVIN 325 11 -
STISNSHAQPF CXA1_MOUSE 324 11 -
STISNSHAQPF CXA1_CHICK 323 11 -

Motif 4 width=11
Element Seqn Id St Int Rpt
GHELQPLAIVD CXA1_BOVIN 350 14 -
GHELQPLAIVD CXA1_MOUSE 349 14 -
GHELQPLTIVD CXA1_CHICK 348 14 -

Motif 5 width=10
Element Seqn Id St Int Rpt
QRPSSRASSR CXA1_BOVIN 361 0 -
QRPSSRASSR CXA1_MOUSE 360 0 -
QRPPSRASSR CXA1_CHICK 359 0 -
Final Motifs
Motif 1  width=11
Element Seqn Id St Int Rpt
RNNSSCRNYNK CXA1_BOVIN 293 293 -
RNNSSCRNYNK CXA1_RAT 292 292 -
RNNSSCRNYNK CXA1_MOUSE 292 292 -
RNNSSCRNYNK CXA1_HUMAN 292 292 -
RNNSSCRNYNK CXA1_CHICK 291 291 -
RNPSSCRNYNK CXA1_XENLA 289 289 -
ERTNSCRNYNK O57474 292 292 -
ERTNSCRNYNK O73863 292 292 -

Motif 2 width=10
Element Seqn Id St Int Rpt
QASEQNWANY CXA1_BOVIN 304 0 -
QASEQNWANY CXA1_RAT 303 0 -
QASEQNWANY CXA1_MOUSE 303 0 -
QASEQNWANY CXA1_HUMAN 303 0 -
QASEQNWANY CXA1_CHICK 302 0 -
QASEQNWANY CXA1_XENLA 300 0 -
QANEQNWANY O57474 303 0 -
QANEQNWANY O73863 303 0 -

Motif 3 width=11
Element Seqn Id St Int Rpt
STISNSHAQPF CXA1_BOVIN 325 11 -
STISNSHAQPF CXA1_RAT 324 11 -
STISNSHAQPF CXA1_MOUSE 324 11 -
STISNSHAQPF CXA1_HUMAN 324 11 -
STISNSHAQPF CXA1_CHICK 323 11 -
STISNTHAQPF CXA1_XENLA 321 11 -
STISNSHAQAF O57474 324 11 -
STISNSHAQAF O73863 324 11 -

Motif 4 width=11
Element Seqn Id St Int Rpt
GHELQPLAIVD CXA1_BOVIN 350 14 -
GHELQPLAIVD CXA1_RAT 349 14 -
GHELQPLAIVD CXA1_MOUSE 349 14 -
GHELQPLAIVD CXA1_HUMAN 349 14 -
GHELQPLTIVD CXA1_CHICK 348 14 -
GHEMQPLTILD CXA1_XENLA 346 14 -
GHELQPLALID O57474 349 14 -
GHELQPLALID O73863 350 15 -

Motif 5 width=10
Element Seqn Id St Int Rpt
QRPSSRASSR CXA1_BOVIN 361 0 -
QRPSSRASSR CXA1_RAT 360 0 -
QRPSSRASSR CXA1_MOUSE 360 0 -
QRPSSRASSR CXA1_HUMAN 360 0 -
QRPPSRASSR CXA1_CHICK 359 0 -
QRPSSRASSH CXA1_XENLA 357 0 -
ARPCSRASSR O57474 360 0 -
ARPCSRASSR O73863 361 0 -