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PR01133

Identifier
CONNEXINA3  [View Relations]  [View Alignment]  
Accession
PR01133
No. of Motifs
3
Creation Date
20-APR-1999
Title
Gap junction alpha-3 protein signature
Database References
PRINTS; PR00206 CONNEXIN
PRODOM; PD020273; PD022318
INTERPRO; IPR002262
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-3 protein (also called connexin46, or Cx46) is a connexin
of ~415 amino acid residues. The bovine form is slightly shorter (401
residues) and is hence known as Cx44, having a molecular mass of ~44 kDa.
Cx46 (together with Cx50) is a connexin isoform expressed in the lens fibres
of the eye. Here, gap junctions join the cells into a functional syncytium,
and also couple the fibres to the epithelial cells on the anterior surface
of the lens. The lens fibres depend on this epithelium for their metabolic
support, since they lose their intra-cellular organelles, and accumulate
high concentrations of crystallins, in order to produce their optical
transparency. Genetically-engineered mice deficient in Cx46 demonstrate the
importance of Cx46 in forming lens fibre gap junctions; these mice develop
normal lenses, but subsequently develop early onset senile-type cataracts
that resemble human nuclear cataracts. Aberrant proteolysis of crystallin
proteins has been observed in the lenses of Cx46-null mice.
 
CONNEXINA3 is a 3-element fingerprint that provides a signature for the
gap junction alpha-3 protein. The fingerprint was derived from an initial
alignment of 2 sequences: the motifs were drawn from conserved regions
within the C-terminal half of the alignment, focusing on those sections that
characterise the gap junction alpha-3 isoform but distinguish it from others
- motif 1 resides within the second putative extracellular domain between 
TM domains 3 and 4; and motifs 2-3 lie within the putative cytoplasmic 
C-terminus. Two iterations on SPTR37_9f were required to reach convergence,
at which point a true set comprising 3 sequences was identified.
Summary Information
3 codes involving  3 elements
0 codes involving 2 elements
Composite Feature Index
3333
2000
123
True Positives
CXA3_BOVIN    CXA3_MOUSE    CXA3_RAT      
Sequence Titles
CXA3_BOVIN  GAP JUNCTION ALPHA-3 PROTEIN (CONNEXIN 44) (CX44) - BOS TAURUS (BOVINE). 
CXA3_MOUSE GAP JUNCTION ALPHA-3 PROTEIN (CONNEXIN 46) (CX46) - MUS MUSCULUS (MOUSE).
CXA3_RAT GAP JUNCTION ALPHA-3 PROTEIN (CONNEXIN 46) (CX46) - RATTUS NORVEGICUS (RAT).
Scan History
SPTR37_9f  2  300  NSINGLE    
Initial Motifs
Motif 1  width=11
Element Seqn Id St Int Rpt
QLQPLYRCDRW CXA3_MOUSE 179 179 -
QLKPLYRCDRW CXA3_BOVIN 168 168 -

Motif 2 width=10
Element Seqn Id St Int Rpt
VSIGFPPYYT CXA3_MOUSE 269 79 -
VTIGFPPYYA CXA3_BOVIN 262 83 -

Motif 3 width=12
Element Seqn Id St Int Rpt
PPLVLLDPGRSS CXA3_MOUSE 391 112 -
PPEPPADPGRSS CXA3_BOVIN 373 101 -
Final Motifs
Motif 1  width=11
Element Seqn Id St Int Rpt
QLQPLYRCDRW CXA3_MOUSE 179 179 -
QLQPLYRCDRW CXA3_RAT 179 179 -
QLKPLYRCDRW CXA3_BOVIN 168 168 -

Motif 2 width=10
Element Seqn Id St Int Rpt
VSIGFPPYYT CXA3_MOUSE 269 79 -
VSIGLPPYYT CXA3_RAT 269 79 -
VTIGFPPYYA CXA3_BOVIN 262 83 -

Motif 3 width=12
Element Seqn Id St Int Rpt
PPLVLLDPGRSS CXA3_MOUSE 391 112 -
PPLVLLDPERSS CXA3_RAT 390 111 -
PPEPPADPGRSS CXA3_BOVIN 373 101 -