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PR01137

Identifier
CONNEXINA8  [View Relations]  [View Alignment]  
Accession
PR01137
No. of Motifs
6
Creation Date
20-APR-1999
Title
Gap junction alpha-8 protein (Cx50) signature
Database References
PRINTS; PR00206 CONNEXIN
PRODOM; PD020275; PD015487; PD020478
INTERPRO; IPR002266
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).
 
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-8 protein (also called connexin50, Cx50, or lens fibre
protein MP70) is a connexin of ~431 amino acid residues. The chicken isoform
is shorter (399 residues) and is hence known as Cx45.6. Cx50 and Cx46 are
the two gap junction proteins normally found in lens fibre cells of the eye.
Evidence from both genetically-engineered mice, and from the identification
of mutations in the human Cx50-encoding gene, highlight the importance of 
this connexin in maintaining lens transparency. Deletion of mice Cx50 
produces a viable phenotype, but these animals start to develop cataracts
(of the zonular pulverant type) at about one week old. They also have 
abnormally small eyes and lenses. Similarly, mutations in the human gene
encoding Cx50 have been associated with the occurrence of congenital 
cataracts. Affected individuals develop cataracts (with zonular pulverent
opacities), and analysis shows they have a single point mutation in the Cx50
coding region, resulting in a non-conservative substitution in the second
putative TM domain of a serine residue for a proline.
 
CONNEXINA8 is a 6-element fingerprint that provides a signature for the
gap junction alpha-8 protein. The fingerprint was derived from an initial
alignment of 3 sequences: the motifs were drawn from conserved regions
within the C-terminal two thirds of the alignment, focusing on those sections
that characterise the gap junction alpha-8 isoform but distinguish it from
others - motifs 1-6 reside within the putative cytoplasmic C-terminus. Two
iterations on SPTR37_9f were required to reach convergence, at which point
a true set comprising 4 sequences was identified.
Summary Information
4 codes involving  6 elements
0 codes involving 5 elements
0 codes involving 4 elements
0 codes involving 3 elements
0 codes involving 2 elements
Composite Feature Index
6444444
5000000
4000000
3000000
2000000
123456
True Positives
CXA8_CHICK    CXA8_HUMAN    CXA8_MOUSE    CXA8_SHEEP    
Sequence Titles
CXA8_CHICK  GAP JUNCTION ALPHA-8 PROTEIN (CONNEXIN 45.6) (CX45.6) - GALLUS GALLUS (CHICKEN). 
CXA8_HUMAN GAP JUNCTION ALPHA-8 PROTEIN (CONNEXIN 50) (CX50) (LENS FIBER PROTEIN MP70) - HOMO SAPIENS (HUMAN).
CXA8_MOUSE GAP JUNCTION ALPHA-8 PROTEIN (CONNEXIN 50) (CX50) (LENS FIBER PROTEIN MP70) - MUS MUSCULUS (MOUSE).
CXA8_SHEEP GAP JUNCTION ALPHA-8 PROTEIN (CONNEXIN 49) (CX49) (LENS FIBER PROTEIN MP70) (MP64) (MP38) - OVIS ARIES (SHEEP).
Scan History
SPTR37_9f  2  250  NSINGLE    
Initial Motifs
Motif 1  width=13
Element Seqn Id St Int Rpt
IQKAKGYQLLEEE CXA8_HUMAN 258 258 -
IQKAKGYQLLEEE CXA8_SHEEP 266 266 -
IQKAKGYQLLEEE CXA8_MOUSE 266 266 -

Motif 2 width=13
Element Seqn Id St Int Rpt
KIVSHYFPLTEVG CXA8_HUMAN 271 0 -
KIVSHYFPLTEVG CXA8_SHEEP 279 0 -
KIVSHYFPLTEVG CXA8_MOUSE 279 0 -

Motif 3 width=7
Element Seqn Id St Int Rpt
MVETSPL CXA8_HUMAN 284 0 -
MVEASPL CXA8_SHEEP 292 0 -
MVETSPL CXA8_MOUSE 292 0 -

Motif 4 width=13
Element Seqn Id St Int Rpt
GPLGDLSRGYQET CXA8_HUMAN 305 14 -
GPLGDLSRAYQET CXA8_SHEEP 313 14 -
GPLADMSRSYQET CXA8_MOUSE 313 14 -

Motif 5 width=11
Element Seqn Id St Int Rpt
LPSYAQVGAQE CXA8_HUMAN 318 0 -
LPSYAQVGAQE CXA8_SHEEP 326 0 -
LPSYAQVGVQE CXA8_MOUSE 326 0 -

Motif 6 width=12
Element Seqn Id St Int Rpt
RPLSRLSKASSR CXA8_HUMAN 412 83 -
RPLSRLSKASSR CXA8_SHEEP 420 83 -
RPLSRLSKASSR CXA8_MOUSE 420 83 -
Final Motifs
Motif 1  width=13
Element Seqn Id St Int Rpt
IQKAKGYQLLEEE CXA8_HUMAN 258 258 -
IQKAKGYQLLEEE CXA8_SHEEP 266 266 -
IQKAKGYQLLEEE CXA8_MOUSE 266 266 -
IPKAKGYKLLEEE CXA8_CHICK 261 261 -

Motif 2 width=13
Element Seqn Id St Int Rpt
KIVSHYFPLTEVG CXA8_HUMAN 271 0 -
KIVSHYFPLTEVG CXA8_SHEEP 279 0 -
KIVSHYFPLTEVG CXA8_MOUSE 279 0 -
KPVSHYFPLTEVG CXA8_CHICK 274 0 -

Motif 3 width=7
Element Seqn Id St Int Rpt
MVETSPL CXA8_HUMAN 284 0 -
MVEASPL CXA8_SHEEP 292 0 -
MVETSPL CXA8_MOUSE 292 0 -
GVEPSPL CXA8_CHICK 286 -1 -

Motif 4 width=13
Element Seqn Id St Int Rpt
GPLGDLSRGYQET CXA8_HUMAN 305 14 -
GPLGDLSRAYQET CXA8_SHEEP 313 14 -
GPLADMSRSYQET CXA8_MOUSE 313 14 -
GPLEDLSRAFDER CXA8_CHICK 306 13 -

Motif 5 width=11
Element Seqn Id St Int Rpt
LPSYAQVGAQE CXA8_HUMAN 318 0 -
LPSYAQVGAQE CXA8_SHEEP 326 0 -
LPSYAQVGVQE CXA8_MOUSE 326 0 -
LPSYAQAKEPE CXA8_CHICK 319 0 -

Motif 6 width=12
Element Seqn Id St Int Rpt
RPLSRLSKASSR CXA8_HUMAN 412 83 -
RPLSRLSKASSR CXA8_SHEEP 420 83 -
RPLSRLSKASSR CXA8_MOUSE 420 83 -
RSLSRLSKASSR CXA8_CHICK 380 50 -