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PR01140

Identifier
CONNEXINB3  [View Relations]  [View Alignment]  
Accession
PR01140
No. of Motifs
4
Creation Date
20-APR-1999
Title
Gap junction beta-3 protein (Cx31) signature
Database References
PRINTS; PR00206 CONNEXIN
PRODOM; PD029912
INTERPRO; IPR002269
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).
 
9. RICHARD, G., SMITH, L.E., BAILEY, R.A., ITIN, P., HOHL, D., EPSTEIN,
E.H., JR., DIGIOVANNA, J.J., COMPTON, J.G. AND BALE, S.J.
Mutations in the human connexin gene GJB3 cause erythrokeratodermia
variablis.
NAT.GENET. 20 366-369 (1998).

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 beta-3 protein (also called connexin31, or Cx31) is a connexin 
of 270 amino acid residues, and belongs to a family that also includes Cx26,
Cx31.1 and Cx32. At the mRNA level, it has been found to be expressed in the
skin, ear, placenta and eye. Mutations in Cx31 have been found to be 
responsible for two quite different inherited human diseases: erythro-
keratomdermia variablis and autosomal dominant hearing impairment. The
former is a hereditary skin disease characterised by transient figurate red
patches of skin and hyperkeratosis. In the Cx31 molecule of these patients,
either a conserved glycine has been substituted by a charged residue, or a
cysteine has been changed to a to serine residue [9]. In the latter,
mutations in Cx31 result in high-frequency hearing impairment, making it 
the second connexin molecule (together with Cx26) in which mutations have
been found to be responsible for an inherited hearing disorder.
 
CONNEXINB3 is a 4-element fingerprint that provides a signature for the
gap junction beta-3 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 beta-3 isoform but distinguish
it from others - motif 1 resides within the putative cytoplasmic loop
between TM domains 2 and 3; motif 2 encodes the C-terminal half of the third
putative TM domain; motif 3 lies within the extracellular domain between TM
domains 3 and 4; and motif 4 resides within the putative cytoplasmic
C-terminus. A single iteration on SPTR37_9f was required to reach convergence,
no further sequences being identified beyond the starting set.
Summary Information
3 codes involving  4 elements
0 codes involving 3 elements
0 codes involving 2 elements
Composite Feature Index
43333
30000
20000
1234
True Positives
CXB3_HUMAN    CXB3_MOUSE    CXB3_RAT      
Sequence Titles
CXB3_HUMAN  GAP JUNCTION BETA-3 PROTEIN (CONNEXIN 31) (CX31) - HOMO SAPIENS (HUMAN). 
CXB3_MOUSE GAP JUNCTION BETA-3 PROTEIN (CONNEXIN 31) (CX31) - MUS MUSCULUS (MOUSE).
CXB3_RAT GAP JUNCTION BETA-3 PROTEIN (CONNEXIN 31) (CX31) - RATTUS NORVEGICUS (RAT).
Scan History
SPTR37_9f  1  300  NSINGLE    
Initial Motifs
Motif 1  width=8
Element Seqn Id St Int Rpt
GEHCAKLY CXB3_RAT 110 110 -
GEQCAKLY CXB3_MOUSE 110 110 -
GDQCAKLY CXB3_HUMAN 110 110 -

Motif 2 width=10
Element Seqn Id St Int Rpt
LHTLWHGFTM CXB3_RAT 149 31 -
LHTLWHGFTM CXB3_MOUSE 149 31 -
LHTLWHGFNM CXB3_HUMAN 149 31 -

Motif 3 width=9
Element Seqn Id St Int Rpt
LVQCASVVP CXB3_RAT 161 2 -
LVQCASIVP CXB3_MOUSE 161 2 -
LVQCANVAP CXB3_HUMAN 161 2 -

Motif 4 width=10
Element Seqn Id St Int Rpt
RIMRGLSKDK CXB3_RAT 213 43 -
RIMRGISKGK CXB3_MOUSE 213 43 -
RVLRGLHKDK CXB3_HUMAN 213 43 -
Final Motifs
Motif 1  width=8
Element Seqn Id St Int Rpt
GEHCAKLY CXB3_RAT 110 110 -
GEQCAKLY CXB3_MOUSE 110 110 -
GDQCAKLY CXB3_HUMAN 110 110 -

Motif 2 width=10
Element Seqn Id St Int Rpt
LHTLWHGFTM CXB3_RAT 149 31 -
LHTLWHGFTM CXB3_MOUSE 149 31 -
LHTLWHGFNM CXB3_HUMAN 149 31 -

Motif 3 width=9
Element Seqn Id St Int Rpt
LVQCASVVP CXB3_RAT 161 2 -
LVQCASIVP CXB3_MOUSE 161 2 -
LVQCANVAP CXB3_HUMAN 161 2 -

Motif 4 width=10
Element Seqn Id St Int Rpt
RIMRGLSKDK CXB3_RAT 213 43 -
RIMRGISKGK CXB3_MOUSE 213 43 -
RVLRGLHKDK CXB3_HUMAN 213 43 -