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PR01135

Identifier
CONNEXINA5  [View Relations]  [View Alignment]  
Accession
PR01135
No. of Motifs
4
Creation Date
20-APR-1999
Title
Gap junction alpha-5 protein (Cx40) signature
Database References
PRINTS; PR00206 CONNEXIN
PRODOM; PD012576; PD012766
INTERPRO; IPR002264
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-5 protein (also called connexin40, or Cx40) is a connexin
of ~357 amino acid residues. The chicken isoform is about ten residues 
longer, and is hence known as connexin42 (Cx42), as it has a molecular mass
of ~42 kDa. Targeted disruption of the gene encoding Cx40 in mice suggests
that Cx40-containing gap junctions are involved in the rapid conduction of
impulses in the His-Purkinje system of the heart, which is responsible for 
the coordinated spread of excitation from the atrioventricular (A-V) node 
to the ventricular myocardium. Mice lacking Cx40 are viable and fertile; 
however, they have subtle electrocardio-graphic abnormalities, such as 
partial A-V block. Studies of the distribution of Cx40 support these 
findings, since Cx40 has been reported to be prominently expressed in the
Purkinje fibres of the heart.
 
CONNEXINA5 is a 4-element fingerprint that provides a signature for the
gap junction alpha-5 protein. The fingerprint was derived from an initial
alignment of 4 sequences: the motifs were drawn from conserved regions
spanning virtually the full alignment length, focusing on those regions
that characterise the gap junction alpha-5 isoform but distinguish it from
others - motifs 1-2 reside within the putative cytoplasmic loop between TM
domains 2 and 3; and motifs 3-4 lie within the putative cytoplasmic
C-terminus. Two iterations on SPTR37_9f were required to reach convergence,
at which point a true set comprising 5 sequences was identified.
Summary Information
5 codes involving  4 elements
0 codes involving 3 elements
0 codes involving 2 elements
Composite Feature Index
45555
30000
20000
1234
True Positives
CXA5_CANFA    CXA5_CHICK    CXA5_HUMAN    CXA5_MOUSE    
CXA5_RAT
Sequence Titles
CXA5_CANFA  GAP JUNCTION ALPHA-5 PROTEIN (CONNEXIN 40) (CX40) - CANIS FAMILIARIS (DOG). 
CXA5_CHICK GAP JUNCTION ALPHA-5 PROTEIN (CONNEXIN 42) (CX42) - GALLUS GALLUS (CHICKEN).
CXA5_HUMAN GAP JUNCTION ALPHA-5 PROTEIN (CONNEXIN 40) (CX40) - HOMO SAPIENS (HUMAN).
CXA5_MOUSE GAP JUNCTION ALPHA-5 PROTEIN (CONNEXIN 40) (CX40) - MUS MUSCULUS (MOUSE).
CXA5_RAT GAP JUNCTION ALPHA-5 PROTEIN (CONNEXIN 40) (CX40) - RATTUS NORVEGICUS (RAT).
Scan History
SPTR37_9f  2  250  NSINGLE    
Initial Motifs
Motif 1  width=10
Element Seqn Id St Int Rpt
VAEKAELSCW CXA5_HUMAN 126 126 -
VAEKAELSCW CXA5_MOUSE 126 126 -
VAEKTELSCW CXA5_CHICK 131 131 -
LAEKAELSCW CXA5_RAT 125 125 -

Motif 2 width=9
Element Seqn Id St Int Rpt
SILIRTTME CXA5_HUMAN 155 19 -
TILIRTTME CXA5_MOUSE 155 19 -
SILIRTAME CXA5_CHICK 160 19 -
TILIRTAME CXA5_RAT 154 19 -

Motif 3 width=10
Element Seqn Id St Int Rpt
TPPPDFNQCL CXA5_HUMAN 261 97 -
TPPPDFNQCL CXA5_MOUSE 261 97 -
TPPPDFNQCL CXA5_CHICK 270 101 -
TPPPDFNQCL CXA5_RAT 259 96 -

Motif 4 width=11
Element Seqn Id St Int Rpt
SSKARSDDLSV CXA5_HUMAN 347 76 -
SSKARSDDLSV CXA5_MOUSE 347 76 -
SSKARSDDLSV CXA5_CHICK 358 78 -
SSKARSDDLSV CXA5_RAT 345 76 -
Final Motifs
Motif 1  width=10
Element Seqn Id St Int Rpt
VAEKAELSCW CXA5_CANFA 125 125 -
VAEKAELSCW CXA5_HUMAN 126 126 -
VAEKAELSCW CXA5_MOUSE 126 126 -
VAEKTELSCW CXA5_CHICK 131 131 -
LAEKAELSCW CXA5_RAT 125 125 -

Motif 2 width=9
Element Seqn Id St Int Rpt
SILIRTTME CXA5_CANFA 154 19 -
SILIRTTME CXA5_HUMAN 155 19 -
TILIRTTME CXA5_MOUSE 155 19 -
SILIRTAME CXA5_CHICK 160 19 -
TILIRTAME CXA5_RAT 154 19 -

Motif 3 width=10
Element Seqn Id St Int Rpt
TPPPDFNQCL CXA5_CANFA 260 97 -
TPPPDFNQCL CXA5_HUMAN 261 97 -
TPPPDFNQCL CXA5_MOUSE 261 97 -
TPPPDFNQCL CXA5_CHICK 270 101 -
TPPPDFNQCL CXA5_RAT 259 96 -

Motif 4 width=11
Element Seqn Id St Int Rpt
SSKARSDDLSV CXA5_CANFA 346 76 -
SSKARSDDLSV CXA5_HUMAN 347 76 -
SSKARSDDLSV CXA5_MOUSE 347 76 -
SSKARSDDLSV CXA5_CHICK 358 78 -
SSKARSDDLSV CXA5_RAT 345 76 -