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PR01665

Identifier
NACHANNEL4  [View Relations]  [View Alignment]  
Accession
PR01665
No. of Motifs
4
Creation Date
13-MAR-2002
Title
Voltage-gated Na+ channel alpha 4 subunit signature
Database References
PRINTS; PR00170 NACHANNEL
Literature References
1. GEORGE, A.L., KNITTLE, T.J. AND TAMKUN, M.M.
Molecular cloning of an atypical voltage-gated sodium channel expressed in
human heart and uterus - Evidence for a distinct gene family.
PROC.NATL.ACAD.SCI.U.S.A. 89(11) 4893-4897 (1992).
 
2. NODA, M., IKEDA, T., KAYANO, T., SUZUKI, H., TAKESHIMA, H., 
KURASAKI, M., TAKAHASHI, H. AND NUMA, S.
Existence of distinct sodium channel messenger RNAs in rat brain.
NATURE 320 188-192 (1986).
 
3. NODA, M., SHIMIZU, S., TANABE, T., TAKAI, T., KAYANO, T., IKEDA, T., 
TAKAHASHI, H., NAKAYAMA, H., KANAOKA, Y., MINAMINO, M., KANGAWA, K., 
MATSUO, H., RAFTERY, M.A., HIROSE, T., INAYAMA, S., HAYASHIDA, H, MIYATA,
T. AND NUMA, S.
Primary structure of Electrophorus electricus sodium channel deduced from 
cDNA sequence.
NATURE 312 121-127 (1984).
 
4. ROGART, R.B., CRIBBS, L.L., MUGLIA, L.K., KEPHART, D.D. AND KAISER, M.W.
Molecular cloning of a putative tetrodotoxin resistant rat heart Na+
channel isoform.
PROC.NATL.ACAD.SCI.U.S.A. 86(20) 8170-8174 (1989).
 
5. SATO, C. AND MATSUMOTO, G.
Proposed tertiary structure of the sodium channel.
BIOCHEM.BIOPHYS.RES.COMMUN. 186 1158-1167 (1992).
 
6. GEORGE, A.L., LEDBETTER, D.H., KALLEN, R.G. AND BARCHI, R.L.
Assignment of a human skeletal muscle sodium channel alpha-subunit gene
HUM.GENET. 88(1) 71-74 (1991).
 
7. BULMAN, E., SCOGGAN, K.A., VAN OENE, M.D., NICOLLE, M.W., HAHN, A.F., 
TOLLAR, L.L. AND EBERS, G.C.
A novel sodium channel mutation in a family with hypokalemic periodic paralysis.
NEUROLOGY 53 1932-1936 (1999).

Documentation
Voltage-dependent sodium channels are transmembrane (TM) proteins
responsible for the depolarising phase of the action potential in most
electrically excitable cells [1]. They may exist in 3 states [3]: the
resting state, where the channel is closed; the activated state, where the
channel is open; and the inactivated state, where the channel is closed
and refractory to opening. Several different structurally and functionally
distinct isoforms are found in mammals, coded for by a multigene family
[4], these being responsible for the different types of sodium ion currents
found in excitable tissues.
                  
The structure of sodium channels is based on 4 internal repeats of a 6-helix
bundle [2] (in which 5 of the membrane-spanning segments are hydrophobic and
the other is positively charged), forming a 24-helical bundle. The charged
segments are believed to be localised within clusters formed by their 5
hydrophobic neighbours: it is postulated that the charged domain may be the
voltage sensor region, possibly moving outward on depolarisation, causing a
conformational change. This model, proposed by Noda et al. [2], contrasts
with that of Sato and Matsumoto [5], in which the TM segments are juxtaposed
octagonally. The basic structural motif (the 6-helix bundle) is also found
in potassium and calcium channel alpha subunits.
 
The SCN4A gene belongs to the Nav1 family, which also includes SCN1A, SCN2A,
SCN3A, SCN5A and SCN8A. This family is typically expressed in the brain,
spinal cord, skeletal muscle, cardiac muscle and peripheral neurons [6].
Mutations in SCN4A are associated with hyperkalaemic periodic paralysis,
paramyotonia congenita and a diverse group of disorders collectively known
as potassium-aggravated myotonia. These are characterised by skeletal muscle
hyperexcitability or muscle weakness, which is exacerbated by exposure to
cold temperature [7].
 
NACHANNEL4 is a 4-element fingerprint that provides a signature for the
voltage-gated Na+ channel alpha 4 subunit. The fingerprint was derived from
an initial alignment of 3 sequences: the motifs were drawn from conserved 
regions spanning the N-terminal third of the alignment, focusing on those
sections that characterise the alpha 4 subunits but distinguish them from
the rest of the voltage-gated Na+ channel superfamily - motif 1 resides at
the N-terminus; motifs 2 and 3 span the loop between the first and second 
repeat; and motif 4 lies in the loop between TM domain 6 of the first repeat
and TM domain 1 of the second repeat. Two iterations on SPTR40_18f 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
CIN4_HUMAN    CIN4_RAT      O70611        Q28371        
Q9ER60
Sequence Titles
CIN4_HUMAN  Sodium channel protein, skeletal muscle alpha-subunit - Homo sapiens (Human). 
CIN4_RAT Sodium channel protein, skeletal muscle alpha-subunit (MU-1) - Rattus norvegicus (Rat).
O70611 RAT SKELETAL MUSCLE TYPE 1 VOLTAGE-GATED SODIUM CHANNEL (RSKM1) VARIANT (RSKM1) - Rattus norvegicus (Rat).
Q28371 SKELETAL MUSCLE SODIUM CHANNEL ALPHA-SUBUNIT - Equus caballus (Horse).
Q9ER60 VOLTAGE-GATED SODIUM CHANNEL - Mus musculus (Mouse).
Scan History
SPTR40_18f 2  300  NSINGLE    
Initial Motifs
Motif 1  width=21
Element Seqn Id St Int Rpt
MASSSLPNLVPPGPHCLRPFT CIN4_RAT 1 1 -
MASSSLPTLVPPGPHCLRPFT Q9ER60 1 1 -
MARPSLCTLVPLGPECLRPFT CIN4_HUMAN 1 1 -

Motif 2 width=15
Element Seqn Id St Int Rpt
HQEELEKAKAAQALE CIN4_RAT 472 450 -
HQEELEKAKAAQALE Q9ER60 472 450 -
HQEELEKAKAAQALE CIN4_HUMAN 478 456 -

Motif 3 width=16
Element Seqn Id St Int Rpt
ADGDPTHNKDCNGSLD CIN4_RAT 491 4 -
ADGDPTHSKDCNGSLD Q9ER60 491 4 -
ADGDPAHGKDCNGSLD CIN4_HUMAN 496 3 -

Motif 4 width=20
Element Seqn Id St Int Rpt
GEKGPPRPSCSADSAISDAM CIN4_RAT 509 2 -
GEKGPPRPSCSAESAISDAM Q9ER60 509 2 -
GEKGAPRQSGSGDSGISDAM CIN4_HUMAN 515 3 -
Final Motifs
Motif 1  width=21
Element Seqn Id St Int Rpt
MASSSLPNLVPPGPHCLRPFT CIN4_RAT 1 1 -
MASSSLPNLVPPGPHCLRPFT O70611 1 1 -
MASSSLPTLVPPGPHCLRPFT Q9ER60 1 1 -
MARPSLCTLVPLGPECLRPFT CIN4_HUMAN 1 1 -
MASSSLPNLVPLGPESLRPFT Q28371 1 1 -

Motif 2 width=15
Element Seqn Id St Int Rpt
HQEELEKAKAAQALE CIN4_RAT 472 450 -
HQEELEKAKAAQALE O70611 472 450 -
HQEELEKAKAAQALE Q9ER60 472 450 -
HQEELEKAKAAQALE CIN4_HUMAN 478 456 -
QQEELEKAKADQALE Q28371 472 450 -

Motif 3 width=16
Element Seqn Id St Int Rpt
ADGDPTHNKDCNGSLD CIN4_RAT 491 4 -
ADGDPTHNKDCNGSLD O70611 491 4 -
ADGDPTHSKDCNGSLD Q9ER60 491 4 -
ADGDPAHGKDCNGSLD CIN4_HUMAN 496 3 -
AGGDPAHSKDCNGSLD Q28371 490 3 -

Motif 4 width=20
Element Seqn Id St Int Rpt
GEKGPPRPSCSADSAISDAM CIN4_RAT 509 2 -
GEKGPPRPSCSADSAISDAM O70611 509 2 -
GEKGPPRPSCSAESAISDAM Q9ER60 509 2 -
GEKGAPRQSGSGDSGISDAM CIN4_HUMAN 515 3 -
GEKGPPRQSCSADSGVSDAM Q28371 509 3 -