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PR01315

Identifier
BATTENIN  [View Relations]  [View Alignment]  
Accession
PR01315
No. of Motifs
9
Creation Date
12-MAY-2000
Title
CLN3 Batten's disease protein (battenin) signature
Database References
Literature References
1. THE INTERNATIONAL BATTEN DISEASE CONSORTIUM.
Isolation of a novel gene underlying Batten disease, CLN3 - The
International Batten Disease Consortium.
CELL 82 949-957 (1995).
  
2. GOLABEK, A. A., KACZMARSKI, W., KIDA, E., KACMARSKI, A., 
MICHALEWSKI, M.P. AND WISNIEWSKI, K.E.
Expression studies of CLN3 protein (Battenin) in fusion with the green
fluorescent protein in mammalian cells in vitro.
MOL.GENET.METAB. 66 277-282 (1999).
  
3. MUNROE, P.B., MITCHISON, H.M., O'RAWE, A.M., ANDERSON, J.W., 
BOUSTANY, R-M, LERNER, T.J., TASCHNER, P.E.M., de VOS, N., BREUNING, M.H.,
GARDINER, R.M. AND MOLE S.E.
Spectrum of mutations in the Batten disease gene, CLN3.
AM.J.HUM.GENET. 61 310-316 (1997).
  
4. GRANGER BL, GREEN, S.A., GABEL, C.A., HOWE, C.L., MELLMAN, I.
AND HELENIUS, A.
Characterization and cloning of lgp110, a lysosomal membrane glycoprotein
from mouse and rat cells.
J.BIOL.CHEM. 265 12036-12043 (1990).
 
5. MICHALEWSKI, M.P., KACZMARSKI, W., GOLABEK, A.A., KIDA, E., 
KACZMARSKI, A. AND WISNIEWSKI, K.E.
Post-translational modification of CLN3 protein and its possible functional
implication.
MOL.GENET.METAB. 66 272-276 (1999).
  
6. SCHAFER, W.R. AND RINE, J.
Protein prenylation.
ANNU.REV.GENET. 30 209-237 (1992).
  
7. CASEY, P.J.
Protein lipidation in cell signalling.
SCIENCE 268 221-225 (1995).
  
8. KACZMARSKI, W., WISNIEWSKI, K.E, GOLABEK, A., KACMARSKI, A., KIDA, E.
AND MICHALEWSKI, M. 
Studies of membrane association of CLN3 protein.
MOL.GENET.METAB. 66 261-264 (1999).
  
9. JARVELA, I., SAINIO, M., RANTAMAKI, T., OLKKONEN, V.M., CARPEN, O.,
PELTONEN, L. AND JALANKO, A.
Biosynthesis and intracellular targeting of the CLN3 protein defective in
Batten disease.
HUM.MOL.GENET. 7 85-90 (1998). 
  
10. MARGRAF, L.R., BORIACK, R.L., ROUTHEUT, A. A. J., CUPPEN I., ALHILALI,
L., BENNETT, C.J. AND BENNETT, M.J.  
Tissue expression and subcellular localization of CLN3, the Batten disease
protein.
MOL.GENET.METAB. 66 283-289 (1999).
  
11. KATZ, M.L., GAO, C-L., PRABHAKARAM, M., SHIBUYA, H., LIU, P-C. AND
JOHNSON. G.S.
Immunochemical localization of the Batten disease (CLN3) protein in 
retina.
INVEST.OPHTHALMOL.VIS.SCI. 38 2375-2386 (1997).

Documentation
Batten's disease, the juvenile variant of neuronal ceroid lipofuscionosis
(NCL), is a recessively inherited disorder affecting children of 5-10
years of age. The disease is characterised by progressive loss of vision,
seizures and psychomotor disturbances. Biochemically, the disease is
characterised by lysosomal accumulation of hydrophobic material, mainly ATP
synthase subunit C, largely in the brain but also in other tissues [1]. 
Batten's disease is one of the most common neurodegenerative diseases, 
affecting children with an incidence of 1/20000 to 1/10000 live births [1].
The disease is fatal within a decade. There are no current treatments
available.
  
Mutations in the CLN3 gene are believed to cause Batten's disease [1]. The
CLN3 gene maps to chromosome p16p12.1. The predicted product of the CLN3
gene is a 438-residue protein. The gene contains at least 15 exons spanning
15kb and is highly conserved in mammals [4]. A 1.02kb deletion in the CLN3
gene, occurring in either one or both alleles, is found in 85% of Batten 
disease chromosomes [1,3]. This deletion causes a frameshift generating a
predicted translated product of 181 amino acid residues (153 from the
protein and 28 novel amino acids before the stop codon) [2]. 22 other 
mutations, including deletions, insertions and point mutations, have been
reported [1,3]. It has been suggested that such mutations result in severely
truncated CLN3 proteins, or affect its structure/conformation [1,3]. CLN3
has no known function.
  
CLN3 proteins, which are believed to associate in complexes, are heavily
glycosylated lysosomal membrane proteins [2], containing complex Asn-linked
oligosaccharides [4]. Extensive glycosylation is important for the stability
of these lysosomal proteins in the highly hydrolytic lysosomal lumen. CLN3
protein contains four potential N-glycosylation sites (residues 49, 71, 85
and 310), two putative O-glycosylation sites (residues 80 and 256), and two
potential glycosaminoglycan sites (residues 162 and 168) [2]. Lysosomal
membranes are involved in acidification of the lysosomal matrix,
sequestration of active lysosomal enzymes, transport of degraded molecules
from the lysosomes, and fusion and fission between lysosomes and other
organelles [2]. 
  
The CLN3 protein is a 43Kd, highly hydrophobic, multi-transmembrane (TM),
phosphorylated protein [2]. Hydrophobicity analysis predicts 6-9 TM
segments, suggesting that CLN3 is a TM protein that may function as a
chaperone or signal transducer [5]. The majority of putative phosphorylation
sites are found in the N-terminal domain, encompassing 150 residues [5].
Phosphorylation is believed to be important for membrane compartment 
interaction, in the formation of functional complexes, and in regulation 
and interactions with other proteins [6]. 
  
CLN3 contains several motifs that may undergo lipid post-translational
modifications (PTMs). PTMs contribute to targeting and anchoring of modified
proteins to distinct biological membranes [7]. There are three general 
classes of lipid modification: N-terminal myristoylation, C-terminal 
prenylation, and palmitoylation of cysteine residues. Such modifications 
are believed to be a common form of PTM occurring in 0.5% of all cellular
proteins, including brain tissue [8]. The C-terminus of the CLN3 contains
various lipid modification sites: C435, target for prenylation; G419, 
target for myristoylation; and C414, target for palmitoylation [8,9].
Prenylation results in protein hydrophobicity, influences interaction with
upstream regulatory proteins and downstream effectors, facilitates protein-
protein interaction (multisubunit assembly) and promotes anchoring to
membrane lipids [8]. The prenylation motif, Cys-A-A-X, is highly conserved
within CLN3 protein sequences of different species [8].
  
In normal human tissue, protein immunoblotting indicates presence of CLN3
in the brain, pancreas, spleen, kidney, skeletal muscle, liver, placenta,
and testis, with detectable amounts in the peripheral nerve [2,10]. CLN3
mRNA expression is found to be little in the brain and considerably greater
in pancreas, kidney, skeletal muscle, liver and lung [10]. The difference 
in distribution of CLN3 mRNA and protein is believed to be a result of
post-transcriptional regulation of the CLN3 gene [10]. CLN3 in the brain is
found in both grey and white matter, with greater concentrations in the
former and localised in astrocytes and neurons. In the pancreas, it is found
in pancreatic islets and peripheral nerves [10]. The subcelluar distribution
of CLN3 is localised to membranes and nuclei [10]. Previous studies also
indicate presence of CLN3 in the mitochondrial membrane or lysosomes [9,11].
  
Species with known CLN3 protein homologues include: Homo sapiens, Canis 
familiaris, Mus musculus, Saccharomyces cerevisiae and Drosophila
melanogaster.
 
BATTENIN is a 9-element fingerprint that provides a signature for the
CLN3 Batten's disease protein. The fingerprint was derived from an initial
alignment of 6 sequences: the motifs were drawn from conserved regions
spanning the full alignment length - motifs 1, 2, 4, 5, 8 and 9 encode
putative TM regions, motif 9 containing prenylation, myristoylation and 
palmitoylation lipid modification sites. Two iterations on SPTR37.10f were
required to reach convergence, at which point a true set comprising 8 
sequences was identified. Three partial matches were also found: O95086
and O95089 are human CLN3 splice variants; and O76703 is a C.elegans
cosmid that bears similarities to CLN3 protein.
Summary Information
   8 codes involving  9 elements
0 codes involving 8 elements
2 codes involving 7 elements
1 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
9888888888
8000000000
7122022122
6100011111
5000000000
4000000000
3000000000
2000000000
123456789
True Positives
BTN1_YEAST    CLN3_CANFA    CLN3_HUMAN    CLN3_MOUSE    
O35934 O60004 P91012 Q93440
True Positive Partials
Codes involving 7 elements
O76703 O95086
Codes involving 6 elements
O95089
Sequence Titles
BTN1_YEAST  BTN1 PROTEIN - SACCHAROMYCES CEREVISIAE (BAKER'S YEAST). 
CLN3_CANFA CLN3 PROTEIN - CANIS FAMILIARIS (DOG).
CLN3_HUMAN CLN3 PROTEIN (BATTEN'S DISEASE PROTEIN) - HOMO SAPIENS (HUMAN).
CLN3_MOUSE CLN3 PROTEIN - MUS MUSCULUS (MOUSE).
O35934 CLN3 - MUS MUSCULUS (MOUSE).
O60004 BTN1P - SACCHAROMYCES CEREVISIAE (BAKER'S YEAST).
P91012 COSMID C01G8 - CAENORHABDITIS ELEGANS.
Q93440 F07B10.1 PROTEIN - CAENORHABDITIS ELEGANS.

O76703 ZC190.1 PROTEIN - CAENORHABDITIS ELEGANS.
O95086 CLN3 PROTEIN - HOMO SAPIENS (HUMAN).

O95089 CLN3 PROTEIN - HOMO SAPIENS (HUMAN).
Scan History
SPTR37_10f 2  75   NSINGLE    
Initial Motifs
Motif 1  width=23
Element Seqn Id St Int Rpt
FWLLGLCNNFSYVVMLSAAHDIL CLN3_CANFA 41 41 -
FWLLGLCNNFSYVVMLSAAHDIL CLN3_HUMAN 41 41 -
FWILGLCNNFSYVVMLSAAHDIL CLN3_MOUSE 41 41 -
FWLFGLINNVLYVVILSAAVDIV BTN1_YEAST 12 12 -
FWLLGLCNNFAYVVMLSAAKDIL P91012 18 18 -
FWLLGLCNNYGYVIMLSAAEDIL Q93440 13 13 -

Motif 2 width=17
Element Seqn Id St Int Rpt
VLLADILPTLIIKLLAP CLN3_CANFA 100 36 -
VLLADILPTLVIKLLAP CLN3_HUMAN 100 36 -
VLLADILPTLVIKLLAP CLN3_MOUSE 100 36 -
VLLADIFPSLAIKLCSP BTN1_YEAST 43 8 -
VLLADIIPALLIKITAP P91012 68 27 -
VLLADNLPALVVQTTFP Q93440 68 32 -

Motif 3 width=23
Element Seqn Id St Int Rpt
GVVLASISSGVGEVTFLSLTAFY CLN3_CANFA 154 37 -
GVVFASISSGLGEVTFLSLTAFY CLN3_HUMAN 154 37 -
GVVLASISSGLGEVTFLSLTAFY CLN3_MOUSE 154 37 -
GISFASISSGFGEVTFLQLTHYY BTN1_YEAST 96 36 -
GVVLASFGSGLGEISYLALSSNY P91012 122 37 -
GVCMASLGQGIGEITFLAMAAHY Q93440 122 37 -

Motif 4 width=21
Element Seqn Id St Int Rpt
WSSGTGGAGLMGALSYLGLTQ CLN3_CANFA 184 7 -
WSSGTGGAGLLGALSYLGLTQ CLN3_HUMAN 184 7 -
WSSGTGGAGLLGSLSYLGLTQ CLN3_MOUSE 184 7 -
WSSGTGGAGIIGGASYMFLTS BTN1_YEAST 126 7 -
WSSGTGGAGLIGASAYALLTD P91012 152 7 -
WSSGTGGAGLIGSFSYAFITQ Q93440 152 7 -

Motif 5 width=23
Element Seqn Id St Int Rpt
GLLWYIVPLVLVYFAEYFINQGL CLN3_CANFA 280 75 -
GLLWYIVPLVVVYFAEYFINQGL CLN3_HUMAN 280 75 -
GLLWYIIPLVLVYFAEYFINQGL CLN3_MOUSE 280 75 -
LVFPYMVPLTTVYLFEYLINQAV BTN1_YEAST 228 81 -
PLLKFMIPLISVYLAEYYINQGL P91012 271 98 -
PLLYLMVPLATVYTAEYMINQGL Q93440 257 84 -

Motif 6 width=16
Element Seqn Id St Int Rpt
WYQMLYQAGVFVSRSS CLN3_CANFA 321 18 -
WYQMLYQAGVFASRSS CLN3_HUMAN 321 18 -
WYQMLYQAGVFASRSS CLN3_MOUSE 321 18 -
TYGTLYQLGVFISRSF BTN1_YEAST 280 29 -
WFQVTYQLGVFISRSS P91012 315 21 -
WYQVLYQLGVFISRSS Q93440 301 21 -

Motif 7 width=13
Element Seqn Id St Int Rpt
WVLALLQCLNLAF CLN3_CANFA 346 9 -
WALALLQCLNLVF CLN3_HUMAN 346 9 -
WVLALLQCLNLAL CLN3_MOUSE 346 9 -
YILAFLQGVNLCI BTN1_YEAST 305 9 -
KSLAVLQIFNAGF P91012 342 11 -
WCLPILQCVNMIF Q93440 328 11 -

Motif 8 width=25
Element Seqn Id St Int Rpt
PSIYLVFLIILYEGLLGGAAYVNTF CLN3_CANFA 369 10 -
PSIYLVFLIILYEGLLGGAAYVNTF CLN3_HUMAN 369 10 -
PSIYLIFIIILHEGLLGGAAYVNTF CLN3_MOUSE 369 10 -
HSPWAVMILIFYEGFLGGASYVNTF BTN1_YEAST 328 10 -
PHILIAFLVILFEGLLGGASYVNTF P91012 365 10 -
PTIIIIFVLIVFEGLLGGSAYVNTY Q93440 351 10 -

Motif 9 width=30
Element Seqn Id St Int Rpt
EFAMAAACISDTLGISLSGLLALPLHDFLC CLN3_CANFA 406 12 -
EFAMAATCISDTLGISLSGLLALPLHDFLC CLN3_HUMAN 406 12 -
EFAMEAACISDTLGISLSGVLALPLHDFLC CLN3_MOUSE 406 12 -
EFAMGAVSIADSFGVFLAALLGLGLEPKLC BTN1_YEAST 365 12 -
EFSMGVVSISDTIGIVFAGFLAMPVHNRIC P91012 402 12 -
EYSLSAASMGNSLGTNIAAFLSIPLYNWVC Q93440 388 12 -
Final Motifs
Motif 1  width=23
Element Seqn Id St Int Rpt
FWILGLCNNFSYVVMLSAAHDIL O35934 41 41 -
FWLLGLCNNFSYVVMLSAAHDIL CLN3_CANFA 41 41 -
FWLLGLCNNFSYVVMLSAAHDIL CLN3_HUMAN 41 41 -
FWILGLCNNFSYVVMLSAAHDIL CLN3_MOUSE 41 41 -
FWLFGLINNVLYVVILSAAVDIV BTN1_YEAST 12 12 -
FWLFGLINNVLYVVILSAAVDIV O60004 12 12 -
FWLLGLCNNFAYVVMLSAAKDIL P91012 18 18 -
FWLLGLCNNYGYVIMLSAAEDIL Q93440 13 13 -

Motif 2 width=17
Element Seqn Id St Int Rpt
VLLADILPTLVIKLLAP O35934 100 36 -
VLLADILPTLIIKLLAP CLN3_CANFA 100 36 -
VLLADILPTLVIKLLAP CLN3_HUMAN 100 36 -
VLLADILPTLVIKLLAP CLN3_MOUSE 100 36 -
VLLADIFPSLAIKLCSP BTN1_YEAST 43 8 -
VLLADIFPSLAIKLCSP O60004 43 8 -
VLLADIIPALLIKITAP P91012 68 27 -
VLLADNLPALVVQTTFP Q93440 68 32 -

Motif 3 width=23
Element Seqn Id St Int Rpt
GVVLASISSGLGEVTFLSLTAFY O35934 154 37 -
GVVLASISSGVGEVTFLSLTAFY CLN3_CANFA 154 37 -
GVVFASISSGLGEVTFLSLTAFY CLN3_HUMAN 154 37 -
GVVLASISSGLGEVTFLSLTAFY CLN3_MOUSE 154 37 -
GISFASISSGFGEVTFLQLTHYY BTN1_YEAST 96 36 -
GISFASISSGFGEVTFLQLTHYY O60004 96 36 -
GVVLASFGSGLGEISYLALSSNY P91012 122 37 -
GVCMASLGQGIGEITFLAMAAHY Q93440 122 37 -

Motif 4 width=21
Element Seqn Id St Int Rpt
WSSGTGGAGLLGSLSYLGLTQ O35934 184 7 -
WSSGTGGAGLMGALSYLGLTQ CLN3_CANFA 184 7 -
WSSGTGGAGLLGALSYLGLTQ CLN3_HUMAN 184 7 -
WSSGTGGAGLLGSLSYLGLTQ CLN3_MOUSE 184 7 -
WSSGTGGAGIIGGASYMFLTS BTN1_YEAST 126 7 -
WSSGTGGAGIIGGASYMFLTS O60004 126 7 -
WSSGTGGAGLIGASAYALLTD P91012 152 7 -
WSSGTGGAGLIGSFSYAFITQ Q93440 152 7 -

Motif 5 width=23
Element Seqn Id St Int Rpt
GLLWYIIPLVLVYFAEYFINQGL O35934 280 75 -
GLLWYIVPLVLVYFAEYFINQGL CLN3_CANFA 280 75 -
GLLWYIVPLVVVYFAEYFINQGL CLN3_HUMAN 280 75 -
GLLWYIIPLVLVYFAEYFINQGL CLN3_MOUSE 280 75 -
LVFPYMVPLTTVYLFEYLINQAV BTN1_YEAST 228 81 -
LVFPYMVPLTTVYLFEYLINQAV O60004 228 81 -
PLLKFMIPLISVYLAEYYINQGL P91012 271 98 -
PLLYLMVPLATVYTAEYMINQGL Q93440 257 84 -

Motif 6 width=16
Element Seqn Id St Int Rpt
WYQMLYQAGVFASRSS O35934 321 18 -
WYQMLYQAGVFVSRSS CLN3_CANFA 321 18 -
WYQMLYQAGVFASRSS CLN3_HUMAN 321 18 -
WYQMLYQAGVFASRSS CLN3_MOUSE 321 18 -
TYGTLYQLGVFISRSF BTN1_YEAST 280 29 -
TYGTLYQLGVFISRSF O60004 280 29 -
WFQVTYQLGVFISRSS P91012 315 21 -
WYQVLYQLGVFISRSS Q93440 301 21 -

Motif 7 width=13
Element Seqn Id St Int Rpt
WVLALLQCLNLAL O35934 346 9 -
WVLALLQCLNLAF CLN3_CANFA 346 9 -
WALALLQCLNLVF CLN3_HUMAN 346 9 -
WVLALLQCLNLAL CLN3_MOUSE 346 9 -
YILAFLQGVNLCI BTN1_YEAST 305 9 -
YILAFLQGVNLCI O60004 305 9 -
KSLAVLQIFNAGF P91012 342 11 -
WCLPILQCVNMIF Q93440 328 11 -

Motif 8 width=25
Element Seqn Id St Int Rpt
PSIYLIFIIILYEGLLGGAAYVNTF O35934 369 10 -
PSIYLVFLIILYEGLLGGAAYVNTF CLN3_CANFA 369 10 -
PSIYLVFLIILYEGLLGGAAYVNTF CLN3_HUMAN 369 10 -
PSIYLIFIIILHEGLLGGAAYVNTF CLN3_MOUSE 369 10 -
HSPWAVMILIFYEGFLGGASYVNTF BTN1_YEAST 328 10 -
RSPWAVMILIFYEGFLGGASYVNTF O60004 328 10 -
PHILIAFLVILFEGLLGGASYVNTF P91012 365 10 -
PTIIIIFVLIVFEGLLGGSAYVNTY Q93440 351 10 -

Motif 9 width=30
Element Seqn Id St Int Rpt
EFAMEAACISDTLGISLSGVLALPLHDFLC O35934 406 12 -
EFAMAAACISDTLGISLSGLLALPLHDFLC CLN3_CANFA 406 12 -
EFAMAATCISDTLGISLSGLLALPLHDFLC CLN3_HUMAN 406 12 -
EFAMEAACISDTLGISLSGVLALPLHDFLC CLN3_MOUSE 406 12 -
EFAMGAVSIADSFGVFLAALLGLGLEPKLC BTN1_YEAST 365 12 -
EFAMGAVSIADSFGVFLAALLGLGLEPKLC O60004 365 12 -
EFSMGVVSISDTIGIVFAGFLAMPVHNRIC P91012 402 12 -
EYSLSAASMGNSLGTNIAAFLSIPLYNWVC Q93440 388 12 -