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PR01986

Identifier
NOTCH3  [View Relations]  [View Alignment]  
Accession
PR01986
No. of Motifs
4
Creation Date
11-JUN-2009
Title
Neurogenic locus Notch protein 3 signature
Database References
PRINTS; PR01983 NOTCH
PROSITE; PS50258 LNR
PFAM; PF00066 Notch; PF06816 NOD; PF07684 NODP

SMART; SM00004 NL
INTERPRO; IPR000800; IPR008297; IPR010660; IPR011656
MIM; 125310; 600276
Literature References
1. KOPAN, R. AND ILAGAN, M.
The canonical notch signaling pathway: unfolding the activation mechanism. 
CELL 137 216-233 (2009).
 
2. ARTAVANIS-TSAKONAS, S., RAND, M.D. AND LAKE, R.J.
Notch signaling: cell fate control and signal integration in development. 
SCIENCE 284 770-776 (1999).
 
3. HARTMANN, D., DE STROOPER, B., SERNEELS. L., CRAESSAERTS, K., 
HERREMAN, A., ANNAERT, W., UMANS, L., LUBKE, T., LENA ILLERT, A., 
VON FIGURA, K. AND SAFTIG, P. 
The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling
but not for alpha-secretase activity in fibroblasts.
HUM.MOL.GENET. 11 2615-2624 (2002).
 
4. DE STROOPER, B., ANNAERT, W., CUPERS, P., SAFTIG, P., CRAESSAERTS, K.,
MUMM, J.S., SCHROETER, E.H., SCHRIJVERS, V., WOLFE, M.S., RAY, W.J., 
GOATE, A.AND KOPAN, R.
A presenilin-1-dependent gamma-secretase-like protease mediates release of 
Notch intracellular domain. 
NATURE 398 518-522 (1999).
 
5. WU, L., ASTER, J.C., BLACKLOW, S.C., LAKE, R., ARTAVANIS-TSAKONAS, S.,
AND GRIFFIN, J.D.
MAML1, a human homologue of Drosophila mastermind, is a transcriptional
co-activator for NOTCH receptors.
NAT.GENET. 26 484-489 (2000).
 
6. GRIDLEY, T. 
Notch signaling and inherited disease syndromes. 
HUM.MOL.GENET. 1 R9-R13 (2003).
 
7. LOUVI, A. AND ARTAVANIS-TSAKONAS, S.
Notch signalling in vertebrate neural development. 
NAT.REV.NEUROSCI. 7 93-102 (2006).
 
8. BELLAVIA, D., CHECQUOLO, S., CAMPESE, A.F., FELLI, M.P., GULINO, A.,
AND SCREPANTI, I. 
Notch3: from subtle structural differences to functional diversity.
ONCOGENE 27 5092-8 (2008).

Documentation
Notch cell surface receptors are large, single-pass type-1 transmembrane
proteins found in a diverse range of metazoan species, from human to
Caenorhabditis species. The fruit fly, Drosophila melanogaster, possesses
only one Notch protein, whereas in C.elegans, two receptors have been found;
by contrast, four Notch paralogues (designated N1-4) have been identified in
mammals, playing both unique and redundant roles.
 
The hetero-oligomer Notch comprises a large extracellular domain (ECD),
containing 10-36 tandem Epidermal Growth Factor (EFG)-like repeats, which
are involved in ligand interactions; a negative regulatory region,
including three cysteine-rich Lin12-Notch Repeats (LNR); a single trans-
membrane domain (TM); a small intracellular domain (ICD), which includes a
RAM (RBPjk-association module) domain; six ankyrin repeats (ANK), which are
involved in protein-protein interactions; and a PEST domain. Drosophila 
Notch also contains an OPA domain [1]. 	 
 
Notch signalling is an evolutionarily conserved pathway involved in a wide
variety of developmental processes, including adult homeostasis and stem 
cell maintainance, cell proliferation and apoptosis [2]. Notch is activated
by a range of ligands - the so-called DSL ligands (Delta/Seratte/LAG-2). 
Activation is also mediated by a sequence of proteolytic events: ligand
binding leads to cleavage of Notch by ADAM proteases [3] at site 2 (S2) and
presenilin-1/g-secretase at sites 3 (S3)and 4 (S4) [4].The last cleavage
releases the Notch intracellular part of the protein (NICD) from the
membrane and, upon release, the NICD translocates to the nucleus where it
associates with a CBF1/RBJk/Su(H)/Lag1 (CSL) family of DNA-binding proteins.
The subsequent recruitment of a co-activator mastermind like (MAML1) protein
[5] promotes transcriptional activation of Notch target genes: well 
established Notch targets are the Hes and Hey gene families.  
     
Aberrant Notch function and signalling has been associated with a number of
human disorders, including Allagile syndrome, spondylocostal dysostosis,
aortic valve disease, CADASIL (Cerebral Autosomal Dominant Arteriopathy with
Subcortical Infarcts and Leukoencephalopathy), and T-cell Acute Lympho-
blastic Leukemia (T-ALL); it has also been implicated in various human
carcinomas [6,7].
 
Notch3 displays a more restrictive distribution than the rest of the Notch
sybtypes, being expressed predominantly in vascular smooth muscle cells, the 
central nervous system, certain thymocytes subsets, and in regulatory T 
cells [8].
 
NOTCH3 is a 4-element fingerprint that provides a signature for neurogenic
locus Notch protein 3. The fingerprint was derived from an initial alignment
of 4 sequences: the motifs were drawn from those regions that characterise
the Notch 3 proteins, but distinguish them from closely related members of
the Notch family - motif 1 lies in a conserved area C-terminal to the LNR
region; motif 2 lies N-terminal to the TM domain; motif 3 spans the
C-terminus of TM domain; and motif 4 resides C-terminal to the ankyrin
region. A single iteration on SPTR57_40f was required to reach convergence,
no further sequences being identified beyond the starting set.
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
B0V2W1_MOUSE  NTC3_MOUSE    Q800E4_DANRE  Q9R172        
Q9UM47
Sequence Titles
B0V2W1_MOUSE Notch gene homolog 3 (Drosophila) - Mus musculus (Mouse). 
NTC3_MOUSE NEUROGENIC LOCUS NOTCH 3 PROTEIN - Mus musculus (Mouse).
Q800E4_DANRE Notch3 - Danio rerio (Zebrafish) (Brachydanio rerio).
Q9R172 NOTCH 3 PROTEIN - Rattus norvegicus (Rat).
Q9UM47 NOTCH3 - Homo sapiens (Human).
Scan History
SPTR57_40f 1  100  NSINGLE    
Initial Motifs
Motif 1  width=14
Element Seqn Id St Int Rpt
LRSSADFLQRLSAI Q9R172 1527 1527 -
LRSSADFLQRLSAI Q9UM47 1525 1525 -
LRSSADFLQRLSAI NTC3_MOUSE 1526 1526 -
LRTQTAFLQKLSAI Q800E4_DANRE 1527 1527 -

Motif 2 width=25
Element Seqn Id St Int Rpt
ERLDFPYPLRDVRGEPLEPPEQSVP Q9R172 1620 79 -
ERLDFPYPLRDVRGEPLEPPEPSVP Q9UM47 1618 79 -
ERLDFPYPLRDVRGEPLEAPEQSVP NTC3_MOUSE 1619 79 -
EMLRFPYPIKEVTSEKREPSITEIP Q800E4_DANRE 1615 74 -

Motif 3 width=17
Element Seqn Id St Int Rpt
DSECPEAKRLKVEEPGM Q9R172 1725 80 -
DTECPEAKRLKVEEPGM Q9UM47 1723 80 -
DSECPEAKRLKVEEPGM NTC3_MOUSE 1724 80 -
DTDCPEAKRLKVEEPSI Q800E4_DANRE 1724 84 -

Motif 4 width=11
Element Seqn Id St Int Rpt
LLNPVAVPLDW Q9R172 2163 421 -
LLNPVAVPLDW Q9UM47 2162 422 -
LLNPVAVPLDW NTC3_MOUSE 2162 421 -
MVSPVSVPFDW Q800E4_DANRE 2222 481 -
Final Motifs
Motif 1  width=14
Element Seqn Id St Int Rpt
LRSSADFLQRLSAI Q9R172 1527 1527 -
LRSSADFLQRLSAI Q9UM47 1525 1525 -
LRSSADFLQRLSAI B0V2W1_MOUSE 1526 1526 -
LRSSADFLQRLSAI NTC3_MOUSE 1526 1526 -
LRTQTAFLQKLSAI Q800E4_DANRE 1527 1527 -

Motif 2 width=25
Element Seqn Id St Int Rpt
ERLDFPYPLRDVRGEPLEPPEQSVP Q9R172 1620 79 -
ERLDFPYPLRDVRGEPLEPPEPSVP Q9UM47 1618 79 -
ERLDFPYPLRDVRGEPLEAPEQSVP B0V2W1_MOUSE 1619 79 -
ERLDFPYPLRDVRGEPLEAPEQSVP NTC3_MOUSE 1619 79 -
EMLRFPYPIKEVTSEKREPSITEIP Q800E4_DANRE 1615 74 -

Motif 3 width=17
Element Seqn Id St Int Rpt
DSECPEAKRLKVEEPGM Q9R172 1725 80 -
DTECPEAKRLKVEEPGM Q9UM47 1723 80 -
DSECPEAKRLKVEEPGM B0V2W1_MOUSE 1724 80 -
DSECPEAKRLKVEEPGM NTC3_MOUSE 1724 80 -
DTDCPEAKRLKVEEPSI Q800E4_DANRE 1724 84 -

Motif 4 width=11
Element Seqn Id St Int Rpt
LLNPVAVPLDW Q9R172 2163 421 -
LLNPVAVPLDW Q9UM47 2162 422 -
LLNPVAVPLDW B0V2W1_MOUSE 2162 421 -
LLNPVAVPLDW NTC3_MOUSE 2162 421 -
MVSPVSVPFDW Q800E4_DANRE 2222 481 -