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PR01987

Identifier
NOTCH4  [View Relations]  [View Alignment]  
Accession
PR01987
No. of Motifs
7
Creation Date
11-JUN-2009
Title
Neurogenic locus Notch protein 4 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; 164951
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. SHIRAYOSHI, Y., YUASA, Y., SUZUKI, T., SUGAYA, K., KAWASE, E., 
IKEMURA, T. AND NAKATSUJI, N.
Proto-oncogene of int-3, a mouse Notch homologue, is expressed in 
endothelial cells during early embryogenesis. 
GENES CELLS 2 213-24 (1997).

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].
 
Notch 4 is selectively expressed in vascular endothelium, and regulates
vascular remodelling [8].
 
NOTCH4 is a 7-element fingerprint that provides a signature for neurogenic
locus Notch protein 4. The fingerprint was derived from an initial alignment 
of 4 sequences: the motifs were drawn from conserved regions spanning 
virtually the full alignment length - motif 1 lies within an EGF repeat;
motifs 2-5 lie in a conserved section C-terminal to the LNR region;
motif 6 lies N-terminal to the TM domain; and motif 7 resides at the
protein C-terminus. Two iterations on SPTR57_40f were required to reach
convergence, at which point a true set comprising 11 sequences was
identified. 
Summary Information
11 codes involving  7 elements
0 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
711111111111111
60000000
50000000
40000000
30000000
20000000
1234567
True Positives
A2CG28_MOUSE  A5A8X3_PIG    B0S882_HUMAN  B2RQR1_MOUSE  
B2RTR4_HUMAN NOTC4_HUMAN NTC4_MOUSE Q5SPL1_HUMAN
Q5SSY7_HUMAN Q5STG5_HUMAN Q6MG89_RAT
Sequence Titles
A2CG28_MOUSE Notch gene homolog 4 (Drosophila) - Mus musculus (Mouse). 
A5A8X3_PIG Notch homolog 4 (Drosophila) - Sus scrofa (Pig).
B0S882_HUMAN Notch homolog 4 (Drosophila) - Homo sapiens (Human).
B2RQR1_MOUSE Notch gene homolog 4 (Drosophila) - Mus musculus (Mouse).
B2RTR4_HUMAN NOTCH4 protein - Homo sapiens (Human).
NOTC4_HUMAN Neurogenic locus notch homolog protein 4 - Homo sapiens (Human).
NTC4_MOUSE NEUROGENIC LOCUS NOTCH HOMOLOG PROTEIN 4 PRECURSOR (TRANSFORMING PROTEIN INT-3) - Mus musculus (Mouse).
Q5SPL1_HUMAN Notch homolog 4 (Drosophila) - Homo sapiens (Human).
Q5SSY7_HUMAN Notch homolog 4 (Drosophila) - Homo sapiens (Human).
Q5STG5_HUMAN Notch homolog 4 (Drosophila) - Homo sapiens (Human).
Q6MG89_RAT Notch homolog 4, [Drosophila] - Rattus norvegicus (Rat).
Scan History
SPTR57_40f 2  100  NSINGLE    
Initial Motifs
Motif 1  width=28
Element Seqn Id St Int Rpt
EGPTCSHKALSCGIHHCHNGGLCLPSPK NTC4_MOUSE 1076 1076 -
EGPTCSRKAPACGNHHCHNGGLCLPSPK Q6MG89_RAT 1076 1076 -
EGPTCSHRAPSCGFHHCHHGGLCLPSPK NOTC4_HUMAN 1080 1080 -
EGPTCSHRAPSCGLHHCHHGGLCLPSPK A5A8X3_PIG 1078 1078 -

Motif 2 width=20
Element Seqn Id St Int Rpt
RPEGEDSEGRPSLALLVVLR NTC4_MOUSE 1281 177 -
RPEGDDSEGGPSLALLVVLS Q6MG89_RAT 1281 177 -
RPEDGDPEWGPSLALLVVLS NOTC4_HUMAN 1285 177 -
RPEDGGSEWGPSLALLVVLS A5A8X3_PIG 1283 177 -

Motif 3 width=28
Element Seqn Id St Int Rpt
DQQLLALARVLSLTLRVGLWVRKDSEGR NTC4_MOUSE 1305 4 -
DQQLLALARVLSLTLRVGLWVRKDSEGR Q6MG89_RAT 1305 4 -
DQQLFALARVLSLTLRVGLWVRKDRDGR NOTC4_HUMAN 1309 4 -
DQQLLALARALSLTLRVGLWVRKDSDGR A5A8X3_PIG 1307 4 -

Motif 4 width=30
Element Seqn Id St Int Rpt
RDSSSWERQAPPTQPLGKETESLGAGFVVV NTC4_MOUSE 1351 18 -
RDSSSWERQAPHTQTPGKETESLGAGFVVV Q6MG89_RAT 1351 18 -
RDPTYQERAAPQTQPLGKETDSLSAGFVVV NOTC4_HUMAN 1355 18 -
PDPSHQERAAPQTQPVGKETDSLSTGFVVV A5A8X3_PIG 1353 18 -

Motif 5 width=30
Element Seqn Id St Int Rpt
PEHPASRCPWDSGLLLRFLAAMAAVGALEP NTC4_MOUSE 1390 9 -
PEHPASRCPRDSGLLLRFLAAMAAVGALEP Q6MG89_RAT 1390 9 -
PDHPASRCPWDPGLLLRFLAAMAAVGALEP NOTC4_HUMAN 1394 9 -
PDHPASRCPWDPGLLLRFLAAMAAVGALEP A5A8X3_PIG 1392 9 -

Motif 6 width=30
Element Seqn Id St Int Rpt
LLPGPLLAAHPQAGTRPPANQLPWPILCSP NTC4_MOUSE 1420 0 -
LLPGPLLAAHPQAGTGSPATRLPWPILCSP Q6MG89_RAT 1420 0 -
LLPGPLLAVHPHAGTAPPANQLPWPVLCSP NOTC4_HUMAN 1424 0 -
LLPGPLLAAHPRAGTAPPANQLPWPVLCSP A5A8X3_PIG 1422 0 -

Motif 7 width=21
Element Seqn Id St Int Rpt
PRDWVALEACGSACSAPIPPP NTC4_MOUSE 1911 461 -
PRDWVALEACGSACSAPIPPP Q6MG89_RAT 1908 458 -
PCDWVALGACGSASNIPIPPP NOTC4_HUMAN 1950 496 -
PCDWVALDSCGPASSTPIPPP A5A8X3_PIG 1941 489 -
Final Motifs
Motif 1  width=28
Element Seqn Id St Int Rpt
EGPTCSHKALSCGIHHCHNGGLCLPSPK B2RQR1_MOUSE 1076 1076 -
EGPTCSHKALSCGIHHCHNGGLCLPSPK NTC4_MOUSE 1076 1076 -
EGPTCSRKAPACGNHHCHNGGLCLPSPK Q6MG89_RAT 1076 1076 -
EGPTCSHRAPSCGFHHCHHGGLCLPSPK B0S882_HUMAN 1079 1079 -
EGPTCSHRAPSCGFHHCHHGGLCLPSPK Q5STG5_HUMAN 1082 1082 -
EGPTCSHRAPSCGFHHCHHGGLCLPSPK Q5SSY7_HUMAN 1080 1080 -
EGPTCSHRAPSCGFHHCHHGGLCLPSPK Q5SPL1_HUMAN 1080 1080 -
EGPTCSHRAPSCGFHHCHHGGLCLPSPK NOTC4_HUMAN 1080 1080 -
EGPTCSHRAPSCGFHHCHHGGLCLPSPK B2RTR4_HUMAN 1079 1079 -
EGPTCSHKALSCGIHHCHNGGLCLPSPK A2CG28_MOUSE 1076 1076 -
EGPTCSHRAPSCGLHHCHHGGLCLPSPK A5A8X3_PIG 1078 1078 -

Motif 2 width=20
Element Seqn Id St Int Rpt
RPEGEDSEGRPSLALLVVLR B2RQR1_MOUSE 1281 177 -
RPEGEDSEGRPSLALLVVLR NTC4_MOUSE 1281 177 -
RPEGDDSEGGPSLALLVVLS Q6MG89_RAT 1281 177 -
RPEDGDPEWGPSLALLVVLS B0S882_HUMAN 1284 177 -
RPEDGDPEWGPSLALLVVLS Q5STG5_HUMAN 1287 177 -
RPEDGDPEWGPSLALLVVLS Q5SSY7_HUMAN 1285 177 -
RPEDGDPEWGPSLALLVVLS Q5SPL1_HUMAN 1285 177 -
RPEDGDPEWGPSLALLVVLS NOTC4_HUMAN 1285 177 -
RPEDGDPEWGPSLALLVVLS B2RTR4_HUMAN 1284 177 -
RPEGEDSEGRPSLALLVVLR A2CG28_MOUSE 1281 177 -
RPEDGGSEWGPSLALLVVLS A5A8X3_PIG 1283 177 -

Motif 3 width=28
Element Seqn Id St Int Rpt
DQQLLALARVLSLTLRVGLWVRKDSEGR B2RQR1_MOUSE 1305 4 -
DQQLLALARVLSLTLRVGLWVRKDSEGR NTC4_MOUSE 1305 4 -
DQQLLALARVLSLTLRVGLWVRKDSEGR Q6MG89_RAT 1305 4 -
DQQLFALARVLSLTLRVGLWVRKDRDGR B0S882_HUMAN 1308 4 -
DQQLFALARVLSLTLRVGLWVRKDRDGR Q5STG5_HUMAN 1311 4 -
DQQLFALARVLSLTLRVGLWVRKDRDGR Q5SSY7_HUMAN 1309 4 -
DQQLFALARVLSLTLRVGLWVRKDRDGR Q5SPL1_HUMAN 1309 4 -
DQQLFALARVLSLTLRVGLWVRKDRDGR NOTC4_HUMAN 1309 4 -
DQQLFALARVLSLTLRVGLWVRKDRDGR B2RTR4_HUMAN 1308 4 -
DQQLLALARVLSLTLRVGLWVRKDSEGR A2CG28_MOUSE 1305 4 -
DQQLLALARALSLTLRVGLWVRKDSDGR A5A8X3_PIG 1307 4 -

Motif 4 width=30
Element Seqn Id St Int Rpt
RDSSSWERQAPPTQPLGKETESLGAGFVVV B2RQR1_MOUSE 1351 18 -
RDSSSWERQAPPTQPLGKETESLGAGFVVV NTC4_MOUSE 1351 18 -
RDSSSWERQAPHTQTPGKETESLGAGFVVV Q6MG89_RAT 1351 18 -
RDPTYQERAAPQTQPLGKETDSLSAGFVVV B0S882_HUMAN 1354 18 -
RDPTYQERAAPQTQPLGKETDSLSAGFVVV Q5STG5_HUMAN 1357 18 -
RDPTYQERAAPQTQPLGKETDSLSAGFVVV Q5SSY7_HUMAN 1355 18 -
RDPTYQERAAPQTQPLGKETDSLSAGFVVV Q5SPL1_HUMAN 1355 18 -
RDPTYQERAAPQTQPLGKETDSLSAGFVVV NOTC4_HUMAN 1355 18 -
RDPTYQERAAPQTQPLGKETDSLSAGFVVV B2RTR4_HUMAN 1354 18 -
RDSSSWERQAPPTQPLGKETESLGAGFVVV A2CG28_MOUSE 1351 18 -
PDPSHQERAAPQTQPVGKETDSLSTGFVVV A5A8X3_PIG 1353 18 -

Motif 5 width=30
Element Seqn Id St Int Rpt
PEHPASRCPWDSGLLLRFLAAMAAVGALEP B2RQR1_MOUSE 1390 9 -
PEHPASRCPWDSGLLLRFLAAMAAVGALEP NTC4_MOUSE 1390 9 -
PEHPASRCPRDSGLLLRFLAAMAAVGALEP Q6MG89_RAT 1390 9 -
PDHPASRCPWDPGLLLRFLAAMAAVGALEP B0S882_HUMAN 1393 9 -
PDHPASRCPWDPGLLLRFLAAMAAVGALEP Q5STG5_HUMAN 1396 9 -
PDHPASRCPWDPGLLLRFLAAMAAVGALEP Q5SSY7_HUMAN 1394 9 -
PDHPASRCPWDPGLLLRFLAAMAAVGALEP Q5SPL1_HUMAN 1394 9 -
PDHPASRCPWDPGLLLRFLAAMAAVGALEP NOTC4_HUMAN 1394 9 -
PDHPASRCPWDPGLLLRFLAAMAAVGALEP B2RTR4_HUMAN 1393 9 -
PEHPASRCPWDSGLLLRFLAAMAAVGALEP A2CG28_MOUSE 1390 9 -
PDHPASRCPWDPGLLLRFLAAMAAVGALEP A5A8X3_PIG 1392 9 -

Motif 6 width=30
Element Seqn Id St Int Rpt
LLPGPLLAAHPQAGTRPPANQLPWPILCSP B2RQR1_MOUSE 1420 0 -
LLPGPLLAAHPQAGTRPPANQLPWPILCSP NTC4_MOUSE 1420 0 -
LLPGPLLAAHPQAGTGSPATRLPWPILCSP Q6MG89_RAT 1420 0 -
LLPGPLLAVHPHAGTAPPANQLPWPVLCSP B0S882_HUMAN 1423 0 -
LLPGPLLAVHPHAGTAPPANQLPWPVLCSP Q5STG5_HUMAN 1426 0 -
LLPGPLLAVHPHAGTAPPANQLPWPVLCSP Q5SSY7_HUMAN 1424 0 -
LLPGPLLAVHPHAGTAPPANQLPWPVLCSP Q5SPL1_HUMAN 1424 0 -
LLPGPLLAVHPHAGTAPPANQLPWPVLCSP NOTC4_HUMAN 1424 0 -
LLPGPLLAVHPHAGTAPPANQLPWPVLCSP B2RTR4_HUMAN 1423 0 -
LLPGPLLAAHPQAGTRPSANQLPWPILCSP A2CG28_MOUSE 1420 0 -
LLPGPLLAAHPRAGTAPPANQLPWPVLCSP A5A8X3_PIG 1422 0 -

Motif 7 width=21
Element Seqn Id St Int Rpt
PRDWVALEACGSACSAPIPPP B2RQR1_MOUSE 1911 461 -
PRDWVALEACGSACSAPIPPP NTC4_MOUSE 1911 461 -
PRDWVALEACGSACSAPIPPP Q6MG89_RAT 1908 458 -
PCDWVALGACGSASNIPIPPP B0S882_HUMAN 1949 496 -
PCDWVALGACGSASNIPIPPP Q5STG5_HUMAN 1952 496 -
PCDWVALGACGSASNIPIPPP Q5SSY7_HUMAN 1950 496 -
PCDWVALGACGSASNIPIPPP Q5SPL1_HUMAN 1950 496 -
PCDWVALGACGSASNIPIPPP NOTC4_HUMAN 1950 496 -
PCDWVALGACGSASNIPIPPP B2RTR4_HUMAN 1949 496 -
PRDWVALEACGSACSAPIPPP A2CG28_MOUSE 1911 461 -
PCDWVALDSCGPASSTPIPPP A5A8X3_PIG 1941 489 -