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PR01681

Identifier
FASLIGAND  [View Relations]  [View Alignment]  
Accession
PR01681
No. of Motifs
7
Creation Date
19-FEB-2002
Title
Fas antigen ligand signature
Database References

PDB; 2TNF; 4TSV
SCOP; 2TNF; 4TSV
CATH; 2TNF; 4TSV
Literature References
1. GOLDSBY, R.A., KINDT, T.J. AND OSBORNE, B.A.
Kuby immunology.
W.H.FREEMAN AND COMPANY, 2000, pp.260-261, 503-504.
 
2. WENZEL, J., SANZENBACHER, R., GHADIMI, M., ZHOU, Q., KAPLAN, D.R.,
KABELITZ, D., FELLER, S.M. AND JANSSEN, O.
Multiple interactions of the cytosolic polyproline region of the CD95 ligand: 
hints for the reverse signal tranduction capacity of a death factor.
FEBS LETT. 509 255-262 (2001).
 
3. YANKEE, T.M., DRAVES, K.E., EWINGS, M.K., CLARK, E.A. AND GRAVES, J.D.
CD95/Fas induces cleavage of the GrpL/Gads adaptor and desensitization of 
antigen receptor signaling.
PROC.NATL.ACAD.SCI.U.S.A. 98 6789-6793 (2001).
 
4. TAKAHASHI, T., TANAKA, M., INAZAWA, J., ABE, T., SUDA, T. AND NAGATA, S.
Human Fas ligand: gene strucure, chromosomal location and species specificity.
INT.IMMUNOL. 6 1567-1574 (1994).

Documentation
Like all apoptotic cell death, T cell receptor (TCR)-mediated death can be
divided into two phases: an inductive phase and an effector phase. The 
effector phase includes a sequence of steps that are common to apoptosis in
many cell types, which, if not interrupted, will lead to cell death. The
induction phase, which often requires the expression of new genes, consists
of a set of signals that activate the effector phase. Outside the thymus,
most, if not all, of the TCR-mediated apoptosis of mature T cells (sometimes
referred to as activation-induced cell death (AICD)) is induced through the
surface antigen Fas pathway: activation through the TCR induces expression
of the Fas (CD95) ligand (FasL); the expression of FasL on either a
neighbouring cell, or on the Fas-bearing cell, induces trimerisation of Fas,
which then initiates a signal-transduction cascade, leading to apoptosis of 
the Fas-bearing cell. This commitment stage requires the activation of key
death-inducing enzymes, termed caspases, which act by cleaving proteins that
are essential for cell survival and proliferation [1,2]. However what 
happens to FasL itself remains unknown. It is possible that it is cleaved
from the effector cells and internalised into the target cells; it may be
downregulated in the effector cells; or it may be phagocytosed by the target
cells [1-4].  
 
Fas is also known to be essential in the death of hyperactivated peripheral
CD4+ cells: in the absence of Fas, mature peripheral T cells do not die, but
the activated cells continue to proliferate, producing cytokines that lead
to grossly enlarged lymph nodes and spleen. Defects in the Fas-FasL system
are associated with various disease syndromes. Mice with non-functional Fas
or FasL display characteristics of lymphoproliferative disorder, such as 
lymphadenopathy, splenomegaly, and elevated secretion of IgM and IgG. These
mice also secrete anti-DNA autoantibodies and rheumatoid factor [3].
 
FasL is a 40kDa type II membrane protein belonging to the tumour necrosis
factor (TNF) family. It is expressed on activated lymphocytes, NK cells,
platelets, certain immune-privileged cells and some tumour cells [1,3]. 
Human and mouse FasL induce apoptosis in cells expressing either mouse or
human Fas with the same specificity. Although the amino acid sequence of
FasL is highly conserved between human and mouse, the similarity between
human and murine Fas is much less pronounced. Greater conservation of the
ligand than the receptor is also observed in other members of the TNF family.
By comparison with other TNF family members, FasL has a long N-terminal 
intracellular region rich in proline residues, which is known to bind to 
the SH3 domain. SH3 domains play important roles in mediating specific
protein-protein interactions, specifically in the cytoskeleton [1].
 
FASLIGAND is a 7-element fingerprint that provides a signature for the Fas 
antigen ligand. The fingerprint was derived from an initial alignment of 5
sequences: the motifs were drawn from conserved sequences spanning virtually
the full alignment length - motif 1 lies in the N-terminal cytoplasmic 
region; motif 2 includes the C-terminus of the type-II membrane protein
signal sequence; and motifs 3-7 span the extracellular domain. A single 
iteration on SPTR39_17f was required to reach convergence, no further
sequences being identified beyond the starting set. Two partial matches
were found, Q9BZP9 and Q99PH8, truncated human and murine FasL isoforms 
that lack the portion of sequence bearing the last 5 motifs.
Summary Information
   7 codes involving  7 elements
0 codes involving 6 elements
0 codes involving 5 elements
0 codes involving 4 elements
0 codes involving 3 elements
2 codes involving 2 elements
Composite Feature Index
77777777
60000000
50000000
40000000
30000000
22200000
1234567
True Positives
FASL_HUMAN    FASL_MOUSE    FASL_RAT      Q9BDM5        
Q9BDN1 Q9BEA8 Q9MYL6
True Positive Partials
Codes involving 2 elements
Q99PH8 Q9BZP9
Sequence Titles
FASL_HUMAN  FAS ANTIGEN LIGAND (APOPTOSIS ANTIGEN LIGAND) (APTL) - Homo sapiens (Human). 
FASL_MOUSE FAS ANTIGEN LIGAND - Mus musculus (Mouse).
FASL_RAT FAS ANTIGEN LIGAND - Rattus norvegicus (Rat).
Q9BDM5 FAS ANTIGEN CD95 - Macaca mulatta (Rhesus macaque).
Q9BDN1 CD95L PROTEIN - Cercocebus torquatus atys (Red-crowned mangabey) (Sooty mangabey).
Q9BEA8 FAS-LIGAND - Sus scrofa (Pig).
Q9MYL6 FAS LIGAND - Macaca nemestrina (Pig-tailed macaque), Macaca fascicularis (Crab eating macaque) (Cynomolgus monkey), and Macaca mulatta (Rhesus macaque).

Q99PH8 FASL ISOFORM - Mus musculus (Mouse).
Q9BZP9 FASL ISOFORM - Homo sapiens (Human).
Scan History
SPTR39_17f 1  100  NSINGLE    
Initial Motifs
Motif 1  width=22
Element Seqn Id St Int Rpt
QQPFNYPYPQIFWVDSSATSPW Q9BEA8 2 2 -
QQPFNYPYPQIYWVDSSASSPW Q9MYL6 2 2 -
QQPFNYPYPQIYWVDSSASSPW Q9BDM5 2 2 -
QQPFNYPYPQIYWVDSSASSPW Q9BDN1 2 2 -
QQPFNYPYPQIYWVDSSASSPW FASL_HUMAN 2 2 -

Motif 2 width=15
Element Seqn Id St Int Rpt
GLGLGMFQLFHLQKE Q9BDM5 95 71 -
GLGLGMFQLFHLQKE Q9MYL6 95 71 -
GLGLGMFQLFHLQKE Q9BDN1 95 71 -
GLGLGMFQLFHLQKE FASL_HUMAN 96 72 -
GLGLGMFQLFHLQKE Q9BEA8 97 73 -

Motif 3 width=14
Element Seqn Id St Int Rpt
EKKEQRKVAHLTGK Q9BDM5 138 28 -
EKKEQRKVAHLTGK Q9MYL6 138 28 -
EKKEQRKVAHLTGK Q9BDN1 138 28 -
EKKELRKVAHLTGK FASL_HUMAN 139 28 -
EKKELRKVAHLTGK Q9BEA8 140 28 -

Motif 4 width=14
Element Seqn Id St Int Rpt
NSRSMPLEWEDTYG Q9BDN1 153 1 -
NSRSMPLEWEDTYG Q9BDM5 153 1 -
NSRSMPLEWEDTYG Q9MYL6 153 1 -
NSRSMPLEWEDTYG FASL_HUMAN 154 1 -
NSRSIPLEWEDTYG Q9BEA8 155 1 -

Motif 5 width=17
Element Seqn Id St Int Rpt
LPLSHKVYMRNSKYPQD Q9BDM5 204 37 -
LPLSHKVYMRNSKYPQD Q9MYL6 204 37 -
LPLSHKVYMRNSKYPQD Q9BDN1 204 37 -
LPLSHKVYMRNSKYPQD FASL_HUMAN 205 37 -
QPLSHKVYTRNSRYPQD Q9BEA8 206 37 -

Motif 6 width=21
Element Seqn Id St Int Rpt
EGKMMSYCTTGQMWAHSSYLG Q9BDM5 225 4 -
EGKMMSYCTTGQMWAHSSYLG Q9MYL6 225 4 -
EGKMMSYCTTGQMWAHSSYLG Q9BDN1 225 4 -
EGKMMSYCTTGQMWARSSYLG FASL_HUMAN 226 4 -
EGKMMNYCTTGQMWARSSYLG Q9BEA8 227 4 -

Motif 7 width=18
Element Seqn Id St Int Rpt
DHLYVNVSELSLVNFEES Q9BDM5 254 8 -
DHLYVNVSELSLVNFEES Q9MYL6 254 8 -
DHLYVNVSELSLVNFEES Q9BDN1 254 8 -
DHLYVNVSELSLVNFEES FASL_HUMAN 255 8 -
DHLYVNVSELSLVNFEES Q9BEA8 256 8 -
Final Motifs
Motif 1  width=22
Element Seqn Id St Int Rpt
QQPVNYPCPQIYWVDSSATSPW FASL_RAT 2 2 -
QQPFNYPYPQIYWVDSSASSPW Q9MYL6 2 2 -
QQPFNYPYPQIYWVDSSASSPW Q9BDN1 2 2 -
QQPFNYPYPQIYWVDSSASSPW Q9BDM5 2 2 -
QQPFNYPYPQIYWVDSSASSPW FASL_HUMAN 2 2 -
QQPFNYPYPQIFWVDSSATSPW Q9BEA8 2 2 -
QQPMNYPCPQIFWVDSSATSSW FASL_MOUSE 2 2 -

Motif 2 width=15
Element Seqn Id St Int Rpt
GLGLGMFQLFHLQKE Q9BDM5 95 71 -
GLGLGMFQLFHLQKE Q9MYL6 95 71 -
GLGLGMFQLFHLQKE Q9BDN1 95 71 -
GLGLGMFQLFHLQKE FASL_HUMAN 96 72 -
GLGLGMFQLFHLQKE Q9BEA8 97 73 -
GMGLGMYQLFHLQKE FASL_MOUSE 94 70 -
GMGLGMYQLFHLQKE FASL_RAT 93 69 -

Motif 3 width=14
Element Seqn Id St Int Rpt
EKKEQRKVAHLTGK Q9BDM5 138 28 -
EKKEQRKVAHLTGK Q9MYL6 138 28 -
EKKEQRKVAHLTGK Q9BDN1 138 28 -
EKKELRKVAHLTGK FASL_HUMAN 139 28 -
EKKELRKVAHLTGK Q9BEA8 140 28 -
EKKEPRSVAHLTGN FASL_MOUSE 137 28 -
ETKKPRSVAHLTGN FASL_RAT 136 28 -

Motif 4 width=14
Element Seqn Id St Int Rpt
NSRSMPLEWEDTYG FASL_HUMAN 154 1 -
NSRSMPLEWEDTYG Q9BDM5 153 1 -
NSRSMPLEWEDTYG Q9MYL6 153 1 -
NSRSMPLEWEDTYG Q9BDN1 153 1 -
NSRSIPLEWEDTYG Q9BEA8 155 1 -
HSRSIPLEWEDTYG FASL_MOUSE 152 1 -
RSRSIPLEWEDTYG FASL_RAT 151 1 -

Motif 5 width=17
Element Seqn Id St Int Rpt
LPLSHKVYMRNSKYPQD Q9BDM5 204 37 -
LPLSHKVYMRNSKYPQD Q9MYL6 204 37 -
LPLSHKVYMRNSKYPQD Q9BDN1 204 37 -
LPLSHKVYMRNSKYPQD FASL_HUMAN 205 37 -
QPLSHKVYTRNSRYPQD Q9BEA8 206 37 -
QPLNHKVYMRNSKYPED FASL_MOUSE 203 37 -
QPLSHKVYMRNFKYPGD FASL_RAT 202 37 -

Motif 6 width=21
Element Seqn Id St Int Rpt
EGKMMSYCTTGQMWAHSSYLG Q9BDM5 225 4 -
EGKMMSYCTTGQMWAHSSYLG Q9MYL6 225 4 -
EGKMMSYCTTGQMWAHSSYLG Q9BDN1 225 4 -
EGKMMSYCTTGQMWARSSYLG FASL_HUMAN 226 4 -
EGKMMNYCTTGQMWARSSYLG Q9BEA8 227 4 -
EEKRLNYCTTGQIWAHSSYLG FASL_MOUSE 224 4 -
EEKKLNYCTTGQIWAHSSYLG FASL_RAT 223 4 -

Motif 7 width=18
Element Seqn Id St Int Rpt
DHLYVNVSELSLVNFEES Q9BDM5 254 8 -
DHLYVNVSELSLVNFEES Q9MYL6 254 8 -
DHLYVNVSELSLVNFEES Q9BDN1 254 8 -
DHLYVNVSELSLVNFEES FASL_HUMAN 255 8 -
DHLYVNVSELSLVNFEES Q9BEA8 256 8 -
DHLYVNISQLSLINFEES FASL_MOUSE 253 8 -
DHLYVNISQLSLINFEES FASL_RAT 252 8 -