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PR01702

Identifier
CD40LIGAND  [View Relations]  [View Alignment]  
Accession
PR01702
No. of Motifs
4
Creation Date
23-JAN-2002
Title
CD40 ligand/CD154 antigen signature
Database References

PRODOM; PD008600
INTERPRO; IPR003263
PDB; 1ALY; 1CDA
SCOP; 1ALY; 1CDA
CATH; 1ALY; 1CDA
Literature References
1. DISANTO, J.P., BONNEFOY, J.Y., GAUCHAT, J.F., FISCHER, A. AND BASILE, G.
CD40 ligand mutations in x-linked immunodeficiency with hyper-IgM.
NATURE 361 541-543 (1993).
 
2. PEITSCH, M.C. AND JONGENEEL, C.V.
A 3-D model for the CD40 ligand predicts that it is a compact trimer similar 
to the tumor necrosis factors.
INT.IMMUNOL. 5 233-238 (1993).
 
3. ALLEN, R.C., ARMITAGE, R.J., CONLEY, M.E., ROSENBLATT, H., JENKINS, N.A., 
COPELAND, N.G., BEDELL, M.A., EDELHOFF, S., DISTECHE, C.M. AND SIMONEAUX, D.K.
CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome.
SCIENCE 259 990-993 (1993).
 
4. KARPUSAS, M., HSU, Y.M., WANG, J.H., THOMSON, J., LEDERMAN, S., CHESS, L. 
AND THOMAS, D.
A crystal structure of an extracellular fragment of human CD40 ligand.
STRUCTURE 3 1031-1039 (1995).
 
5. SINGH, J., GARBER, E., VLIJMER, H., KARPUSAS, M., HSU, Y.M., ZHENG, Z. 
AND NAISMITH, J.H.
The role of polar interactions in the molecular recognition of CD40L with 
its receptor CD40.
PROTEIN SCI. 7 1124-1135 (1998).
 
6. KARPUSAS, M., LUCCI, J., FERRANT, J., BENJAMIN, C., TAYLOR, F.R., 
STRAUCH, K., GARBER, E. AND HSU, Y.M.
Structure of CD40L ligand in complex with the Fab fragment of a neutralizing 
humanized antibody.
STRUCTURE (CAMB) 9 321-329 (2001).
 
7. BISHOP, G.A. AND HOSTAGER, B.S.
Signaling by CD40 and its mimics in B cell activation.
IMMUNOL.RES. 24 97-109 (2001).

Documentation
CD40 ligand (CD40L or CD154) is a member of the tumor necrosis factor  
(TNF) family of cell-surface proteins and soluble cytokines that plays a 
critical role in both thymus-dependent humoral immunity and cellular immune 
responses. It has been implicated in biological pathways involving 
epithelial cells, fibroblasts and platelets. It is involved in T cell-
mediated B cell activation, a process that occurs through the interaction
of CD40L on activated T cells with CD40 receptor expressed on B cells. It
results in various B cell responses, including immunoglobulin isotype 
switching and B cell differentiation and proliferation, upregulation 
of surface molecules contributing to antigen presentation, development of 
the germinal centre, as well as regulation of apoptosis [1,3-6]. 
 
Several distinct structural motifs in the CD40 cytoplasmic domain regulate 
various signalling pathways, which involve both the TNF-R associated factors
(TRAFs) and additional signalling proteins, leading to the activation of
kinases and transcription factors. The physiological importance of CD40L has
been demonstrated by the fact that expression of defective CD40L proteins 
causes an immunodeficiency state known as the hyper-IgM syndrome, 
characterised by an inability to produce immunoglubulins of the IgG, IgA and
IgE isotypes, indicating faulty T-cell dependent B-cell activation [3,4,7].
 
The CD40L sequence is compatible with the jelly-roll beta-strand structure
characteristic of the TNFs. Like the TNFs, CD40L is predicted to form a 
compact trimer, although the interactions between monomers are distinct
from those found in the TNFs. A high degree of structural conservation with
low similarity at the primary structure level is not without precedent among
proteins with a high beta-strand content: among the lipocalins, for example,
the sequences of the bilin- and retinol-binding proteins are only 16% 
identical, yet their 3D structural alignment differs by less than 2A in 
their alpha-carbon positions.
 
A 3D model of CD40L based on the known structure of TNFalpha has been built.
According to the model, CD40L is no more different from TNFalpha or TNFbeta
than they are from each other. However, although the receptor-binding
domains of these 3 molecules are extremely similar in structure, the N-
terminal domains of the proteins are quite different. Moreover, considerable 
differences are apparent in several loops, including those predicted to be
involved in CD40 binding. TNFbeta is a classical secreted protein containing
a signal peptide - no transmembrane (TM) form has been detected; TNFalpha,
on the other hand, is synthesised as a type II TM protein and then undergoes
post-translational cleavage, liberating the extracellular domain (i.e., the
trimer) as a soluble effector - nevertheless a substantial amount of 
TNFalpha remains associated with the membrane. CD40L seems to lie at the
other end of the spectrum, in that it has not been detected as a naturally
occurring secretory product. Ironically, it may function as a receptor for
one of the many soluble forms of members of the TNF receptor family [2].
 
CD40LIGAND is a 4-element fingerprint that provides a signature for the CD40 
ligand (CD154) family of proteins. The fingerprint was derived from an 
initial alignment of 5 sequences: the motifs were drawn from conserved 
regions spanning virtually the full alignment length - motif 1 encodes the
type II membrane protein signal sequence; motif 3 encompasses beta-strand 8;
and motif 4 spans alpha-helix 1 and strand 11. Two iterations on SPTR39_17f
were required to reach convergence, at which point a true set comprising 11
sequences was identified.
Summary Information
11 codes involving  4 elements
0 codes involving 3 elements
0 codes involving 2 elements
Composite Feature Index
411111111
30000
20000
1234
True Positives
Q9BDC7        Q9BDM3        Q9BDM7        Q9BDN3        
Q9R254 Q9Z2V2 TNF5_BOVIN TNF5_CANFA
TNF5_FELCA TNF5_HUMAN TNF5_MOUSE
Sequence Titles
Q9BDC7      CD154 PROTEIN - Macaca mulatta (Rhesus macaque), and Cercocebus torquatus atys (Red-crowned mangabey) (Sooty mangabey). 
Q9BDM3 CD154 PROTEIN - Aotus trivirgatus (Night monkey) (Douroucouli).
Q9BDM7 CD154 PROTEIN - Macaca nemestrina (Pig-tailed macaque).
Q9BDN3 CD154 PROTEIN - Callithrix jacchus (Common marmoset).
Q9R254 CD40 LIGAND - Rattus norvegicus (Rat).
Q9Z2V2 CD40 LIGAND - Rattus norvegicus (Rat).
TNF5_BOVIN CD40 LIGAND (TNF-RELATED ACTIVATION PROTEIN) (TRAP) (T CELL ANTIGEN GP39) - Bos taurus (Bovine).
TNF5_CANFA CD40 LIGAND - Canis familiaris (Dog).
TNF5_FELCA CD40 LIGAND (CD154 ANTIGEN) - Felis silvestris catus (Cat).
TNF5_HUMAN CD40 LIGAND (CD40-L) (TNF-RELATED ACTIVATION PROTEIN) (TRAP) (T CELL ANTIGEN GP39) (CD154 ANTIGEN) - Homo sapiens (Human).
TNF5_MOUSE CD40 LIGAND (TNF-RELATED ACTIVATION PROTEIN) (TRAP) (T CELL ANTIGEN GP39) - Mus musculus (Mouse).
Scan History
SPTR39_17f 2  200  NSINGLE    
Initial Motifs
Motif 1  width=18
Element Seqn Id St Int Rpt
KIFMYLLTVFLITQMIGS TNF5_HUMAN 22 22 -
KIFMYLLTIFLITQMIGS Q9BDC7 22 22 -
KIFMYLLTIFLITQMIGS Q9BDM7 22 22 -
KIFMYLLTVFLITQMIGS TNF5_CANFA 22 22 -
KIFMYLLTVFLITQMIGS TNF5_MOUSE 22 22 -

Motif 2 width=12
Element Seqn Id St Int Rpt
YLHRRLDKIEDE TNF5_HUMAN 45 5 -
YLHRRLDKIEDE Q9BDC7 45 5 -
YLHRRLDKIEDE Q9BDM7 45 5 -
YLHRRLDKIEDE TNF5_CANFA 45 5 -
YLHRRLDKVEEE TNF5_MOUSE 45 5 -

Motif 3 width=11
Element Seqn Id St Int Rpt
ERILLRAANTH TNF5_HUMAN 202 145 -
ERILLRAANTH Q9BDC7 202 145 -
ERILLRAANTH Q9BDM7 181 124 -
ERVLLRAASSR TNF5_CANFA 201 144 -
ERILLKAANTH TNF5_MOUSE 201 144 -

Motif 4 width=16
Element Seqn Id St Int Rpt
SQVSHGTGFTSFGLLK TNF5_HUMAN 245 32 -
SQVSHGTGFTSFGLLK Q9BDC7 245 32 -
SQVSHGTGFTSFGLLK Q9BDM7 224 32 -
SQVSHGTGFTSFGLLK TNF5_CANFA 244 32 -
SQVIHRVGFSSFGLLK TNF5_MOUSE 244 32 -
Final Motifs
Motif 1  width=18
Element Seqn Id St Int Rpt
KIFMYLLTVFLITQMIGS Q9BDM3 22 22 -
KIFMYLLTVFLITQMIGS TNF5_HUMAN 22 22 -
KIFMYLLTVFLITQMIGS TNF5_BOVIN 22 22 -
KIFMYLLTVFLITQMIGS Q9BDN3 22 22 -
KIFMYLLTIFLITQMIGS Q9BDC7 22 22 -
KIFMYLLTIFLITQMIGS Q9BDM7 22 22 -
KIFMYLLTVFLITQMIGS Q9Z2V2 22 22 -
KIFMYLLTVFLITQMIGS TNF5_FELCA 22 22 -
KIFMYLLTVFLITQMIGS Q9R254 22 22 -
KIFMYLLTVFLITQMIGS TNF5_CANFA 22 22 -
KIFMYLLTVFLITQMIGS TNF5_MOUSE 22 22 -

Motif 2 width=12
Element Seqn Id St Int Rpt
YLHRRLDKIEDE Q9BDM3 45 5 -
YLHRRLDKIEDE TNF5_HUMAN 45 5 -
YLHRRLDKIEDE TNF5_BOVIN 45 5 -
YLHRRLDKIEDE Q9BDN3 45 5 -
YLHRRLDKIEDE Q9BDC7 45 5 -
YLHRRLDKIEDE Q9BDM7 45 5 -
YLHRRLDKVEEE Q9Z2V2 45 5 -
YLHRRLDKIEDE TNF5_FELCA 45 5 -
YLHRRLDKVEEE Q9R254 45 5 -
YLHRRLDKIEDE TNF5_CANFA 45 5 -
YLHRRLDKVEEE TNF5_MOUSE 45 5 -

Motif 3 width=11
Element Seqn Id St Int Rpt
ERILLRAANTH Q9BDM3 202 145 -
ERILLRAANTH TNF5_HUMAN 202 145 -
ERILLRAANTH TNF5_BOVIN 202 145 -
ERILLRAANTH Q9BDN3 202 145 -
ERILLRAANTH Q9BDC7 202 145 -
ERILLRAANTH Q9BDM7 181 124 -
ERILLRAANTH Q9Z2V2 201 144 -
ERVLLRAANAR TNF5_FELCA 201 144 -
ERILLRAANTH Q9R254 201 144 -
ERVLLRAASSR TNF5_CANFA 201 144 -
ERILLKAANTH TNF5_MOUSE 201 144 -

Motif 4 width=16
Element Seqn Id St Int Rpt
SQVSHGTGFTSFGLLK Q9BDM3 245 32 -
SQVSHGTGFTSFGLLK TNF5_HUMAN 245 32 -
SQVSHGTGFTSFGLLK TNF5_BOVIN 245 32 -
SQVSHGTGFTSFGLLK Q9BDN3 245 32 -
SQVSHGTGFTSFGLLK Q9BDC7 245 32 -
SQVSHGTGFTSFGLLK Q9BDM7 224 32 -
SQVIHGIGFSSFGLLK Q9Z2V2 244 32 -
SQVSHGTGFTSFGLLK TNF5_FELCA 244 32 -
SQVIHGIGFSSIGLLK Q9R254 244 32 -
SQVSHGTGFTSFGLLK TNF5_CANFA 244 32 -
SQVIHRVGFSSFGLLK TNF5_MOUSE 244 32 -