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PR01717

Identifier
CD28ANTIGEN  [View Relations]  [View Alignment]  
Accession
PR01717
No. of Motifs
4
Creation Date
08-MAR-2002
Title
CD28 antigen signature
Database References

PDB; 1H6E; 1AH1
SCOP; 1AH1
CATH; 1AH1
Literature References
1. LEE, K.P., TAYLOR, C., PETRYNIA, B., TURKA, L.A., JUNE, C.H. AND 
THOMPSON, C.B. 
The genomic organization of the CD28 gene. Implication for the 
regulation of CD28 mRNA expression and heterogeneity.
J.IMMUNOL. 145 344-352 (1990).
 
2. GROSS, J.A., JOHN, T. AND ALLISON, J.P.
The murine homologue of the T lymphocyte antigen CD28. Molecular 
cloning and cell surface expression.
J.IMMUNOL. 144 3201-3210 (1990).
 
3. MITTRUCKER, H.W., KURSAR, M., KOHLER, A., HURWITZ, R. AND 
KAUFMANN, S.H.E.
Role oF CD28 for the generation and expansion of antigen-specific 
CD8+ T lymphocytes during infection with Listeria monocytogenes.
J.IMMUNOL. 167 5620-5627 (2001).
 
4. SURESH, M., WHITMIRE, J.K., HARRINGTON, L.E., LARSEN, C.P., 
PEARSON, T.C., ALTMAN, J.D. AND AHMED, R.
Role of CD28-B7 interactions in generation and maintenance of CD28 T 
cell memory.
J.IMMUNOL. 167 5565-5573 (2001).
 
5. APPLEMAN, L.J., PUIJENBROEK, A.A.F.L., SHU, K.M., NADLER, L.M. 
AND BOUSSIOTIS, V.A.
CD28 costimulation mediates down-regulation of p27kip1 and cell 
cycle progression by activation of the P13K/PKB signaling pathway in 
primaty human T cells.
J.IMMUNOL. 168 2729-2736 (2002).
 
6. FRAUWIRTH, K.A. AND THOMPSON, C.B.
Activation and inhibition of lymphocytes by costimulation. 
J.CLIN.INVEST. 109 295-299 (2002).
 
7. CARRENO, B.M. AND COLLINS, M.
The B7 family of ligands and its receptors: new pathways for 
costimulation and inhibition of immune responses.
ANNU.REV.IMMUNOL. 20 29-53 (2002).

Documentation
Antigen (Ag) recognition by the T cell receptor (TCR) induces activation of
T lymphocytes. However, TCR-mediated signals alone are insufficient for
efficient T cell activation, and additional co-stimulatory signals are 
required. One of the most important surface molecules that delivers 
co-stimulatory signals for T cells is CD28. The human T lymphocyte Ag CD28 
(Tp44) is a homodimeric 90kDa glycoprotein expressed on the surface of the
majority of human peripheral T cells and lymphocytes. Stimulation of CD4+ T
cells in the absence of CD28 co-signalling causes impaired proliferation, 
reduced cytokine production and altered generation of helper T cell subsets.
Co-stimulation via CD28 promotes T cell viability, clonal expansion,
cytokine production and effector functions, while also regulating apoptosis
of activated T cells, suggesting its importance in regulating long-term T 
cell survival [1-4]. 
 
Ligands for CD28 and the structurally related CTLA-4 (CD152) are the
molecules B7.1 (CD80) and B7.2 (CD86). B7.1 and B7.2 are expressed on
professional antigen presenting cells (APCs) and their expression is up-
regulated during an immune response. Ligation of CD28 by its natural ligands
results in tyrosine phosphorylation at a YMNM motif within its cytoplasmic
tail. The phosphorylated motif subsequently interacts with the Src homology
2 domain in the p85 regulatory subunit of P13K, activating the p110 
catalytic subunit. One of the P13K-dependent downstream targets, resulting 
from the antibody cross-linking of CD28, is the phoshporylation and 
activation of Akt (or PKB). Constitutively active Akt is able to substitute
for CD28 signals, and stimulates IL-2 production when introduced into mature
CD28-deficient cells. Another molecule affected by CD28 stimulation is the
proto-oncogene Vav, which acts as a guanine-nucleotide exchange factor for
Rac and CDC42, allowing these molecules to switch from the inactive GDP-
bound state to the active GTP-bound state [5,6].
 
Another interesting feature of CD28, is its ability to induce expression of
PDE7, a cAMP phosphodiesterase, thus reducing cellular cAMP levels. cAMP has
been reported to affect nearly every pathway important for lymphocyte
activation, leading to inhibition of T cell proliferation. Specifically,
increased intracellular cAMP has been implicated in the induction of T cell
anergy, a non-responsive state that occurs after T cells are stimulated
through TCR/CD3 in the absence of co-stimulation. This can have therapeutic 
implications, in that blockage of CD28 co-stimulation can be profoundly
immunosuppressive, preventing induction of pathogenic T cell responses in
autoimmune disease models, and allowing for prolonged acceptance of 
allografts in models of organ transplantation [6]. 
 
Finally, CD28 co-stimulation directly controls T cell cycle progression by 
down-regulating the cdk inhibitor p27kip1, which actually integrates
mitogenic MEK and P13K-dependent signals from both TCR and CD28 [5].
 
B7 ligands bind to both activating CD28 and inhibitory CTLA-4 (CD152)
receptors. Expression of both receptors and ligands is tightly regulated, 
allowing discrimination between signals that result in activation or 
inhibition of an immune response. CTLA-4 shares about 30% amino acid 
identity with CD28, and both bind to B7-1 and B7-2 ligands. However, the 
interaction of CD28 with its ligand is weaker than the interaction of 
CTLA-4. Crystal structures of CTLA-4-B7 complexes are characterised by
homodimers of CTLA-4 that contain B-7 binding sites located distantly to 
the CTLA-4 dimer interface, suggesting that CTLA-4 homodimers can bind to
noncovalent homodimers of B7-1 or B7-2 to form a lattice of CTLA-4-B7 
interactions. CD28 also forms homodimers, with a conserved cysteine located
proximal to the transmembrane domain linking the monomers in CD28 and 
CTLA-4. By similarity, CD28 may also form lattice structures with B7-1 and
B7-2, which could serve to potentiate the co-stimulatory signals delivered 
through CD28 [7].
 
CD28ANTIGEN is a 4-element fingerprint that provides a signature for the
CD28 antigen family of proteins. The fingerprint was derived from an initial
alignment of 7 sequences: the motifs were drawn from conserved regions
largely spanning the C-terminal portion of the alignment. Two iterations on
SPTR39_17f were required to reach convergence, at which point a true set
comprising 18 sequences was identified. 
Summary Information
18 codes involving  4 elements
0 codes involving 3 elements
0 codes involving 2 elements
Composite Feature Index
418181818
30000
20000
1234
True Positives
CD28_BOVIN    CD28_CHICK    CD28_HUMAN    CD28_MOUSE    
CD28_RABIT CD28_RAT O02757 O97630
Q13964 Q9BDM6 Q9BDM8 Q9BDN2
Q9BDN5 Q9BDN8 Q9GKP3 Q9JLV4
Q9N0N8 Q9N2I4
Sequence Titles
CD28_BOVIN  T-CELL-SPECIFIC SURFACE GLYCOPROTEIN CD28 PRECURSOR - Bos taurus (Bovine). 
CD28_CHICK T-CELL-SPECIFIC SURFACE GLYCOPROTEIN CD28 HOMOLOG PRECURSOR (CHT28) - Gallus gallus (Chicken).
CD28_HUMAN T-CELL-SPECIFIC SURFACE GLYCOPROTEIN CD28 PRECURSOR (TP44) - Homo sapiens (Human).
CD28_MOUSE T-CELL-SPECIFIC SURFACE GLYCOPROTEIN CD28 PRECURSOR - Mus musculus (Mouse).
CD28_RABIT T-CELL-SPECIFIC SURFACE GLYCOPROTEIN CD28 PRECURSOR - Oryctolagus cuniculus (Rabbit).
CD28_RAT T-CELL-SPECIFIC SURFACE GLYCOPROTEIN CD28 PRECURSOR - Rattus norvegicus (Rat).
O02757 T-CELL-SPECIFIC SURFACE GLYCOPROTEIN CD28 - Felis silvestris catus (Cat).
O97630 T-CELL SPECIFIC SURFACE GLYCOPROTEIN CD28 PRECURSOR - Ovis aries (Sheep).
Q13964 GLYCOPROTEIN CD28 - Homo sapiens (Human).
Q9BDM6 CD28 PROTEIN PRECURSOR - Macaca mulatta (Rhesus macaque).
Q9BDM8 CD28 PROTEIN PRECURSOR - Macaca nemestrina (Pig-tailed macaque).
Q9BDN2 CD28 PROTEIN PRECURSOR - Callithrix jacchus (Common marmoset).
Q9BDN5 CD28 PROTEIN - Cercocebus torquatus atys (Red-crowned mangabey) (Sooty mangabey).
Q9BDN8 CD28 PROTEIN PRECURSOR - Papio anubis (Olive baboon).
Q9GKP3 COSTIMULATORY MOLECULE B7 RECEPTOR CD28 - Canis familiaris (Dog).
Q9JLV4 CD28 ANTIGEN - Marmota monax (Woodchuck).
Q9N0N8 T-CELL COSTIMULATORY MOLECULE CD28 - Canis familiaris (Dog).
Q9N2I4 CD28 - Felis silvestris catus (Cat).
Scan History
SPTR39_17f 2  150  NSINGLE    
Initial Motifs
Motif 1  width=12
Element Seqn Id St Int Rpt
NEKSNGTIIHVK CD28_HUMAN 125 125 -
NEKSNGTIIHVK Q9BDM8 125 125 -
NEKSNGTIIHVK CD28_BOVIN 124 124 -
SEKSNGTIIHVK Q9BDN2 125 125 -
NEKSNGTIIHIK CD28_RAT 126 126 -
NERSNGTIIHIK CD28_MOUSE 126 126 -
NEKSNGTVIHVR CD28_CHICK 124 124 -

Motif 2 width=13
Element Seqn Id St Int Rpt
VRSKRSRLLHSDY CD28_HUMAN 179 42 -
MRSKRSRLLHSDY Q9BDM8 179 42 -
MKNKRNRMLQSDY CD28_BOVIN 178 42 -
MRSRRSRLLHSDY Q9BDN2 179 42 -
TNSRRNRLLQSDY CD28_RAT 177 39 -
TNSRRNRLLQVTT CD28_MOUSE 177 39 -
QKSKRNRYRQSDY CD28_CHICK 176 40 -

Motif 3 width=11
Element Seqn Id St Int Rpt
NMTPRRPGPTR CD28_HUMAN 193 1 -
NMTPRRPGPTR Q9BDM8 193 1 -
NMTPRRPGPTR CD28_BOVIN 192 1 -
NMTPRCPGPTR Q9BDN2 193 1 -
NMTPRRLGPTR CD28_RAT 191 1 -
NMTPRRPGLTR CD28_MOUSE 191 1 -
NMTPRHPPHQK CD28_CHICK 190 1 -

Motif 4 width=16
Element Seqn Id St Int Rpt
KHYQPYAPPRDFAAYR CD28_HUMAN 204 0 -
KHYQPYAPPRDSAAYR Q9BDM8 204 0 -
RHYQPYAPARDFAAYR CD28_BOVIN 203 0 -
RHYQPYAPPRDFAAYR Q9BDN2 204 0 -
KHYQPYAPARDFAAYR CD28_RAT 202 0 -
KPYQPYAPARDFAAYR CD28_MOUSE 202 0 -
KGYPSYAPTRDYTAYR CD28_CHICK 202 1 -
Final Motifs
Motif 1  width=12
Element Seqn Id St Int Rpt
NEKSNGTIIHVK Q9BDN5 125 125 -
NEKSNGTIIHVK Q9BDN8 125 125 -
NEKSNGTIIHVK CD28_HUMAN 125 125 -
NEKSNGTIIHVK Q13964 41 41 -
NEKSNGTIIHVK Q9BDM8 125 125 -
NEKSNGTIIHVK CD28_RABIT 126 126 -
NEKSNGTIIHVK O02757 126 126 -
NEKSNGTIIHVK Q9N2I4 126 126 -
NEKSNGTIIHVK CD28_BOVIN 124 124 -
NEKSNGTIIHEK Q9BDM6 125 125 -
NEKSNGTIIHVK Q9GKP3 126 126 -
NEKSNGTIIHVK O97630 124 124 -
SEKSNGTIIHVK Q9BDN2 125 125 -
NEKSNGTIIHIK CD28_RAT 126 126 -
NEKSNGTIIHVK Q9N0N8 126 126 -
NEKSNGTVIHVK Q9JLV4 126 126 -
NERSNGTIIHIK CD28_MOUSE 126 126 -
NEKSNGTVIHVR CD28_CHICK 124 124 -

Motif 2 width=13
Element Seqn Id St Int Rpt
MRSKRSRLLHSDY Q9BDN5 179 42 -
MRSKRSRLLHSDY Q9BDN8 179 42 -
VRSKRSRLLHSDY CD28_HUMAN 179 42 -
VRSKRSRLLHSDY Q13964 95 42 -
MRSKRSRLLHSDY Q9BDM8 179 42 -
MKSKKNRLLQSDY CD28_RABIT 180 42 -
MKTKRSRILQSDY O02757 180 42 -
MKTKRSRILQSDY Q9N2I4 180 42 -
MKNKRNRMLQSDY CD28_BOVIN 178 42 -
MRSKRSRLLHSDY Q9BDM6 179 42 -
IKSKSSRILQSDY Q9GKP3 180 42 -
MKSKRNRMHQSDY O97630 178 42 -
MRSRRSRLLHSDY Q9BDN2 179 42 -
TNSRRNRLLQSDY CD28_RAT 177 39 -
IKSKSSRILQSDY Q9N0N8 180 42 -
TKRQRTRLLQSDY Q9JLV4 180 42 -
TNSRRNRLLQVTT CD28_MOUSE 177 39 -
QKSKRNRYRQSDY CD28_CHICK 176 40 -

Motif 3 width=11
Element Seqn Id St Int Rpt
NMTPRRPGPTR Q9BDN5 193 1 -
NMTPRRPGPTR Q9BDN8 193 1 -
NMTPRRPGPTR CD28_HUMAN 193 1 -
NMTPRRPGPTR Q13964 109 1 -
NMTPRRPGPTR Q9BDM8 193 1 -
NMTPRRPGPTR CD28_RABIT 194 1 -
NMTPRRPGPTR O02757 194 1 -
NMTPRRPGPTR Q9N2I4 194 1 -
NMTPRRPGPTR CD28_BOVIN 192 1 -
NMTPRRPGPTR Q9BDM6 193 1 -
NMTPRRPGPTR Q9GKP3 194 1 -
NMTPRRPGPTR O97630 192 1 -
NMTPRCPGPTR Q9BDN2 193 1 -
NMTPRRLGPTR CD28_RAT 191 1 -
NMTPREAGPTR Q9N0N8 194 1 -
NMTPRRPGPSR Q9JLV4 194 1 -
NMTPRRPGLTR CD28_MOUSE 191 1 -
NMTPRHPPHQK CD28_CHICK 190 1 -

Motif 4 width=16
Element Seqn Id St Int Rpt
KHYQPYAPPRDFAAYR Q9BDN5 204 0 -
KHYQPYAPPRDFAAYR Q9BDN8 204 0 -
KHYQPYAPPRDFAAYR CD28_HUMAN 204 0 -
KHYQPYAPPRDFAAYR Q13964 120 0 -
KHYQPYAPPRDSAAYR Q9BDM8 204 0 -
KHYQPYAPARDFAAYR CD28_RABIT 205 0 -
RHYQPYAPARDFAAYR O02757 205 0 -
RHYQPYAPARDFAAYR Q9N2I4 205 0 -
RHYQPYAPARDFAAYR CD28_BOVIN 203 0 -
KHYQPCAPPRDFAAYR Q9BDM6 204 0 -
RHYQPYAPARDFAAYR Q9GKP3 205 0 -
RHYQPYAPTRDFAAYR O97630 203 0 -
RHYQPYAPPRDFAAYR Q9BDN2 204 0 -
KHYQPYAPARDFAAYR CD28_RAT 202 0 -
RHYQPYAPARDFAAYR Q9N0N8 205 0 -
KHYQPYAPARDFAAYR Q9JLV4 205 0 -
KPYQPYAPARDFAAYR CD28_MOUSE 202 0 -
KGYPSYAPTRDYTAYR CD28_CHICK 202 1 -