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PR01781

Identifier
LATPROTEIN  [View Relations]  [View Alignment]  
Accession
PR01781
No. of Motifs
6
Creation Date
27-FEB-2002
Title
Linker for activation of T cells (LAT) signature
Database References
Literature References
1. WANGE, R.L.
LAT, the linker for activation of T cells: a bridge between T cell-
specific and general signaling pathways.
SCI.STKE. 1-19 (2000).
 
2. HARDER, T. AND KUHN, M.
Selective accumulation of raft-associated membrane protein in LAT 
and in T cell receptor-signaling assemblies.
J.CELL BIOL. 151 199-207 (2000).
 
3. GRINGHUIS, S.I., VOORT, E.A., LEOW, A., LEVARHT, E.W., 
BREEDVELD, F.C. AND VERWEIJ, C.L.
Effect of redox balance alternations on cellular localization of LAT 
and downstream T-cell receptor signaling pathways.
MOL.CELL BIOL. 22 400-411 (2002).

Documentation
A key event in the regulation of the adaptive immune response is the binding
of major histocompatibility complex (MHC)-peptide complexes to T cell 
antigen receptors (TCRs). The formation of such ternary complexes induces 
significant biochemical changes within T cells of the host animal. The first 
detectable response of the T cell is the rapid accumulation of numerous 
tyrosine-phosphorylated proteins within the cell. Increased phosphotyrosine 
occurs as a consequence of the activation of several different TCR-
associated, hematopoietic-specific protein kinases (PTKs), thereby perturbing
the balance between those enzymes that add, and those that remove,  
phosphates from key tyrosine residues. These initial phosphorylation events 
are required for the subsequent activation of the small guanosine 
triphosphatase (GTPase) proteins Ras and Rac, the lipid kinase P13K and PLC-
gamma1. Activation of these cytoplasmic signalling proteins ultimately leads
to activation of various transcription factors (NF-AT, NF-kB, and AP-1) and
increased transcription from genes that have an important role in initiating
T cell proliferation, such as interleukin-2 (IL-2) [1,2].
 
An unresolved question in the field has been which molecules and what 
sequence of events tie together the early tyrosine phosphorylation events 
with the activation of these downstream signalling molecules. A likely 
candidate for linking the proximal and distal portions of the TCR signalling
pathway is a 36kDa transmembrane (TM) protein termed LAT. LAT becomes 
phosphorylated after TCR engagement, thereby creating binding sites for the 
Src homology 2 (SH2) domains of other proteins, including PLC-gamma1, Grb2,
Gads, Grap, 3BP2 and Shb. It also indirectly binds SOS, c-Cbl, Vav, SLP-76
and Itk [1].
 
LAT is expressed in peripheral blood lymphocytes, thymus and spleen, as
well as in other blood cells, including megakaryocytes, platelets, natural 
killer cells and mast cells. It is excluded from the cytosol, and is found 
at the plasma membrane and in the perinuclear compartment. The cellular 
localisation of LAT seems to be extremely sensitive to alternations in the 
intracellular redox balance. Reduced intracellular levels of antioxidants 
result in the membrane displacement of LAT (a consequence of a 
conformational change interfering with its insertion into the membrane), 
abrogation of TCR-mediated signalling and, consequently, hyporesponsiveness 
of T lymphocytes [1,3].
 
The amino acid sequence of LAT contains no recognised functional domains, 
but, consistent with its strong tyrosine phosphorylation upon TCR 
stimulation, its predicted cytoplasmic tail contains 10 tyrosines, 9 of 
which are conserved between mouse, rat and human proteins. In addition, 
LAT also has 2 cysteine residues (Cys26 and Cys29 in human) that are 
conserved among human, rat, mouse and bovine proteins. These residues lie 
proximal to the inner face of the plasma membrane: Cys26 within the TM 
region and Cys29 located juxtamembrane. These membrane-proximal residues 
are thought to play a vital role in LAT function. In fact, LAT is subject to
post-translational palmitoylation of these residues, which appears to be 
necessary to target LAT to lipid rafts in the membrane, where it can 
recruit key cytosolic signalling proteins to the aggregated rafts upon TCR 
stimulation. Raft membrane domains are envisaged as lateral assemblies of 
sphingolipids and cholesterol that form ordered membrane phases [1,2].
 
LATPROTEIN is a 6-element fingerprint that provides a signature for LAT 
proteins. The fingerprint was derived from an initial alignment of 3 
sequences: the motifs were drawn from conserved regions spanning virtually 
the full alignment length - all reside in the putative cytoplasmic domain,
motifs 4 and 5 each including GRB2-binding motifs. A single iteration on 
SPTR39_17f was required to reach convergence, no further sequences being 
identified beyond the starting set.
Summary Information
3 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
6333333
5000000
4000000
3000000
2000000
123456
True Positives
LAT_HUMAN     LAT_MOUSE     LAT_RAT       
Sequence Titles
LAT_HUMAN   LINKER FOR ACTIVATION OF T CELLS (36 KDA PHOSPHO-TYROSINE ADAPTOR PROTEIN) (PP36) (P36-38) - Homo sapiens (Human). 
LAT_MOUSE LINKER FOR ACTIVATION OF T CELLS (36 KDA PHOSPHO-TYROSINE ADAPTOR PROTEIN) (PP36) (P36-38) - Mus musculus (Mouse).
LAT_RAT LINKER FOR ACTIVATION OF T CELLS (36 KDA PHOSPHO-TYROSINE ADAPTOR PROTEIN) (PP36) (P36-38) - Rattus norvegicus (Rat).
Scan History
SPTR39_17f 1  150  NSINGLE    
Initial Motifs
Motif 1  width=13
Element Seqn Id St Int Rpt
SYDSTSTESLYPR LAT_MOUSE 36 36 -
SYDSASTESLYPR LAT_RAT 36 36 -
SYDSTSSDSLYPR LAT_HUMAN 35 35 -

Motif 2 width=14
Element Seqn Id St Int Rpt
YPLVTSFPPLRQPD LAT_MOUSE 67 18 -
YPLVTSFPPLRQPD LAT_RAT 67 18 -
YPPVTSYPPLSQPD LAT_HUMAN 64 16 -

Motif 3 width=14
Element Seqn Id St Int Rpt
PIPRSPQPLGGSHR LAT_MOUSE 83 2 -
PIPRSPQPLGGSHR LAT_RAT 83 2 -
PIPRSPQPLGGSHR LAT_HUMAN 80 2 -

Motif 4 width=9
Element Seqn Id St Int Rpt
EDYVNVPES LAT_MOUSE 173 76 -
EDYVNVPES LAT_RAT 173 76 -
DDYVNVPES LAT_HUMAN 198 104 -

Motif 5 width=17
Element Seqn Id St Int Rpt
ESAEASLDGSREYVNVS LAT_MOUSE 183 1 -
ESAEASLDGSREYVNVS LAT_RAT 183 1 -
ESAEASLDGSREYVNVS LAT_HUMAN 208 1 -

Motif 6 width=10
Element Seqn Id St Int Rpt
PDYENLQELN LAT_MOUSE 233 33 -
PDYENLQELN LAT_RAT 232 32 -
PDYENLQELN LAT_HUMAN 253 28 -
Final Motifs
Motif 1  width=13
Element Seqn Id St Int Rpt
SYDSTSTESLYPR LAT_MOUSE 36 36 -
SYDSASTESLYPR LAT_RAT 36 36 -
SYDSTSSDSLYPR LAT_HUMAN 35 35 -

Motif 2 width=14
Element Seqn Id St Int Rpt
YPLVTSFPPLRQPD LAT_MOUSE 67 18 -
YPLVTSFPPLRQPD LAT_RAT 67 18 -
YPPVTSYPPLSQPD LAT_HUMAN 64 16 -

Motif 3 width=14
Element Seqn Id St Int Rpt
PIPRSPQPLGGSHR LAT_MOUSE 83 2 -
PIPRSPQPLGGSHR LAT_RAT 83 2 -
PIPRSPQPLGGSHR LAT_HUMAN 80 2 -

Motif 4 width=9
Element Seqn Id St Int Rpt
EDYVNVPES LAT_MOUSE 173 76 -
EDYVNVPES LAT_RAT 173 76 -
DDYVNVPES LAT_HUMAN 198 104 -

Motif 5 width=17
Element Seqn Id St Int Rpt
ESAEASLDGSREYVNVS LAT_MOUSE 183 1 -
ESAEASLDGSREYVNVS LAT_RAT 183 1 -
ESAEASLDGSREYVNVS LAT_HUMAN 208 1 -

Motif 6 width=10
Element Seqn Id St Int Rpt
PDYENLQELN LAT_MOUSE 233 33 -
PDYENLQELN LAT_RAT 232 32 -
PDYENLQELN LAT_HUMAN 253 28 -