Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In addition to triggering the activation of B- or T-cell antigen receptors, the binding of a ligand to its receptor at the cell surface can sometimes determine the physiological outcome of interactions between antigen-presenting cells, T and B lymphocytes. The protein SLAM (also known as CDw150), which is present on the surface of B and T cells, forms such a receptor-ligand pair as it is a self-ligand. We now show that a T-cell-specific, SLAM-associated protein (SAP), which contains an SH2 domain and a short tall, acts as an inhibitor by blocking recruitment of the SH2-domain-containing signal-transduction molecule SHP-2 to a docking site in the SLAM cytoplasmic region. The gene encoding SAP maps to the same area of the X chromosome as the locus for X-linked lymphoproliferative disease (XLP) and we found mutations in the SAP gene in three XLP patients. Absence of the inhibitor SAP in XLP patients affects T/B-cell interactions induced by SLAM, leading to an inability to control B-cell proliferation caused by Epstein-Barr virus infections.
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PMID:The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. 977 94

X-linked lymphoproliferative disease (XLP) is a rare inherited immunodeficiency to Epstein-Barr virus (EBV). The gene responsible for XLP has recently been identified as the four-exon SH2D1A gene encoding a 128-amino-acid protein that contains an SH2-domain. Functional studies indicate the SH2D1A protein acts as a regulator of at least two signal transduction pathways initiated by the cell surface molecules SLAM and 2B4, respectively, and possibly related to the host immune response to EBV infection. We have carried out a systematic mutation study of the SH2D1A gene in our series of 19 typical and 8 atypical XLP patients by polymerase chain reaction (PCR), reverse transcription/PCR, and sequencing, and have reconstructed the haplotypes of the patients. Four out of the 13 mutations detected are previously unreported. The identification of SH2D1A mutations in carriers from all three XLP families screened and the detection of mutations in two out of eight atypical patients indicates the usefulness of a DNA-based diagnosis for XLP disease.
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PMID:SH2D1A mutation analysis for diagnosis of XLP in typical and atypical patients. 1059 19

2B4 is a cell surface glycoprotein of the Ig-superfamily structurally related to CD2-like molecules such as CD2, CD48, CD58, CD84, Ly-9, and SLAM. Engagement of 2B4 on NK cells with specific antibodies or with its ligand CD48 enhances NK cell-mediated cytotoxicity. 2B4 is also expressed on both CD8+ T cells and myeloid cells, but its function in these cells remains unknown. Signal transduction through 2B4 involves recruitment of the SH2-containing adapter molecule SAP to cytoplasmic tyrosines. SAP is deficient in patients affected by X-linked lymphoproliferative disorder (XLP), which is triggered following EBV infection. Thus, an interruption of signaling through 2B4 and related molecules may impair NK cell recognition of virally infected cells and contribute to XLP.
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PMID:2B4: an NK cell activating receptor with unique specificity and signal transduction mechanism. 1065 76

X-linked lymphoproliferative disease (XLP) is a rare and severe immune deficiency, characterized by abnormal immune responses to the Epstein-Barr virus. Recently, the gene responsible for XLP, SH2D1A, has been identified and shown to code for a small cytoplasmic protein with an SH2 domain that interacts with SLAM and 2B4, two receptorial molecules involved in signal transduction in T and NK cells, respectively. A variety of SH2D1A gene mutations have been reported thus far in XLP males. Here we describe a single-strand conformation polymorphism assay for mutation analysis in XLP. Four novel patients with SH2D1A mutations are described. These mutants, and the others previously reported in the literature, have been included in a Registry (SH2D1Abase) that is fully accessible on the World Wide Web. A three-dimensional model of the SH2 domain of the SH2D1A protein has been developed, based on homology with other SH2 domains. The structural consequences of disease-causing SH2D1A mutations are discussed.
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PMID:Structural basis for SH2D1A mutations in X-linked lymphoproliferative disease. 1069 88

X-linked lymphoproliferative disease (XLP) is characterized by a selective immune deficiency to EBV. The molecular basis of XLP has been attributed to mutations of signaling lymphocytic activation molecule-associated protein, an intracellular molecule known to associate with the lymphocyte-activating surface receptors SLAM and 2B4. We have identified a single nucleotide mutation in SLAM-associated protein that affects the NK cell function of males carrying the mutated gene. In contrast to normal controls, both NK and lymphokine-activated killer cell cytotoxicity was significantly reduced in two XLP patients. In addition to decreased baseline cytotoxicity, ligation of 2B4 significantly augmented NK lytic function in normal controls but failed to enhance the cytotoxicity of NK cells from XLP patients. These findings suggest that association of SAP with 2B4 is necessary for optimal NK/lymphokine-activated killer cytotoxicity and imply that alterations in SAP/2B4 signaling contribute to the immune dysfunction observed in XLP.
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PMID:Defective NK cell activation in X-linked lymphoproliferative disease. 1103 54

X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency, involving primarily T and natural killer (NK) cells, which in the majority of cases exacerbates following exposure to Epstein-Barr virus (EBV). Prior to EBV infection, most boys with the defective XLP gene appear to be clinically healthy EBV infection in males with the defective XLP gene leads to three main phenotypes: severe and mostly fatal infectious mononucleosis (58%), lymphoproliferative disorders mostly of B-cell origin (30%) and/or dysgammaglobulinemia (31%). Later in life, dysgammaglobulinemia and malignant lymphoma may also develop in about 53% and 56% of EBV-negative XLP males, respectively This fact suggests that EBV may only act as a potent trigger of the earliest and most serious clinical phenotype of XLP, i.e. fatal infectious mononucleosis. XLP has an unfavorable prognosis. Successful transplanta tion of hematopoietic stem cells can cure this immunodeficiency In the future, gene therapy may eventually become an additional option to prevent XLP. The gene responsible for XLP, SH2-domain containing gene 1A (SH2D1A) has recently been identified and sequenced. SH2D1A encodes a polypeptide of 128 amino acids containing a single SH2 domain. Until now, 45 different SH2D1A gene mutations have been identified in patients with XLP SH2D1A is thought to play an important role in signal transduction in T and NK cells. In vitro, SH2D1A has been shown to interact as an adaptor protein with the signaling pathways through SLAM, a T-cell co-stimulatory molecule, and 2B4, an NK-cell-activating receptor. Further functional studies of the SH2D1A protein will probably provide new insights into the pathogenesis of severe infectious mononucleosis, malignant lymphomas and immunodeficiency in patients with XLP.
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PMID:X-linked lymphoproliferative disease is caused by deficiency of a novel SH2 domain-containing signal transduction adaptor protein. 1121 3

X-linked lymphoproliferative disease (XLP) is a rare immune disorder commonly triggered by infection with Epstein-Barr virus. Major disease manifestations include fatal acute infectious mononucleosis, B-cell lymphoma, and progressive dys-gammaglobulinemia. SAP/SH2D1A, the product of the gene mutated in XLP, is a small protein that comprises a single SH2 domain and a short tail of 26 amino acids. SAP binds to a specific motif in the cytoplasmic tails of the cell surface receptors SLAM and 2B4, where it blocks recruitment of the phosphatase SHP-2. Here it is reported that Ly-9 and CD84, 2 related glycoproteins differentially expressed on hematopoietic cells, also recruit SAP. Interactions between SAP and Ly-9 or CD84 were analyzed using a novel yeast 2-hybrid system, by COS cell transfections and in lymphoid cells. Recruitment of SAP is most efficient when the specific tyrosine residues in the cytoplasmic tails of Ly-9 or CD84 are phosphorylated. It is concluded that in activated T cells, the SAP protein binds to and regulates signal transduction events initiated through the engagement of SLAM, 2B4, CD84, and Ly-9. This suggests that combinations of dysfunctional signaling pathways initiated by these 4 cell surface receptors may cause the complex phenotypes of XLP. (Blood. 2001;97:3867-3874)
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PMID:Cell surface receptors Ly-9 and CD84 recruit the X-linked lymphoproliferative disease gene product SAP. 1138 28

X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency characterized by extreme susceptibility to Epstein-Barr virus. The XLP disease gene product SH2D1A (SAP) interacts via its SH2 domain with a motif (TIYXXV) present in the cytoplasmic tail of the cell-surface receptors CD150/SLAM, CD84, CD229/Ly-9, and CD244/2B4. Characteristically, the SH2D1A three-pronged interaction with Tyr(281) of CD150 can occur in absence of phosphorylation. Here we analyze the effect of SH2D1A protein missense mutations identified in 10 XLP families. Two sets of mutants were found: (i) mutants with a marked decreased protein half-life (e.g. Y7C, S28R, Q99P, P101L, V102G, and X129R) and (ii) mutants with structural changes that differently affect the interaction with the four receptors. In the second group, mutations that disrupt the interaction between the SH2D1A hydrophobic cleft and Val +3 of its binding motif (e.g. T68I) and mutations that interfere with the SH2D1A phosphotyrosine-binding pocket (e.g. C42W) abrogated SH2D1A binding to all four receptors. Surprisingly, a mutation in SH2D1A able to interfere with Thr -2 of the CD150 binding motif (mutant T53I) severely impaired non-phosphotyrosine interactions while preserving unaffected the binding of SH2D1A to phosphorylated CD150. Mutant T53I, however, did not bind to CD229 and CD224, suggesting that SH2D1A controls several critical signaling pathways in T and natural killer cells. Because no correlation is present between identified types of mutations and XLP patient clinical presentation, additional unidentified genetic or environmental factors must play a strong role in XLP disease manifestations.
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PMID:Characterization of SH2D1A missense mutations identified in X-linked lymphoproliferative disease patients. 1147 68

The T and natural killer (NK) cell-specific gene SAP (SH2D1A) encodes a 'free SH2 domain' that binds a specific tyrosine motif in the cytoplasmic tail of SLAM (CD150) and related cell surface proteins. Mutations in SH2D1A cause the X-linked lymphoproliferative disease, a primary immunodeficiency. Here we report that a second gene encoding a free SH2 domain, EAT-2, is expressed in macrophages and B lympho cytes. The EAT-2 structure in complex with a phosphotyrosine peptide containing a sequence motif with Tyr281 of the cytoplasmic tail of CD150 is very similar to the structure of SH2D1A complexed with the same peptide. This explains the high affinity of EAT-2 for the pTyr motif in the cytoplasmic tail of CD150 but, unlike SH2D1A, EAT-2 does not bind to non-phosphorylated CD150. EAT-2 binds to the phosphorylated receptors CD84, CD150, CD229 and CD244, and acts as a natural inhibitor, which interferes with the recruitment of the tyrosine phosphatase SHP-2. We conclude that EAT-2 plays a role in controlling signal transduction through at least four receptors expressed on the surface of professional antigen-presenting cells.
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PMID:Structural basis for the interaction of the free SH2 domain EAT-2 with SLAM receptors in hematopoietic cells. 1168 25

The SH2 domain protein SAP/SH2D1A, encoded by the X-linked lymphoproliferative (XLP) syndrome gene, associates with the hematopoietic cell surface receptor SLAM in a phosphorylation-independent manner. By screening a repertoire of synthetic peptides, the specificity of SAP/SH2D1A has been mapped and a consensus sequence motif for binding identified, T/S-x-x-x-x-V/I, where x represents any amino acid. Remarkably, this motif contains neither a Tyr nor a pTyr residue, a hallmark of conventional SH2 domain-ligand interactions. The structures of the protein, determined by NMR, in complex with two distinct peptides provide direct evidence in support of a "three-pronged" binding mechanism for the SAP/SH2D1A SH2 domain in contrast to the "two-pronged" binding for conventional SH2 domains. Differences in the structures of the two complexes suggest considerable flexibility in the SH2 domain, as further confirmed and characterized by hydrogen exchange studies. The structures also explain binding defects observed in disease-causing SAP/SH2D1A mutants and suggest that phosphorylation-independent interactions mediated by SAP/SH2D1A likely play an important role in the pathogenesis of XLP.
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PMID:A "three-pronged" binding mechanism for the SAP/SH2D1A SH2 domain: structural basis and relevance to the XLP syndrome. 1182 24


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