title: Characterization of SH2D1A missense mutations identified in X-linked lymphoproliferative disease patients.
abstract: 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.
authors.affiliation: Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: M
authors.initials: M
authors.lastname: Morra
authors.forename: M
authors.initials: M
authors.lastname: Simarro-Grande
authors.forename: M
authors.initials: M
authors.lastname: Martin
authors.forename: A S
authors.initials: AS
authors.lastname: Chen
authors.forename: A
authors.initials: A
authors.lastname: Lanyi
authors.forename: O
authors.initials: O
authors.lastname: Silander
authors.forename: S
authors.initials: S
authors.lastname: Calpe
authors.forename: J
authors.initials: J
authors.lastname: Davis
authors.forename: T
authors.initials: T
authors.lastname: Pawson
authors.forename: M J
authors.initials: MJ
authors.lastname: Eck
authors.forename: J
authors.initials: J
authors.lastname: Sumegi
authors.forename: P
authors.initials: P
authors.lastname: Engel
authors.forename: S C
authors.initials: SC
authors.lastname: Li
authors.forename: C
authors.initials: C
authors.lastname: Terhorst
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics*; D003001:Cloning, Molecular; D004305:Dose-Response Relationship, Drug; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D008232:Lymphoproliferative Disorders / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D014162:Transfection; D018909:src Homology Domains
chemical_list: D000596:Amino Acids; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C114953:SH2D1A protein, human; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein