title: Structural basis for the interaction of the free SH2 domain EAT-2 with SLAM receptors in hematopoietic cells.
abstract: 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.
authors.affiliation: Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA. mmorra@caregroup.harvard.edu
authors.forename: M
authors.initials: M
authors.lastname: Morra
authors.forename: J
authors.initials: J
authors.lastname: Lu
authors.forename: F
authors.initials: F
authors.lastname: Poy
authors.forename: M
authors.initials: M
authors.lastname: Martin
authors.forename: J
authors.initials: J
authors.lastname: Sayos
authors.forename: S
authors.initials: S
authors.lastname: Calpe
authors.forename: C
authors.initials: C
authors.lastname: Gullo
authors.forename: D
authors.initials: D
authors.lastname: Howie
authors.forename: S
authors.initials: S
authors.lastname: Rietdijk
authors.forename: A
authors.initials: A
authors.lastname: Thompson
authors.forename: A J
authors.initials: AJ
authors.lastname: Coyle
authors.forename: C
authors.initials: C
authors.lastname: Denny
authors.forename: M B
authors.initials: MB
authors.lastname: Yaffe
authors.forename: P
authors.initials: P
authors.lastname: Engel
authors.forename: M J
authors.initials: MJ
authors.lastname: Eck
authors.forename: C
authors.initials: C
authors.lastname: Terhorst
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism*; D001483:Base Sequence; D001779:Blood Coagulation Factors; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000502:physiology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn; D011956:Receptors, Cell Surface / Q000378:metabolism; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D014961:X-Ray Diffraction; D018909:src Homology Domains / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D001779:Blood Coagulation Factors; D002352:Carrier Proteins; D006023:Glycoproteins; D007136:Immunoglobulins; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; C114953:SH2D1A protein, human; C103572:SH2D1B protein, human; C000604059:SLAMF1 protein, human; C499569:Sh2d1a protein, mouse; C491225:Sh2d1b1 protein, mouse; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D014157:Transcription Factors; C091963:activated protein C receptor; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; C494957:FYN protein, human; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases