Structural basis for the interaction of the free SH2 domain EAT-2 with SLAM receptors in hematopoietic cells.
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.
Pubmed ID: 11689425 RIS Download
Adaptor Proteins, Signal Transducing | Amino Acid Motifs | Animals | Antigens, CD | B-Lymphocytes | Base Sequence | Blood Coagulation Factors | COS Cells | Carrier Proteins | Glycoproteins | Humans | Immunoglobulins | Intracellular Signaling Peptides and Proteins | Macromolecular Substances | Macrophages | Mice | Models, Molecular | Molecular Sequence Data | Protein Binding | Protein Tyrosine Phosphatase, Non-Receptor Type 11 | Protein Tyrosine Phosphatase, Non-Receptor Type 6 | Protein Tyrosine Phosphatases | Proto-Oncogene Proteins | Proto-Oncogene Proteins c-fyn | Receptors, Cell Surface | SH2 Domain-Containing Protein Tyrosine Phosphatases | Sequence Homology, Amino Acid | Signal Transduction | Signaling Lymphocytic Activation Molecule Associated Protein | Signaling Lymphocytic Activation Molecule Family Member 1 | Transcription Factors | Two-Hybrid System Techniques | X-Ray Diffraction | src Homology Domains