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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

Authors

  • Morra M
  • Lu J
  • Poy F
  • Martin M
  • Sayos J
  • Calpe S
  • Gullo C
  • Howie D
  • Rietdijk S
  • Thompson A
  • Coyle AJ
  • Denny C
  • Yaffe MB
  • Engel P
  • Eck MJ
  • Terhorst C

Journal

The EMBO journal

Publication Data

November 1, 2001

Associated Grants

  • Agency: NIAID NIH HHS, Id: P01-AI-35714

Mesh Terms

  • 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
  • Transcription Factors
  • Two-Hybrid System Techniques
  • X-Ray Diffraction
  • src Homology Domains