1KA6: SAP/SH2D1A bound to peptide n-pY

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.
PDB ID: 1KA6Download
MMDB ID: 73749
PDB Deposition Date: 2001/10/31
Updated in MMDB: 2009/07
Experimental Method:
solution nmr
Source Organism:
Homo sapiens
Similar Structures:
Molecular Components in 1KA6
Label Count Molecule
Proteins (2 molecules)
SH2 Domain Protein 1A(Gene symbol: SH2D1A)
Molecule annotation
Peptide N-py(Gene symbol: SLAMF1)
Molecule annotation
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Citing MMDB