Crystal structures of the XLP protein SAP reveal a class of SH2 domains with extended, phosphotyrosine-independent sequence recognition.
SAP, the product of the gene mutated in X-linked lymphoproliferative syndrome (XLP), consists of a single SH2 domain that has been shown to bind the cytoplasmic tail of the lymphocyte coreceptor SLAM. Here we describe structures that show that SAP binds phosphorylated and nonphosphorylated SLAM peptides in a similar mode, with the tyrosine or phosphotyrosine residue inserted into the phosphotyrosine-binding pocket. We find that specific interactions with residues N-terminal to the tyrosine, in addition to more characteristic C-terminal interactions, stabilize the complexes. A phosphopeptide library screen and analysis of mutations identified in XLP patients confirm that these extended interactions are required for SAP function. Further, we show that SAP and the similar protein EAT-2 recognize the sequence motif TIpYXX(V/I).
Poy
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Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Yaffe
M B
MB
Sayos
J
J
Saxena
K
K
Morra
M
M
Sumegi
J
J
Cantley
L C
LC
Terhorst
C
C
Eck
M J
MJ
D000595:Amino Acid Sequence; D015703:Antigens, CD; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics; D018360:Crystallography, X-Ray; D006023:Glycoproteins / Q000737:chemistry*; D006801:Humans; D007136:Immunoglobulins / Q000737:chemistry*; D047908:Intracellular Signaling Peptides and Proteins; D008232:Lymphoproliferative Disorders / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry; D019151:Peptide Library; D010748:Phosphopeptides / Q000737:chemistry; D019000:Phosphotyrosine / Q000737:chemistry; D011485:Protein Binding; D011956:Receptors, Cell Surface; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D014157:Transcription Factors / Q000737:chemistry; D018909:src Homology Domains
D015703:Antigens, CD; D002352:Carrier Proteins; D006023:Glycoproteins; D007136:Immunoglobulins; D047908:Intracellular Signaling Peptides and Proteins; D010446:Peptide Fragments; D019151:Peptide Library; D010748:Phosphopeptides; D011956:Receptors, Cell Surface; C114953:SH2D1A protein, human; C103572:SH2D1B protein, human; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D014157:Transcription Factors; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D019000:Phosphotyrosine