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PDBsum entry 4m4z
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Signaling protein
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PDB id
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4m4z
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References listed in PDB file
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Key reference
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Title
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Crystal structure of src-Like adaptor protein 2 reveals close association of sh3 and sh2 domains through β-Sheet formation.
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Authors
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L.E.Wybenga-Groot,
C.J.Mcglade.
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Ref.
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Cell Signal, 2013,
25,
2702-2708.
[DOI no: ]
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PubMed id
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Abstract
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The Src-like adaptor proteins (SLAP/SLAP2) are key components of Cbl-dependent
downregulation of antigen receptor, cytokine receptor, and receptor tyrosine
kinase signaling in hematopoietic cells. SLAP and SLAP2 consist of adjacent SH3
and SH2 domains that are most similar in sequence to Src family kinases (SFKs).
Notably, the SH3-SH2 connector sequence is significantly shorter in SLAP/SLAP2
than in SFKs. To understand the structural implication of a short SH3-SH2
connector sequence, we solved the crystal structure of a protein encompassing
the SH3 domain, SH3-SH2 connector, and SH2 domain of SLAP2 (SLAP2-32). While
both domains adopt typical folds, the short SH3-SH2 connector places them in
close association. Strand βe of the SH3 domain interacts with strand βA of the
SH2 domain, resulting in the formation of a continuous β sheet that spans the
length of the protein. Disruption of the SH3/SH2 interface through mutagenesis
decreases SLAP-32 stability in vitro, consistent with inter-domain binding being
an important component of SLAP2 structure and function. The canonical peptide
binding pockets of the SH3 and SH2 domains are fully accessible, in contrast to
other protein structures that display direct interaction between SH3 and SH2
domains, in which either peptide binding surface is obstructed by the
interaction. Our results reveal potential sites of novel interaction for SH3 and
SH2 domains, and illustrate the adaptability of SH2 and SH3 domains in mediating
interactions. As well, our results suggest that the SH3 and SH2 domains of SLAP2
function interdependently, with implications on their mode of substrate binding.
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