Article

Dynamic interaction of CD2 with the GYF and the SH3 domain of compartmentalized effector molecules

Harvard University, Cambridge, Massachusetts, United States
The EMBO Journal (Impact Factor: 10.43). 12/2002; 21(22):5985-95. DOI: 10.1093/emboj/cdf602
Source: PubMed

ABSTRACT

Intracellular protein interaction domains are essential for eukaryotic signaling. In T cells, the CD2BP2 adaptor binds two membrane-proximal proline-rich motifs in the CD2 cytoplasmic tail via its GYF domain, thereby regulating interleukin-2 production. Here we present the structure of the GYF domain in complex with a CD2 tail peptide. Unlike SH3 domains, which use two surface pockets to accommodate proline residues of ligands, the GYF domain employs phylogenetically conserved hydrophobic residues to create a single interaction surface. NMR analysis shows that the Fyn but not the Lck tyrosine kinase SH3 domain competes with CD2BP2 GYF-domain binding to the same CD2 proline-rich sequence in vitro. To test the in vivo significance of this competition, we used co-immunoprecipitation experiments and found that CD2BP2 is the ligand of the membrane-proximal proline-rich tandem repeat of CD2 in detergent-soluble membrane compartments, but is replaced by Fyn SH3 after CD2 is translocated into lipid rafts upon CD2 ectodomain clustering. This unveils the mechanism of a switch of CD2 function due to an extracellular mitogenic signal.

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Available from: Ronald Kühne, May 13, 2014
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    • "While a scaffolding function of the protein at the T cell membrane is conceivable (though controversial) (Freund et al., 2002; Heinze et al., 2007), a more unifying concept of CD2BP2 function arose from the observation that its GYF domain (amino acids 280– 341 of the protein) confers localization to the spliceosome. "
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    Full-text · Article · Jun 2015 · Journal of Molecular Cell Biology
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    • "The main helix is tilted away from the sheet, providing space for an array of stacked aromatic side chains which create the binding site for the PPG motif of the peptide ligand (reviewed in Kofler and Freund (2006)). Monovalent interactions between GYF domains and peptide targets have reported dissociation constants of about 200 lM (Freund et al., 2002). The GYF domain is thought to be involved in splicing and splicing-associated processes, immune cell function and antigen presentation (Kofler and Freund, 2006). "
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    Full-text · Article · Aug 2013 · Journal of Structural Biology
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    • "The small interface between the peptides and their protein domain partners facilitates low-affinity weak interactions that are easily formed and disrupted to regulate cellular responses. Indeed cell surface receptors that mediate immune responses are often coupled to intracellular signaling pathways by recognition of modular protein interaction domains that bind a short LM for example, CD2:CD2BP interaction (KD = μM) [54]. "
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