Journal
EMBO JOURNAL
Volume 21, Issue 22, Pages 5985-5995Publisher
OXFORD UNIV PRESS
DOI: 10.1093/emboj/cdf602
Keywords
CD2; GYF domain; lipid rafts; NMR; SH3 domain
Categories
Funding
- NCRR NIH HHS [RR 00995] Funding Source: Medline
- NIAID NIH HHS [R01 AI019807, R56 AI019807, AI 19807, AI 37581, R37 AI019807, R01 AI037581] Funding Source: Medline
- NIGMS NIH HHS [GM 47467, P01 GM047467] Funding Source: Medline
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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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