InterPro domain: IPR003169

The glycine-tyrosine-phenylalanine (GYF) domain is an around 60-amino acid domain which contains a conserved GP[YF]xxxx[MV]xxWxxx[GN]YF motif. It was identified in the human intracellular protein termed CD2 binding protein 2 (CD2BP2), which binds to a site containing two tandem PPPGHR segments within the cytoplasmic region of CD2. Binding experiments and mutational analyses have demonstrated the critical importance of the GYF tripeptide in ligand binding. A GYF domain is also found in several other eukaryotic proteins of unknown function [ 1 ]. It has been proposed that the GYF domain found in these proteins could also be involved in proline-rich sequence recognition [ 2 ].

Resolution of the structure of the CD2BP2 GYF domain by NMR spectroscopy revealed a compact domain with a beta-beta-alpha-beta-beta topology, where the single alpha-helix is tilted away from the twisted, anti-parallel beta-sheet. The conserved residues of the GYF domain create a contiguous patch of predominantly hydrophobic nature which forms an integral part of the ligand-binding site [ 3 ]. There is limited homology within the C-terminal 20-30 amino acids of various GYF domains, supporting the idea that this part of the domain is structurally but not functionally important [ 3 ].

1. Identification of a proline-binding motif regulating CD2-triggered T lymphocyte activation. Proc. Natl. Acad. Sci. U.S.A. 95, 14897-902
2. The GYF domain is a novel structural fold that is involved in lymphoid signaling through proline-rich sequences. Nat. Struct. Biol. 6, 656-60
3. Dynamic interaction of CD2 with the GYF and the SH3 domain of compartmentalized effector molecules. EMBO J. 21, 5985-95