InterPro domain: IPR035445

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 ].

This entry also matches Arabidopsis histone methyltransferases ATXR3/SDG2 and ATXR7/SDG25, which contain two partial GYF domains towards the N terminus [ 4 ]. Histone methyltransferase ATXR7 is involved in regulation of flowering time [ 5 ]. It is specifically required for the trimethylation of 'Lys-4' of histone H3 (H3K4me3) at the FLC locus, it prevents the trimethylation on 'Lys-27' (H3K27me3) at the same locus. ATXR3 is also required for H3K4 trimethylation and is crucial for both sporophyte and gametophyte development in plants [ 6 , 7 ].

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
4. Comparative analysis of SET domain proteins in maize and Arabidopsis reveals multiple duplications preceding the divergence of monocots and dicots. Plant Physiol. 132, 907-25
5. ARABIDOPSIS TRITHORAX-RELATED7 is required for methylation of lysine 4 of histone H3 and for transcriptional activation of FLOWERING LOCUS C. Plant Cell 21, 3257-69
6. Arabidopsis SET DOMAIN GROUP2 is required for H3K4 trimethylation and is crucial for both sporophyte and gametophyte development. Plant Cell 22, 3232-48
7. SET DOMAIN GROUP2 is the major histone H3 lysine [corrected] 4 trimethyltransferase in Arabidopsis. Proc. Natl. Acad. Sci. U.S.A. 107, 18557-62