title: Alternative binding modes of proline-rich peptides binding to the GYF domain.
abstract: Recognition of proline-rich sequences plays an important role for the assembly of multiprotein complexes during the course of eukaryotic signal transduction and is mediated by a set of protein folds that share characteristic features. The GYF (glycine-tyrosine-phenylalanine) domain is known as a member of the superfamily of recognition domains for proline-rich sequences. Recent studies on the complexation of the CD2BP2-GYF domain with CD2 peptides showed that the peptide adopts an extended conformation and forms a polyproline type-II helix involving residues Pro4-Pro7 [Freund et al. (2002) EMBO J. 21, 5985-5995]. R/K/GxxPPGxR/K is the key signature for the peptides that bind to the GYF domain [Kofler et al. (2004) J. Biol. Chem. 279, 28292-28297]. In our combined theoretical and experimental study, we show that the peptides adopt a polyproline II helical conformation in the unbound form as well as in the complex. From molecular dynamics simulations, we identify a novel binding mode for the G8W mutant and the wild-type peptide (shifted by one proline in register). In contrast, the conformation of the peptide mutant H9M remains close to the experimentally derived wild-type GYF-peptide complex. Possible functional implications of this altered conformation of the bound ligand are discussed in the light of our experimental and theoretical results.
authors.affiliation: Zentrum für Bioinformatik, Universität des Saarlandes, D-66041 Saarbrücken, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
authors.forename: Michael
authors.initials: M
authors.lastname: Kofler
authors.forename: Iris
authors.initials: I
authors.lastname: Antes
authors.forename: Christian
authors.initials: C
authors.lastname: Freund
authors.forename: Volkhard
authors.initials: V
authors.lastname: Helms
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs / Q000235:genetics; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D018801:CD2 Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D003198:Computer Simulation; D005998:Glycine / Q000235:genetics; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010649:Phenylalanine; D011485:Protein Binding / Q000235:genetics; D011487:Protein Conformation; D017434:Protein Structure, Tertiary / Q000235:genetics; D012997:Solvents; D013816:Thermodynamics; D014443:Tyrosine
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018801:CD2 Antigens; C120378:CD2BP2 protein, human; D002352:Carrier Proteins; D008024:Ligands; D010455:Peptides; D012997:Solvents; C011083:polyproline; D014443:Tyrosine; D010649:Phenylalanine; D005998:Glycine