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See detailCyclophilin a binds to linear peptide motifs containing a consensus that is present in many human proteins
Piotukh, K.; Gu, Wei UL; Kofler, M. et al

in Journal of Biological Chemistry (2005), 280(25), 23668-23674

Cyclophilin A ( CypA) is a peptidyl-prolyl cis/trans-isomerase that is involved in multiple signaling events of eukaryotic cells. It might either act as a catalyst for prolyl bond isomerization, or it can ... [more ▼]

Cyclophilin A ( CypA) is a peptidyl-prolyl cis/trans-isomerase that is involved in multiple signaling events of eukaryotic cells. It might either act as a catalyst for prolyl bond isomerization, or it can form stoichiometric complexes with target proteins. We have investigated the linear sequence recognition code for CypA by phage display and found the consensus motif FGPXLp to be selected after five rounds of panning. The peptide FGP-DLPAGD showed inhibition of the isomerase reaction and NMR chemical shift mapping experiments highlight the CypA interaction epitope. Ligand docking suggests that the peptide was able to bind to CypA in the cis- and trans-conformation. Protein Data Bank searches reveal that many human proteins contain the consensus motif, and several of these protein motifs are shown to interact with CypA in vitro. These sequences represent putative target sites for binding of CypA to intracellular proteins. [less ▲]

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See detailAlternative binding modes of proline-rich peptides binding to the GYF domain
Gu, Wei UL; Kofler, M.; Antes, I. et al

in Biochemistry (2005), 44(17), 6404-6415

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 ... [more ▼]

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 at. (2004) J. Biol. Chem. 279, 28292-28297]. In our combined theoretical and experimental study, we show that the peptides adopt a polyproline 11 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. [less ▲]

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