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4-Fluoroproline derivative peptides: effect on PPII conformation and SH3 affinity

DOI: 10.1002/psc.750 DOI Help
PMID: 16506148 PMID Help

Authors: Paolo Ruzza (Institute of Biomolecular Chemistry, Padova, Italy) , Giuliano Siligardi (Diamond Light Source) , Arianna Donella-deana (Department of Biological Chemistry, University of Padua) , Andrea Calderan (Institute of Biomolecular Chemistry, Padua Unit, CNR) , Rohanah Hussain (Diamond Light Source) , Chiara Rubini (Institute of Biomolecular Chemistry of CNR, Padova Unit, 35131 Padova, Italy) , Luca Cesaro (Department of Biological Chemistry, University of Padua) , Alessio Osler (Institute of Biomolecular Chemistry, Padua Unit, CNR) , Andrea Guiotto (Institute of Biomolecular Chemistry, Padua Unit, CNR) , Lorenzo A. Pinna (Department of Biological Chemistry, University of Padua) , Gianfranco Borin (Institute of Biomolecular Chemistry, Padua Unit, CNR)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Peptide Science , VOL 12 (7) , PAGES 462-471

State: Published (Approved)
Published: July 2006

Abstract: Eukaryotic signal transduction involves the assembly of transient protein-protein complexes mediated by modular interaction domains. Specific Pro-rich sequences with the consensus core motif PxxP adopt the PPII helix conformation upon binding to SH3 domains. For short Pro-rich peptides, little or no ordered secondary structure is usually observed before binding interactions. The association of a Pro-rich peptide with the SH3 domain involves unfavorable binding entropy due to the loss of rotational freedom on forming the PPII helix. With the aim of stabilizing the PPII helix conformation in the Pro-rich HPKI decapeptide PPPLPPKPKF (P2), a series of P2 analogues was prepared, in which specific Pro positions were alternatively occupied by 4(S)- or 4(R)-4-fluoro-L-proline. The interactions of these peptides with the SH3 domain of the HPK1-binding partner HS1 were quantitatively analyzed by the NILIA-CD approach. A CD thermal analysis of the P2 analogues was performed to assess their propensity to adopt the PPII helix conformation. Contrary to our expectations, the K-d values of the analogues were lower than that of the parent peptide P2. These results clearly show that the induction of a stable PPII helix conformation in short Pro-rich peptides is not sufficient to increase their affinity toward the SH3 domain and that the effect of 4-fluoroproline strongly depends on the position of this residue in the sequence and the chirality of the substituent in the pyrrolidine ring. Copyright (c) 2006 European Peptide Society and John Wiley & Sons, Ltd.

Journal Keywords: 4-Fluoroproline; Hs1; Nilia-Cd; Protein–Peptide Interactions; Sh3 Domain

Subject Areas: Biology and Bio-materials, Chemistry


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