title: Structure and activity of the peptidyl-prolyl isomerase domain from the histone chaperone Fpr4 toward histone H3 proline isomerization.
abstract: The FK506-binding protein (FKBP) family of peptidyl-prolyl isomerases (PPIases) is characterized by a common catalytic domain that binds to the inhibitors FK506 and rapamycin. As one of four FKBPs within the yeast Saccharomyces cerevisiae, Fpr4 has been described as a histone chaperone, and is in addition implicated in epigenetic function in part due to its mediation of cis-trans conversion of proline residues within histone tails. To better understand the molecular details of this activity, we have determined the solution structure of the Fpr4 C-terminal PPIase domain by using NMR spectroscopy. This canonical FKBP domain actively increases the rate of isomerization of three decapeptides derived from the N terminus of yeast histone H3, whereas maintaining intrinsic cis and trans populations. Observation of the uncatalyzed and Fpr4-catalyzed isomerization rates at equilibrium demonstrate Pro(16) and Pro(30) of histone H3 as the major proline targets of Fpr4, with little activity shown against Pro(38). This alternate ranking of the three target prolines, as compared with affinity determination or the classical chymotrypsin-based fluorescent assay, reveals the mechanistic importance of substrate residues C-terminal to the peptidyl-prolyl bond.
authors.affiliation: From the Institut Européen de Chimie et Biologie, 2 rue Robert Escarpit, 33607 Pessac, France.
authors.forename: Yoan R
authors.initials: YR
authors.lastname: Monneau
authors.affiliation: From the Institut Européen de Chimie et Biologie, 2 rue Robert Escarpit, 33607 Pessac, France,; the INSERM U869, University of Bordeaux, 33076 Bordeaux, France, and.
authors.forename: Heddy
authors.initials: H
authors.lastname: Soufari
authors.affiliation: the Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia V8W 3P6, Canada.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Nelson
authors.affiliation: From the Institut Européen de Chimie et Biologie, 2 rue Robert Escarpit, 33607 Pessac, France,; the INSERM U869, University of Bordeaux, 33076 Bordeaux, France, and. Electronic address: c.mackereth@iecb.u-bordeaux.fr.
authors.forename: Cameron D
authors.initials: CD
authors.lastname: Mackereth
mesh_terms: D002384:Catalysis; D056488:Histone Chaperones / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D019696:Peptidylprolyl Isomerase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011392:Proline / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D022021:Tacrolimus Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D056488:Histone Chaperones; D006657:Histones; D029701:Saccharomyces cerevisiae Proteins; D011392:Proline; D022021:Tacrolimus Binding Proteins; C513494:Fpr4 protein, S cerevisiae; D019696:Peptidylprolyl Isomerase
keywords: Epigenetics; FKBP; Histones; NMR; Prolyl Isomerase; Protein Structure