title: Concerted action of the ribosome and the associated chaperone trigger factor confines nascent polypeptide folding.
abstract: How nascent polypeptides emerging from ribosomes fold into functional structures is poorly understood. Here, we monitor disulfide bond formation, protease resistance, and enzymatic activity in nascent polypeptides to show that in close proximity to the ribosome, conformational space and kinetics of folding are restricted. Folding constraints decrease incrementally with distance from the ribosome surface. Upon ribosome binding, the chaperone Trigger Factor counters folding also of longer nascent chains, to extents varying between different chain segments. Trigger Factor even binds and unfolds pre-existing folded structures, the unfolding activity being limited by the thermodynamic stability of nascent chains. Folding retardation and unfolding activities are not shared by the DnaK chaperone assisting later folding steps. These ribosome- and Trigger Factor-specific activities together constitute an efficient mechanism to prevent or even revert premature folding, effectively limiting misfolded intermediates during protein synthesis.
authors.affiliation: Center for Molecular Biology of the University of Heidelberg, German Cancer Research Center, DKFZ-ZMBH Alliance, Heidelberg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Hoffmann
authors.forename: Annemarie H
authors.initials: AH
authors.lastname: Becker
authors.forename: Beate
authors.initials: B
authors.lastname: Zachmann-Brand
authors.forename: Elke
authors.initials: E
authors.lastname: Deuerling
authors.forename: Bernd
authors.initials: B
authors.lastname: Bukau
authors.forename: Günter
authors.initials: G
authors.lastname: Kramer
mesh_terms: D001426:Bacterial Proteins; D004220:Disulfides / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism; D008954:Models, Biological; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry / Q000378:metabolism; D019696:Peptidylprolyl Isomerase / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D012260:Ribonucleases / Q000737:chemistry / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism*; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D004220:Disulfides; D029968:Escherichia coli Proteins; D018840:HSP70 Heat-Shock Proteins; D018832:Molecular Chaperones; D013762:Tetrahydrofolate Dehydrogenase; D012260:Ribonucleases; C019760:Bacillus amyloliquefaciens ribonuclease; C063842:dnaK protein, E coli; C403324:trigger factor, E coli; D019696:Peptidylprolyl Isomerase