Journal Article

DKFZ-2025-00967

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Proteome-wide determinants of co-translational chaperone binding in bacteria.

Galmozzi, C. V. ; Tippmann, F. ; Wruck, F. ; Auburger, J. J. ; Kats, I.DKFZ* ; Guennigmann, M. ; Till, K. ; O Brien, E. P. ; Tans, S. J. ; Kramer, G. ; Bukau, B.DKFZ*

2025
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41467-025-59067-9

Abstract: Chaperones are essential to the co-translational folding of most proteins. However, the principles of co-translational chaperone interaction throughout the proteome are poorly understood, as current methods are restricted to few substrates and cannot capture nascent protein folding or chaperone binding sites, precluding a comprehensive understanding of productive and erroneous protein biosynthesis. Here, by integrating genome-wide selective ribosome profiling, single-molecule tools, and computational predictions using AlphaFold we show that the binding of the main E. coli chaperones involved in co-translational folding, Trigger Factor (TF) and DnaK correlates with 'unsatisfied residues' exposed on nascent partial folds - residues that have begun to form tertiary structure but cannot yet form all native contacts due to ongoing translation. This general principle allows us to predict their co-translational binding across the proteome based on sequence only, which we verify experimentally. The results show that TF and DnaK stably bind partially folded rather than unfolded conformers. They also indicate a synergistic action of TF guiding intra-domain folding and DnaK preventing premature inter-domain contacts, and reveal robustness in the larger chaperone network (TF, DnaK, GroEL). Given the complexity of translation, folding, and chaperone functions, our predictions based on general chaperone binding rules indicate an unexpected underlying simplicity.

Keyword(s): Escherichia coli Proteins: metabolism (MeSH) ; Escherichia coli Proteins: genetics (MeSH) ; Escherichia coli Proteins: chemistry (MeSH) ; Proteome: metabolism (MeSH) ; Proteome: genetics (MeSH) ; Escherichia coli: metabolism (MeSH) ; Escherichia coli: genetics (MeSH) ; Protein Folding (MeSH) ; HSP70 Heat-Shock Proteins: metabolism (MeSH) ; HSP70 Heat-Shock Proteins: genetics (MeSH) ; HSP70 Heat-Shock Proteins: chemistry (MeSH) ; Protein Binding (MeSH) ; Molecular Chaperones: metabolism (MeSH) ; Molecular Chaperones: genetics (MeSH) ; Protein Biosynthesis (MeSH) ; Ribosomes: metabolism (MeSH) ; Peptidylprolyl Isomerase: metabolism (MeSH) ; Peptidylprolyl Isomerase: genetics (MeSH) ; Binding Sites (MeSH) ; Escherichia coli Proteins ; Proteome ; dnaK protein, E coli ; trigger factor, E coli ; HSP70 Heat-Shock Proteins ; Molecular Chaperones ; Peptidylprolyl Isomerase

Note: DKFZ-ZMBH Alliance / #LA:Z999#

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Contributing Institute(s):

1. B260 Bioinformatik der Genomik und Systemgenetik (B260)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2025

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