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Cell. 2017 Jul 13;170(2):298-311.e20. doi: 10.1016/j.cell.2017.06.038.

Profiling Ssb-Nascent Chain Interactions Reveals Principles of Hsp70-Assisted Folding.

Author information

1
Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, Heidelberg, Germany; German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany.
2
Bioinformatics and Genomics Graduate Program, The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, USA.
3
Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, Heidelberg, Germany; German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany; The Donnelly Centre, University of Toronto, 160 College Street, Toronto ON, Canada.
4
Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, Heidelberg, Germany.
5
Institute of Biochemistry, University of Cologne, Zuelpicher Str. 47, Cologne, Germany.
6
Bioinformatics and Genomics Graduate Program, The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, USA; Department of Chemistry, Pennsylvania State University, University Park, PA, USA.
7
Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, Heidelberg, Germany; German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany. Electronic address: g.kramer@zmbh.uni-heidelberg.de.
8
Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, Heidelberg, Germany; German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany. Electronic address: bukau@zmbh.uni-heidelberg.de.

Abstract

The yeast Hsp70 chaperone Ssb interacts with ribosomes and nascent polypeptides to assist protein folding. To reveal its working principle, we determined the nascent chain-binding pattern of Ssb at near-residue resolution by in vivo selective ribosome profiling. Ssb associates broadly with cytosolic, nuclear, and hitherto unknown substrate classes of mitochondrial and endoplasmic reticulum (ER) nascent proteins, supporting its general chaperone function. Ssb engages most substrates by multiple binding-release cycles to a degenerate sequence enriched in positively charged and aromatic amino acids. Timely association with this motif upon emergence at the ribosomal tunnel exit requires ribosome-associated complex (RAC) but not nascent polypeptide-associated complex (NAC). Ribosome footprint densities along orfs reveal faster translation at times of Ssb binding, mainly imposed by biases in mRNA secondary structure, codon usage, and Ssb action. Ssb thus employs substrate-tailored dynamic nascent chain associations to coordinate co-translational protein folding, facilitate accelerated translation, and support membrane targeting of organellar proteins.

KEYWORDS:

Hsp70; NAC; RAAC; Selective ribosome profiling; Ssb; chaperone; co-translational folding; translation

PMID:
28708998
DOI:
10.1016/j.cell.2017.06.038
[Indexed for MEDLINE]
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