A ribosome-associated chaperone enables substrate triage in a cotranslational protein targeting complex.

Nature Communications
Hao-Hsuan HsiehShu-Ou Shan

Abstract

Protein biogenesis is essential in all cells and initiates when a nascent polypeptide emerges from the ribosome exit tunnel, where multiple ribosome-associated protein biogenesis factors (RPBs) direct nascent proteins to distinct fates. How distinct RPBs spatiotemporally coordinate with one another to affect accurate protein biogenesis is an emerging question. Here, we address this question by studying the role of a cotranslational chaperone, nascent polypeptide-associated complex (NAC), in regulating substrate selection by signal recognition particle (SRP), a universally conserved protein targeting machine. We show that mammalian SRP and SRP receptors (SR) are insufficient to generate the biologically required specificity for protein targeting to the endoplasmic reticulum. NAC co-binds with and remodels the conformational landscape of SRP on the ribosome to regulate its interaction kinetics with SR, thereby reducing the nonspecific targeting of signalless ribosomes and pre-emptive targeting of ribosomes with short nascent chains. Mathematical modeling demonstrates that the NAC-induced regulations of SRP activity are essential for the fidelity of cotranslational protein targeting. Our work establishes a molecular model for how ...Continue Reading

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Citations

May 8, 2021·The FEBS Journal·Sarah O'KeefeStephen High
Sep 25, 2021·Nature Reviews. Molecular Cell Biology·Ramanujan S Hegde, Robert J Keenan

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Methods Mentioned

BETA
GTPase
protein folding
affinity purification
FRET
Fluorescence
in vitro transcription
size exclusion chromatography
in
PCR
Assay

Software Mentioned

MicroManager
Chimera

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