Fidelity of Cotranslational Protein Targeting to the Endoplasmic Reticulum.

Hao-Hsuan Hsieh,Shu-ou Shan

doi:10.3390/ijms23010281

Hao-Hsuan Hsieh, Shu-ou Shan

Open Access

https://doi.org/10.3390/ijms23010281

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Abstract

Fidelity of protein targeting is essential for the proper biogenesis and functioning of organelles. Unlike replication, transcription and translation processes, in which multiple mechanisms to recognize and reject noncognate substrates are established in energetic and molecular detail, the mechanisms by which cells achieve a high fidelity in protein localization remain incompletely understood. Signal recognition particle (SRP), a conserved pathway to mediate the localization of membrane and secretory proteins to the appropriate cellular membrane, provides a paradigm to understand the molecular basis of protein localization in the cell. In this chapter, we review recent progress in deciphering the molecular mechanisms and substrate selection of the mammalian SRP pathway, with an emphasis on the key role of the cotranslational chaperone NAC in preventing protein mistargeting to the ER and in ensuring the organelle specificity of protein localization.

Highlights

Over ~30% of the newly synthesized proteins in eukaryotic cells are initially delivered to the endoplasmic reticulum (ER) membrane, where they initiate their journeys through the endomembrane system including the ER, the Golgi apparatus, secretory vesicles, and the plasma membrane [1,2]
We review recent progress in understanding the molecular mechanism and substrate selection of the eukaryotic signal recognition particle (SRP) pathway, with an emphasis on results demonstrating how regulation of SRP by the cotranslational chaperone NAC enhances the fidelity of protein targeting to the ER
These include allosteric regulation by macromolecular crowding at the ribosome exit site, kinetic competition with translation elongation, rivalry of opposing targeting pathways with overlapping but distinct substrate preferences, and surveillance and error correction mechanisms at the organelle membrane

Summary

Introduction

Over ~30% of the newly synthesized proteins in eukaryotic cells are initially delivered to the endoplasmic reticulum (ER) membrane, where they initiate their journeys through the endomembrane system including the ER, the Golgi apparatus, secretory vesicles, and the plasma membrane [1,2]. We review recent progress in understanding the molecular mechanism and substrate selection of the eukaryotic SRP pathway, with an emphasis on results demonstrating how regulation of SRP by the cotranslational chaperone NAC enhances the fidelity of protein targeting to the ER Based on these and recent work on related pathways, we suggest that cells evolved multiple mechanisms to overcome the physicochemical challenges in recognizing degenerate targeting signals. These include allosteric regulation by macromolecular crowding at the ribosome exit site, kinetic competition with translation elongation, rivalry of opposing targeting pathways with overlapping but distinct substrate preferences, and surveillance and error correction mechanisms at the organelle membrane. It is likely that each individual mechanism generates a modest degree of specificity, but collectively, the combination of these mechanisms ensures the accuracy of membrane protein localization and organelle biogenesis

SRP-Dependent Cotranslational Protein Targeting

NAC: A Triage Factor during Cotranslational Protein Targeting

Perspectives and Open Questions