Interactions between nascent proteins translated by adjacent ribosomes drive homomer assembly

Bertolini, Matilde; Fenzl, Kai; Kats, Ilia; Wruck, Florian; Tippmann, Frank; Schmitt, Jaro; Auburger, Josef J.; Tans, Sander J.; Bukau, Bernd; Krämer, Günter

doi:10.1126/science.abc7151

Cited by 92 publications

(203 citation statements)

References 58 publications

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“…On the basis of our current understanding, we propose that the Sec61 complex provides the central component of this flexible platform, acting as a dynamic hub for membrane translocation at the ER. This begs the question as to how alternative membrane insertion pathways or particular Sec61-assistants are engaged by different client TMPs and how their actions can be co-ordinated; a feat that becomes increasingly complex when one considers the recent finding that both homomeric and heteromeric TMP complexes can begin their assembly co-translationally [129,130].…”

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confidence: 99%

Membrane protein biogenesis at the ER: the highways and byways

2021

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The Sec61 complex is the major protein translocation channel of the endoplasmic reticulum (ER), where it plays a central role in the biogenesis of membrane and secretory proteins. Whilst Sec61-mediated protein translocation is typically coupled to polypeptide synthesis, suggestive of significant complexity, an obvious characteristic of this core translocation machinery is its surprising simplicity. Over thirty years after its initial discovery, we now understand that the Sec61 complex is in fact the central piece of an elaborate jigsaw puzzle, which can be partly solved using new research findings. We propose that the Sec61 complex acts as a dynamic hub for cotranslational protein translocation at the ER, proactively recruiting a range of accessory complexes that enhance and regulate its function in response to different protein clients. It is now clear that the Sec61 complex does not have a monopoly on co-translational insertion, with some transmembrane proteins preferentially utilising the ER membrane complex instead. We also have a better understanding of post-insertion events, where at least one membrane-embedded chaperone complex can capture the newly inserted transmembrane domains of multi-span proteins and co-ordinate their assembly into a native structure. Having discovered this array of Sec61-associated components and competitors, our next challenge is to understand how they act together in order to expand the range and complexity of the membrane proteins that can be synthesised at the ER. Furthermore, this diversity of components and pathways may open up new opportunities for targeted therapeutic interventions designed to selectively modulate protein biogenesis at the ER. AbbreviationsBiP, immunoglobulin binding protein; CCDC47, coiled-coil domain containing 47 protein, also known as calumin; EMC, ER membrane complex; ER, endoplasmic reticulum; GET, guided entry of tail-anchored proteins; hSnd2, human SRP-independent protein 2, also known as TMEM208; NAC, nascent polypeptide-associated complex; NOMO, nodal modulating protein; PAT, protein associated with the ER translocon; RNC, ribosome-nascent chain; SGTA, small glutamine-rich tetratricopeptide repeat-containing protein alpha; SND, SRPindependent proteins or pathway; SPC, signal peptidase complex; SRP, signal recognition particle; TA, tail-anchored; TMCO1, transmembrane and coiled-coil domains 1 protein; TMD, transmembrane domain; TMEM147, transmembrane protein 147; TMEM208, transmembrane protein 208; TMP, transmembrane protein; TRAM, translocating chain-associated membrane protein; TRAP, transloconassociated protein; TRC40, transmembrane recognition complex of 40 kDa, also known as Asna1.

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confidence: 99%

Membrane protein biogenesis at the ER: the highways and byways

2021

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“…Co-translational binding of the synthesized protein with its future functional partners has long been known for polycistronic mRNAs of prokaryotes—however, it also turned out to be quite common in the eukaryotic world [ 197 ]. This is true not only for the products synthesized by neighboring ribosomes from the same transcript [ 198 ], but also, more importantly, for the products encoded by different mRNAs. This was shown for the first time for several hetero-oligomeric complexes in yeast [ 199 – 201 ], then it was confirmed for membrane [ 202 ], nuclear [ 203 ] and cytoplasmic [ 204 – 206 ] protein complexes in human cells.…”

Section: Cytosolic Ribonucleoprotein Granules and “Translation Factories” As A Platform For Mrna Localization And Translationmentioning

confidence: 99%

mRNA Targeting, Transport and Local Translation in Eukaryotic Cells: From the Classical View to a Diversity of New Concepts

Lashkevich

Dmitriev

2021

Mol Biol

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Spatial organization of protein biosynthesis in the eukaryotic cell has been studied for more than fifty years, thus many facts have already been included in textbooks. According to the classical view, mRNA transcripts encoding secreted and transmembrane proteins are translated by ribosomes associated with endoplasmic reticulum membranes, while soluble cytoplasmic proteins are synthesized on free polysomes. However, in the last few years, new data has emerged, revealing selective translation of mRNA on mitochondria and plastids, in proximity to peroxisomes and endosomes, in various granules and at the cytoskeleton (actin network, vimentin intermediate filaments, microtubules and centrosomes). There are also long-standing debates about the possibility of protein synthesis in the nucleus. Localized translation can be determined by targeting signals in the synthesized protein, nucleotide sequences in the mRNA itself, or both. With RNA-binding proteins, many transcripts can be assembled into specific RNA condensates and form RNP particles, which may be transported by molecular motors to the sites of active translation, form granules and provoke liquid-liquid phase separation in the cytoplasm, both under normal conditions and during cell stress. The translation of some mRNAs occurs in specialized “translation factories,” assemblysomes, transperons and other structures necessary for the correct folding of proteins, interaction with functional partners and formation of oligomeric complexes. Intracellular localization of mRNA has a significant impact on the efficiency of its translation and presumably determines its response to cellular stress. Compartmentalization of mRNAs and the translation machinery also plays an important role in viral infections. Many viruses provoke the formation of specific intracellular structures, virus factories, for the production of their proteins. Here we review the current concepts of the molecular mechanisms of transport, selective localization and local translation of cellular and viral mRNAs, their effects on protein targeting and topogenesis, and on the regulation of protein biosynthesis in different compartments of the eukaryotic cell. Special attention is paid to new systems biology approaches, providing new cues to the study of localized translation.

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“…Two main modes of cotranslational complex assembly can be distinguished, based on the synthesis state of the interaction partners. One mode is the assembly of a nascent and one fully synthesized polypeptide, recently termed co-post assembly ( Bertolini et al, 2021 ). The alternative mode, termed co-co assembly, involves the interaction of two nascent chains ( Figure 3 ).…”

Section: Cotranslational Formation Of Protein Complexesmentioning

confidence: 99%

“…Using a ribosome profiling-based method, a recent study showed that also the alternative cotranslational assembly mode, co-co assembly, is a prevalent mechanism employed for the assembly of many homomeric protein complexes in human cells ( Bertolini et al, 2021 ). The study presented evidence that co-co assembly promotes the isoform-specific formation of homomeric complexes, an effect that was previously suggested to mitigate the impact of dominant-negative mutations in the tumor suppressor p53 ( Nicholls et al, 2002 ).…”

Section: Cotranslational Formation Of Protein Complexesmentioning

confidence: 99%

“…Importantly, co-co assembly of human lamins could be recapitulated by heterologous expression in E. coli , indicating that co-co assembly is compatible with bacterial translation and the chaperone machineries and may be employed to assemble bacterial protein complexes. Co-co assembly may be mostly employed to assemble homomers with N-terminal oligomerization domains, presumably by the interaction of nascent proteins synthesized by nearby ribosomes on the same mRNA ( Bertolini et al, 2021 ). Ensuring efficient, isoform-specific interactions might in fact be a primary function of co-co assembly.…”

Section: Cotranslational Formation Of Protein Complexesmentioning

confidence: 99%

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Mechanisms of Cotranslational Protein Maturation in Bacteria

Koubek

Schmitt

Galmozzi

2021

Front. Mol. Biosci.

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Growing cells invest a significant part of their biosynthetic capacity into the production of proteins. To become functional, newly-synthesized proteins must be N-terminally processed, folded and often translocated to other cellular compartments. A general strategy is to integrate these protein maturation processes with translation, by cotranslationally engaging processing enzymes, chaperones and targeting factors with the nascent polypeptide. Precise coordination of all factors involved is critical for the efficiency and accuracy of protein synthesis and cellular homeostasis. This review provides an overview of the current knowledge on cotranslational protein maturation, with a focus on the production of cytosolic proteins in bacteria. We describe the role of the ribosome and the chaperone network in protein folding and how the dynamic interplay of all cotranslationally acting factors guides the sequence of cotranslational events. Finally, we discuss recent data demonstrating the coupling of protein synthesis with the assembly of protein complexes and end with a brief discussion of outstanding questions and emerging concepts in the field of cotranslational protein maturation.

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Interactions between nascent proteins translated by adjacent ribosomes drive homomer assembly

Cited by 92 publications

References 58 publications

Membrane protein biogenesis at the ER: the highways and byways

Membrane protein biogenesis at the ER: the highways and byways

mRNA Targeting, Transport and Local Translation in Eukaryotic Cells: From the Classical View to a Diversity of New Concepts

Mechanisms of Cotranslational Protein Maturation in Bacteria

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