Co-translational assembly of mammalian nuclear multisubunit complexes

Kamenova, Ivanka; Mukherjee, Pooja; Conic, Sascha; Mueller, Florian; El-Saafin, Farrah; Bardot, Paul; Garnier, Jean‐Marie; Dembelé, Doulaye; Capponi, Simona; Timmers, H. Th. Marc; Vincent, Stéphane; Tora, Làszlò

doi:10.1038/s41467-019-09749-y

Cited by 101 publications

(177 citation statements)

References 55 publications

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“…Indeed some proteins are by themselves toxic to the cell [112] or unstable, intrinsically disordered and prone to aggregation [2,113]. Recent studies suggest that several mammalian nuclear transcription complexes assemble cotranslationally [114]. A systematic study of eukaryotic subunit assembly during translation by selective ribosome profiling shows that out of 12 hetero-oligomeric complexes studied, nine assembled cotranslationally and the remainder assembled with chaperone assistance [26].…”

Section: Cotranslational Subunits Assemblymentioning

confidence: 99%

Cotranslational Folding of Proteins on the Ribosome

2020

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Many proteins in the cell fold cotranslationally within the restricted space of the polypeptide exit tunnel or at the surface of the ribosome. A growing body of evidence suggests that the ribosome can alter the folding trajectory in many different ways. In this review, we summarize the recent examples of how translation affects folding of single-domain, multiple-domain and oligomeric proteins. The vectorial nature of translation, the spatial constraints of the exit tunnel, and the electrostatic properties of the ribosome-nascent peptide complex define the onset of early folding events. The ribosome can facilitate protein compaction, induce the formation of intermediates that are not observed in solution, or delay the onset of folding. Examples of single-domain proteins suggest that early compaction events can define the folding pathway for some types of domain structures. Folding of multi-domain proteins proceeds in a domain-wise fashion, with each domain having its role in stabilizing or destabilizing neighboring domains. Finally, the assembly of protein complexes can also begin cotranslationally. In all these cases, the ribosome helps the nascent protein to attain a native fold and avoid the kinetic traps of misfolding.

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Section: Cotranslational Subunits Assemblymentioning

confidence: 99%

Cotranslational Folding of Proteins on the Ribosome

2020

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“…Our data also suggests that triggering iSRC by mild proteostasis stress may offer an opportunity to ameliorate OxPhos-deficiency in mitochondrial diseases. On the other hand, many protein complexes assemble co-translationally to prevent aggregation of free subunits (Kamenova et al, 2019;Shiber et al, 2018). Nuclear-encoded RC-subunits do not enjoy that opportunity as these are imported from cytoplasm before their assembly inside mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Improved Supra-Organization Is A Conformational And Functional Adaptation Of Respiratory Complexes

Rawat

Ghosh

Mondal

et al. 2020

Preprint

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Multiple surveillance mechanisms accelerate proteasome mediated degradation of misfolded proteins to prevent protein aggregation inside and outside mitochondria. But how cells safeguard mitochondrial function despite increased protein aggregation during proteasome inactivation? Here, using two-dimensional complexome profiling, we extensively characterize the dynamic states of respiratory complexes (RCs) in proteasome-inhibited cells.We report that RC-subunits are increasingly integrated into supra-organizations to optimize catalytic activity simultaneous to their aggregation inside mitochondria. Complex-II (CII) and CV are incorporated into oligomers. CI, CIII, and CIV subcomplexes are associated into holocomplexes followed by integration into supercomplexes. Time-course experiments reveal that the core (CI+CIII 2 ) stoichiometry of supercomplex (I+III 2 +IV) is preserved during earlystress while CIV composition varies. Simultaneously, increased CI-activity suggests conformational optimization of supercomplexes for better function. Re-establishment of steady-state stoichiometry and relative increase in supercomplex-quantity consolidates functional adaptation during prolonged proteasome-inhibition. Together, we name this preemptive adaptive mechanism as 'improved Supra-organization of Respiratory Complexes' (iSRC). We find that iSRC is active in multiple protein-unfolding stresses, in multiple celltypes that differ in proteostatic and metabolic demands, and reversible upon stresswithdrawal.

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“…It was shown that unassembled proteins are prone to degradation through exposure of degrons that are normally shielded when in complex [64]. Alternatively, studies in bacteria, yeast and mammalian cells suggest many multi-subunit complexes are built during translation, where proteins undergoing translation already begin interacting with their partners [65][66][67]. Preventing cotranslational binding and folding often results in degradation of the translating partners, suggesting a competition between protein folding and complex formation with degradation.…”

Section: Discussionmentioning

confidence: 99%

N-terminal protein acetylation by NatB modulates the levels of Nmnats, the NAD⁺biosynthetic enzymes inSaccharomyces cerevisiae

Croft

Venkatakrishnan

Raj

et al. 2019

Preprint

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ABSTRACTNAD+ is an essential metabolite participating in cellular biochemical processes and signaling. The regulation and interconnection among multiple NAD+ biosynthesis pathways are not completely understood. We previously identified the N-terminal (Nt) protein acetyltransferase complex NatB as a NAD+ homeostasis factor. Cells lacking NatB show an approximate 50% reduction in the NAD+ level and aberrant metabolism of NAD+ precursors, which are associated with a decrease of nicotinamide mononucleotide adenylyltransferases (Nmnat) protein levels. Here we show this decrease in NAD+ and Nmnat protein levels is specifically due to the absence of Nt-acetylation of Nmnat (Nma1 and Nma2) proteins, and not other NatB substrates. Nt-acetylation is a critical regulator of protein degradation by the N-end rule pathways, indicating absence of Nt-acetylation may alter Nmnat protein stability. Interestingly, the rate of protein turnover (t1/2) of non-Nt-acetylated Nmnats does not significantly differ from Nt-acetylated Nmnats, suggesting reduced Nmnat levels in NmatB mutants are not due to increased post-translational degradation of non-Nt-acetylated Nmnats. In line with these observations, deletion or depletion of N-rule pathway ubiquitin E3 ligases in NatB mutants is not sufficient to restore NAD+ levels. Moreover, the status of Nt-acetylation does not alter the rate of translation initiation of Nmnats. Collectively our studies suggest absence of Nt-acetylation may increase co-translational degradation of nascent Nmnat polypeptides, which results in reduced Nmnat levels in NatB mutants. Nmnat activities are essential for all routes of NAD+ biosynthesis. Understanding the regulation of Nmnat protein homeostasis will facilitate our understanding of the molecular basis and regulation of NAD+ metabolism.

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Co-translational assembly of mammalian nuclear multisubunit complexes

Cited by 101 publications

References 55 publications

Cotranslational Folding of Proteins on the Ribosome

Cotranslational Folding of Proteins on the Ribosome

Improved Supra-Organization Is A Conformational And Functional Adaptation Of Respiratory Complexes

N-terminal protein acetylation by NatB modulates the levels of Nmnats, the NAD⁺biosynthetic enzymes inSaccharomyces cerevisiae

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Co-translational assembly of mammalian nuclear multisubunit complexes

Cited by 101 publications

References 55 publications

Cotranslational Folding of Proteins on the Ribosome

Cotranslational Folding of Proteins on the Ribosome

Improved Supra-Organization Is A Conformational And Functional Adaptation Of Respiratory Complexes

N-terminal protein acetylation by NatB modulates the levels of Nmnats, the NAD+biosynthetic enzymes inSaccharomyces cerevisiae

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Product

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N-terminal protein acetylation by NatB modulates the levels of Nmnats, the NAD⁺biosynthetic enzymes inSaccharomyces cerevisiae