Cotranslational folding of spectrin domains via partially structured states

Nilsson, Ola; Nickson, Adrian A.; Hollins, Jeffrey J.; Wickles, Stephan; Steward, Annette; Beckmann, Roland; Heijne, Gunnar von; Clarke, Jane

doi:10.1038/nsmb.3355

Cited by 109 publications

(176 citation statements)

References 51 publications

(63 reference statements)

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“…A range of structural and biophysical studies have indicated that certain NCs can form secondarystructure and even simple tertiary-structure motifs within the ribosome exit tunnel: the dimensions of the exit tunnel permit the formation of -helices within the central and lower tunnel regions, the formation of a small zinc-finger motif at the lower tunnel region and the formation of a -hairpin motif of transmembrane helices at the vestibule (Woolhead et al, 2004;Lu & Deutsch, 2005;Kosolapov et al, 2009;Bhushan et al, 2010;Nilsson et al, 2015). While the 20 Å width of the ribosome exit tunnel vestibule seems to preclude the formation of higher-order tertiary structure, simple tertiary-structure formation for smaller proteins has been found to be possible, such as a partially folded three-helix bundle at the exit of the vestibule (Nilsson et al, 2017).…”

Section: The Ribosome Exit Tunnel: a Site For Elongation Regulation Amentioning

confidence: 99%

“…D73, 509-521 'senses' the passage of NCs. It orchestrates co-translational events including translational arrest at the elongation step of protein biosynthesis (Nakatogawa & Ito, 2001;Murakami et al, 2004) and limited folding of the NCs Nilsson et al, 2017), and represents a major hub for the recruitment of molecular chaperones, NC-modifying enzymes and the translocation machinery Balchin et al, 2016).…”

Section: The Ribosome Exit Tunnel: a Site For Elongation Regulation Amentioning

confidence: 99%

“…Advances in cryo-EM have been instrumental in showing how certain NC sequences can interact with the PTC and exit tunnel, and arrest the elongation process (Seidelt et al, 2009;Bhushan et al, 2011;Sohmen et al, 2015;Zhang et al, 2015;Arenz et al, 2016). Cryo-EM of RNCs has also shown features of co-translational folding as it occurs within the exit tunnel, where NCs have been shown to form simple tertiary motifs (Nilsson et al, 2015(Nilsson et al, , 2017. These studies have been complemented by RNC studies using NMR spectroscopy, which is unique in its capacity to describe both the structure and the dynamic characteristics of the emerging NC as it exists beyond the tunnel and forms higher-order tertiary structure (Hsu et al, 2007;Cabrita et al, 2009Cabrita et al, , 2016Cassaignau et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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The ribosome and its role in protein folding: looking through a magnifying glass

Javed

Christodoulou

Cabrita

et al. 2017

Acta Crystallogr D Struct Biol

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Protein folding, a process that underpins cellular activity, begins cotranslationally on the ribosome. During translation, a newly synthesized polypeptide chain enters the ribosomal exit tunnel and actively interacts with the ribosome elements -the r-proteins and rRNA that line the tunnel -prior to emerging into the cellular milieu. While understanding of the structure and function of the ribosome has advanced significantly, little is known about the process of folding of the emerging nascent chain (NC). Advances in cryoelectron microscopy are enabling visualization of NCs within the exit tunnel, allowing early glimpses of the interplay between the NC and the ribosome. Once it has emerged from the exit tunnel into the cytosol, the NC (still attached to its parent ribosome) can acquire a range of conformations, which can be characterized by NMR spectroscopy. Using experimental restraints within molecular-dynamics simulations, the ensemble of NC structures can be described. In order to delineate the process of co-translational protein folding, a hybrid structural biology approach is foreseeable, potentially offering a complete atomic description of protein folding as it occurs on the ribosome.

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Section: The Ribosome Exit Tunnel: a Site For Elongation Regulation Amentioning

confidence: 99%

Section: The Ribosome Exit Tunnel: a Site For Elongation Regulation Amentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The ribosome and its role in protein folding: looking through a magnifying glass

Javed

Christodoulou

Cabrita

et al. 2017

Acta Crystallogr D Struct Biol

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“…As a result, the entire cotranslational folding pathway must be considered when interpreting the effect of a pause in translation. We anticipate that an optimal translation protocol [48] could be predicted with knowledge of the substructure-specific folding and translation rates, as well as their propensities for forming non-native interactions, including interactions with the surface of the ribosome [49]. In addition, an optimal translation protocol is likely to be affected by the presence of misfolded intermediates, which may be avoided by increasing the local translation rate [50,51].…”

Section: Discussionmentioning

confidence: 99%

Evidence of evolutionary selection for co-translational folding

Jacobs

Shakhnovich

2017

Preprint

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Recent experiments and simulations have demonstrated that proteins can fold on the ribosome. However, the extent and generality of fitness effects resulting from co-translational folding remain open questions. Here we report a genome-wide analysis that uncovers evidence of evolutionary selection for co-translational folding. We describe a robust statistical approach to identify loci within genes that are both significantly enriched in slowly translated codons and evolutionarily conserved. Surprisingly, we find that domain boundaries can explain only a small fraction of these conserved loci. Instead, we propose that regions enriched in slowly translated codons are associated with co-translational folding intermediates, which may be smaller than a single domain. We show that the intermediates predicted by a native-centric model of co-translational folding account for the majority of these loci across more than 500 E. coli proteins. By making a direct connection to protein folding, this analysis provides strong evidence that many synonymous substitutions have been selected to optimize translation rates at specific locations within genes. More generally, our results indicate that kinetics, and not just thermodynamics, can significantly alter the efficiency of self-assembly in a biological context. INTRODUCTIONMany proteins can begin folding to their native states before their synthesis is complete [1,2]. As much as one-third of a bacterial proteome is believed to fold cotranslationally [3], with an even higher percentage likely in more slowly translated eukaryotic proteomes. Numerous experiments on both natural and engineered aminoacid sequences have shown that folding during synthesis can have profound effects: compared to denatured and refolded chains, co-translationally folded proteins may be less prone to misfolding [4][5][6][7][8][9][10][11], aggregation [12] and degradation [13], or they may preferentially adopt alternate stable structures [14][15][16]. Because the timescales for protein synthesis and folding are often similar [17,18], it is clear that the rate of translation can be used to tune the self-assembly of peptide chains in vivo [19,20]. To this point, however, there exists little evidence that evolution has selected specifically for efficient co-translational folding kinetics across any substantial fraction of an organism's proteome.In this work, we provide evidence that evolutionary selection has tuned protein-translation rates to optimize co-translational folding pathways. Our approach is motivated by the hypothesis that pauses during protein synthesis may be beneficial for promoting the formation of native structure. By increasing the separation between the timescales for folding and translation, such pauses may promote the assembly of on-pathway intermediates, which, in turn, template the growth of further native structure. Many experimental and computational studies have shown that protein-folding naturally proceeds in a step-wise manner via structurally distinct intermediates [21,22], and that...

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“…Even if it's not my own line of research, it's been quite an experience to help bring this new technology to Sweden. And, of course, we couldn't resist the temptation to integrate cryo-EM in some of our own projects: we now use APs to immobilize newly folded protein domains in the ribosome exit tunnel, and solve the structures using cryo-EM (35,36) (Fig. 8).…”

Section: Reflections: Membrane Protein Serendipitymentioning

confidence: 99%