Inferring translational heterogeneity from ribosome profiling data

Bordignon, Pedro do Couto; Pechmann, Sebastian

doi:10.1101/866582

Cited by 3 publications

(2 citation statements)

References 113 publications

(110 reference statements)

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“…However, any comparative analyses depends on a level of resolution that serves as a common denominator. The hope is that the presented results will motivate future studies to characterize in vivo protein folding landscapes include the role of the protein termini [53], and the interplay between translation, folding, and protein export pathways [54].…”

Section: Discussionmentioning

confidence: 89%

Heterogeneous folding landscapes and predetermined breaking points within a protein family

Pechmann

2024

Preprint

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The accurate prediction of protein structures with artificial intelligence has been a spectacular success. Yet, how proteins fold into their native structures inside the cell remains incompletely understood. Of particular interest is to rationalize how proteins interact with the protein homeostasis network, an organism specific set of protein folding and quality control enzymes. Failure of protein homeostasis leads to widespread misfolding and aggregation, and thus neurodegeneration. Here, I present a comparative analysis of the folding across a protein family from a single organism, the Saccharomyces cerevisiae small GTPases. Using computational modelling to directly probe folding dynamics, this work shows how near identical structures from the same folding environment exhibit heterogeneous folding landscapes. Remarkably, yeast small GTPases are found to unfold along different pathways either via the N- or C-terminus initiated by structure-encoded predetermined breaking points. Moreover, degrons as recognition signals for ubiquitin-dependent degradation were systematically depleted from the initial unfolding sites, as if to protect from too rapid degradation upon spontaneous unfolding. In turn, Hsp70 Ssb chaperone binding correlated only with N-terminal hydrophobicity. The presented results highlight a direct coordination of folding pathway and protein homeostasis interaction signals across a protein family. A deeper understanding of the interdependence of proteins with their folding environment will help to rationalize and combat disease linked to protein misfolding and dysregulation. More generally, this work underlines the importance of understanding protein folding in the cellular context, and highlights valuable constraints towards a systems-level understanding of protein homeostasis.

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Section: Discussionmentioning

confidence: 89%

Heterogeneous folding landscapes and predetermined breaking points within a protein family

Pechmann

2024

Preprint

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“…Last, the protein coding mRNA sequences encode an additional layer of information on the kinetics of translation elongation (62) thus protein folding (63,64) including interactions with chaperones (23,24,65). Next to selectively placed signatures of translation attenuation, for instance through use of nonoptimal, more slowly translated codons that can provide extra time for folding events and thus limit the conformational search space, an overall high or low content of nonoptimal codons can bias the overall translation speed.…”

Section: Codon Usage Can Compensate For Chaperoningmentioning

confidence: 99%

Programmed trade-offs in protein folding networks

Pechmann

2020

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Maintaining protein homeostasis, i.e. a folded and functional proteome, depends on the efficient allocation of cellular protein quality control resources. Decline and dysregulation of protein homeostasis are directly associated to conditions of aging and neurodegeneration. Molecular chaperones as specialized protein quality control enzymes form the core of protein homeostasis. However, how chaperones selectively interact with their substrate proteins thus allocate their overall limited capacity remains poorly understood. Here, I present an integrated analysis of sequence and structural determinants that define interactions of the Saccharomyces cerevisiae Hsp70 Ssb. Structural homologues that differentially interact with Ssb for de novo folding were found to systematically differ in complexity of their folding landscapes, selective use of nonoptimal codons, and presence of short discriminative sequences. All analyzed characteristics contributed to the prediction of Ssb interactions in highly complementary manner, highlighting pervasive trade-offs in chaperone-assisted protein folding landscapes. However, short discriminative sequences were found to contribute by far the strongest signal towards explaining Ssb interactions. This observation suggested that some chaperone interactions may be directly programmed in the amino acid sequences rather than responding to folding challenges, possibly for regulatory advantages.

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Heterogeneous folding landscapes and predetermined breaking points within a protein family

Pechmann

2024

Protein Science

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The accurate prediction of protein structures with artificial intelligence has been a spectacular success. Yet, how proteins fold into their native structures inside the cell remains incompletely understood. Of particular interest is to rationalize how proteins interact with the protein homeostasis network, an organism specific set of protein folding and quality control enzymes. Failure of protein homeostasis leads to widespread misfolding and aggregation, and thus neurodegeneration. Here, I present a comparative analysis of the folding of 16 single‐domain proteins from the same organism across a protein family, the Saccharomyces cerevisiae small GTPases. Using computational modeling to directly probe protein folding dynamics, this work shows how near identical structures from the same folding environment can exhibit heterogeneous folding landscapes. Remarkably, yeast small GTPases are found to unfold along different pathways either via the N‐ or C‐terminus initiated by structure‐encoded predetermined breaking points. Degrons as recognition signals for ubiquitin‐dependent degradation were systematically absent from the initial unfolding sites, as if to protect from too rapid degradation upon spontaneous unfolding or before completion of the folding. The presented results highlight a direct coordination of folding pathway and protein homeostasis interaction signals across a protein family. A deeper understanding of the interdependence of proteins with their folding environment will help to rationalize and combat diseases linked to protein misfolding and dysregulation. More generally, this work underlines the importance of understanding protein folding in the cellular context, and highlights valuable constraints towards a systems‐level understanding of protein homeostasis.

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Inferring translational heterogeneity from ribosome profiling data

Cited by 3 publications

References 113 publications

Heterogeneous folding landscapes and predetermined breaking points within a protein family

Heterogeneous folding landscapes and predetermined breaking points within a protein family

Programmed trade-offs in protein folding networks

Heterogeneous folding landscapes and predetermined breaking points within a protein family

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