Non-Refoldability is Pervasive Across the<i>E. coli</i>Proteome

To, Philip; Whitehead, Briana; Tarbox, Haley E.; Fried, Stephen D.

doi:10.1101/2020.08.28.273110

Cited by 5 publications

(4 citation statements)

References 47 publications

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“…Indeed, the design of Rossmann-like proteins is readily realized compared to P-loops-like proteins with the swapped strand topology ( Romero Romero et al, 2018 ). Furthermore, systematic assays of refoldability of the E. coli proteome, and a comparison of the folds to which these proteins belong, indicated that Rossmann is among the most refoldable folds while P-loop NTPases are among the poorly refolding ones ( To et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

On the emergence of P-Loop NTPase and Rossmann enzymes from a Beta-Alpha-Beta ancestral fragment

Longo

Jabłońska

Vyas

et al. 2020

eLife

127

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This article is dedicated to the memory of Michael G. Rossmann. Dating back to the last universal common ancestor, P-loop NTPases and Rossmanns comprise the most ubiquitous and diverse enzyme lineages. Despite similarities in their overall architecture and phosphate binding motif, a lack of sequence identity and some fundamental structural differences currently designates them as independent emergences. We systematically searched for structure and sequence elements shared by both lineages. We detected homologous segments that span the first βαβ motif of both lineages, including the phosphate binding loop and a conserved aspartate at the tip of β2. The latter ligates the catalytic metal in P-loop NTPases, while in Rossmanns it binds the nucleotide’s ribose moiety. Tubulin, a Rossmann GTPase, demonstrates the potential of the β2-Asp to take either one of these two roles. While convergence cannot be completely ruled out, we show that both lineages likely emerged from a common βαβ segment that comprises the core of these enzyme families to this very day.

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Section: Resultsmentioning

confidence: 99%

On the emergence of P-Loop NTPase and Rossmann enzymes from a Beta-Alpha-Beta ancestral fragment

Longo

Jabłońska

Vyas

et al. 2020

eLife

127

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“…A recent study by To et al . [182] interrogated the refoldability of the E. coli proteome and found that two-thirds out of approximately 1200 proteins were reversibly refoldable on a biologically relevant timescale of 2 h. This group was enriched with monomeric proteins (75% refoldable), single-domain proteins (70% refoldable), small proteins (less than 20 kDa, 80% refoldable) and proteins without any annotated domains (and hence, more likely to be disordered, 87% refoldable).…”

Section: Refoldabilitymentioning

confidence: 99%

Peptides before and during the nucleotide world: an origins story emphasizing cooperation between proteins and nucleic acids

Fried

Fujishima

Makarov

et al. 2022

J. R. Soc. Interface.

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Recent developments in Origins of Life research have focused on substantiating the narrative of an abiotic emergence of nucleic acids from organic molecules of low molecular weight, a paradigm that typically sidelines the roles of peptides. Nevertheless, the simple synthesis of amino acids, the facile nature of their activation and condensation, their ability to recognize metals and cofactors and their remarkable capacity to self-assemble make peptides (and their analogues) favourable candidates for one of the earliest functional polymers. In this mini-review, we explore the ramifications of this hypothesis. Diverse lines of research in molecular biology, bioinformatics, geochemistry, biophysics and astrobiology provide clues about the progression and early evolution of proteins, and lend credence to the idea that early peptides served many central prebiotic roles before they were encodable by a polynucleotide template, in a putative ‘peptide-polynucleotide stage’. For example, early peptides and mini-proteins could have served as catalysts, compartments and structural hubs. In sum, we shed light on the role of early peptides and small proteins before and during the nucleotide world, in which nascent life fully grasped the potential of primordial proteins, and which has left an imprint on the idiosyncratic properties of extant proteins.

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“…These conformations are robustly achieved in vivo via a folding process that involves interactions of the folding chain with molecular chaperones and other maturation factors. The folding process often cannot be reproduced in vitro , in the absence of chaperones and other cellular components 1 – 5 . However, some small proteins fold spontaneously in vitro in the absence of any other macromolecules 6 .…”

Section: Introductionmentioning

confidence: 99%

Energy-dependent protein folding: modeling how a protein folding machine may work

et al. 2021

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Background: Proteins fold robustly and reproducibly in vivo, but many cannot fold in vitro in isolation from cellular components. Despite the remarkable progress that has been achieved by the artificial intelligence approaches in predicting the protein native conformations, the pathways that lead to such conformations, either in vitro or in vivo, remain largely unknown. The slow progress in recapitulating protein folding pathways in silico may be an indication of the fundamental deficiencies in our understanding of folding as it occurs in nature. Here we consider the possibility that protein folding in living cells may not be driven solely by the decrease in Gibbs free energy and propose that protein folding in vivo should be modeled as an active energy-dependent process. The mechanism of action of such a protein folding machine might include direct manipulation of the peptide backbone. Methods: To show the feasibility of a protein folding machine, we conducted molecular dynamics simulations that were augmented by the application of mechanical force to rotate the C-terminal amino acid while simultaneously limiting the N-terminal amino acid movements. Results: Remarkably, the addition of this simple manipulation of peptide backbones to the standard molecular dynamics simulation indeed facilitated the formation of native structures in five diverse alpha-helical peptides. Steric clashes that arise in the peptides due to the forced directional rotation resulted in the behavior of the peptide backbone no longer resembling a freely jointed chain. Conclusions: These simulations show the feasibility of a protein folding machine operating under the conditions when the movements of the polypeptide backbone are restricted by applying external forces and constraints. Further investigation is needed to see whether such an effect may play a role during co-translational protein folding in vivo and how it can be utilized to facilitate folding of proteins in artificial environments.

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Non-Refoldability is Pervasive Across theE. coliProteome

Cited by 5 publications

References 47 publications

On the emergence of P-Loop NTPase and Rossmann enzymes from a Beta-Alpha-Beta ancestral fragment

On the emergence of P-Loop NTPase and Rossmann enzymes from a Beta-Alpha-Beta ancestral fragment

Peptides before and during the nucleotide world: an origins story emphasizing cooperation between proteins and nucleic acids

Energy-dependent protein folding: modeling how a protein folding machine may work

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