De Novo Evolutionary Emergence of a Symmetrical Protein Is Shaped by Folding Constraints

Smock, Robert G.; Yadid, Itamar; Dym, Orly; Clarke, Jane; Tawfik, Dan S.

doi:10.1016/j.cell.2015.12.024

Cited by 94 publications

(107 citation statements)

References 39 publications

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“…These observations suggest that repeat proteins arose through repeated duplication at an early stage in the evolution of larger proteins from smaller fragments (68)(69)(70). Available examples show that globular organization can arise from continued repetitive growth that closes the linear geometry, and by the fusion of nonidentical units (69,71), and so would carry forward their foldon-like properties.…”

Section: Results and Considerationsmentioning

confidence: 99%

The case for defined protein folding pathways

Englander

Mayne

2017

Proc. Natl. Acad. Sci. U.S.A.

124

143

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We consider the differences between the many-pathway protein folding model derived from theoretical energy landscape considerations and the defined-pathway model derived from experiment. A basic tenet of the energy landscape model is that proteins fold through many heterogeneous pathways by way of amino acid-level dynamics biased toward selecting native-like interactions. The many pathways imagined in the model are not observed in the structureformation stage of folding by experiments that would have found them, but they have now been detected and characterized for one protein in the initial prenucleation stage. Analysis presented here shows that these many microscopic trajectories are not distinct in any functionally significant way, and they have neither the structural information nor the biased energetics needed to select native vs. nonnative interactions during folding. The opposed defined-pathway model stems from experimental results that show that proteins are assemblies of small cooperative units called foldons and that a number of proteins fold in a reproducible pathway one foldon unit at a time. Thus, the same foldon interactions that encode the native structure of any given protein also naturally encode its particular foldon-based folding pathway, and they collectively sum to produce the energy bias toward native interactions that is necessary for efficient folding. Available information suggests that quantized native structure and stepwise folding coevolved in ancient repeat proteins and were retained as a functional pair due to their utility for solving the difficult protein folding problem.protein folding | foldons | energy landscape theory P rotein folding is among the most important reactions in all of biology. However, 50 y after C. B. Anfinsen showed that proteins can fold spontaneously without outside help (1, 2), and despite the intensive work of thousands of researchers leading to more than five publications per day in the current literature, there is still no general agreement on the most primary questions (3-5). How do proteins fold? Why do they fold in that way? How is the course of folding encoded in a 1D amino acid sequence? These questions have fundamental significance for protein science and its numerous applications. Over the years these questions have generated a large literature leading to different models for the folding process.The "new view" folding model, derived from hypothetical energy landscape and statistical mechanical considerations (6-12), proposes that folding proteins navigate to their native state through very many independent pathways. The many trajectories in Fig. 1A imply an unfolded protein conformationally searching for its lowestenergy native state by way of dynamic bond rotations in a way that is guided by its energy landscape, as for any chemical reaction. For effective performance, folding proteins must "know" how to select native as opposed to nonnative interactions. This information is said to be contained in the shape of the energy landscape, but how it is ...

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Section: Results and Considerationsmentioning

confidence: 99%

The case for defined protein folding pathways

Englander

Mayne

2017

Proc. Natl. Acad. Sci. U.S.A.

124

143

View full text Add to dashboard Cite

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“…Importantly, beta-propeller folds have remarkable structural plasticity and are prone to strand-swapping between blades, large insertions of entire functional beta-sheet domains, thus making possible assembling of functional supramolecular beta-propeller units3435. Therefore, one can speculate that the dissecting of the usual beta-propeller fold (as shown in Fig.…”

Section: Discussionmentioning

confidence: 99%

New Insights into Molecular Organization of Human Neuraminidase-1: Transmembrane Topology and Dimerization Ability

Maurice

Baud

Bocharova

et al. 2016

Sci Rep

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Neuraminidase 1 (NEU1) is a lysosomal sialidase catalyzing the removal of terminal sialic acids from sialyloconjugates. A plasma membrane-bound NEU1 modulating a plethora of receptors by desialylation, has been consistently documented from the last ten years. Despite a growing interest of the scientific community to NEU1, its membrane organization is not understood and current structural and biochemical data cannot account for such membrane localization. By combining molecular biology and biochemical analyses with structural biophysics and computational approaches, we identified here two regions in human NEU1 - segments 139–159 (TM1) and 316–333 (TM2) - as potential transmembrane (TM) domains. In membrane mimicking environments, the corresponding peptides form stable α-helices and TM2 is suited for self-association. This was confirmed with full-size NEU1 by co-immunoprecipitations from membrane preparations and split-ubiquitin yeast two hybrids. The TM2 region was shown to be critical for dimerization since introduction of point mutations within TM2 leads to disruption of NEU1 dimerization and decrease of sialidase activity in membrane. In conclusion, these results bring new insights in the molecular organization of membrane-bound NEU1 and demonstrate, for the first time, the presence of two potential TM domains that may anchor NEU1 in the membrane, control its dimerization and sialidase activity.

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“…Thus, the energy landscape defines a protein's ability to fold in a biologically reasonable time scale, avoid misfolding, and prevent frequent unfolding-all of which are likely important for the overall fitness of an organism. Indeed, numerous studies have proposed how protein folding might affect molecular evolution (2)(3)(4)(5)(6)(7)(8), and there is growing evidence that folding pathways and their associated kinetics and energetics are evolutionarily constrained. To date, however, there is little experimental evidence detailing how folding properties have changed throughout evolution.…”

mentioning

confidence: 99%

Evolutionary trend toward kinetic stability in the folding trajectory of RNases H

Lim

Hart

Harms

2016

Proc. Natl. Acad. Sci. U.S.A.

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Proper folding of proteins is critical to producing the biological machinery essential for cellular function. The rates and energetics of a protein's folding process, which is described by its energy landscape, are encoded in the amino acid sequence. Over the course of evolution, this landscape must be maintained such that the protein folds and remains folded over a biologically relevant time scale. How exactly a protein's energy landscape is maintained or altered throughout evolution is unclear. To study how a protein's energy landscape changed over time, we characterized the folding trajectories of ancestral proteins of the ribonuclease H (RNase H) family using ancestral sequence reconstruction to access the evolutionary history between RNases H from mesophilic and thermophilic bacteria. We found that despite large sequence divergence, the overall folding pathway is conserved over billions of years of evolution. There are robust trends in the rates of protein folding and unfolding; both modern RNases H evolved to be more kinetically stable than their most recent common ancestor. Finally, our study demonstrates how a partially folded intermediate provides a readily adaptable folding landscape by allowing the independent tuning of kinetics and thermodynamics.protein folding | energy landscape | protein evolution | ancestral sequence reconstruction B ecause most proteins need to fold to function, there must be selective pressures for efficient folding and maintenance of structure. Although many studies have investigated the evolution of protein function, a detailed understanding of the evolutionary constraints on protein folding is lacking.The amino acid sequence of a protein encodes its energy landscape, which determines its folding trajectory-its mechanism, rates, and energetics (1). Thus, the energy landscape defines a protein's ability to fold in a biologically reasonable time scale, avoid misfolding, and prevent frequent unfolding-all of which are likely important for the overall fitness of an organism. Indeed, numerous studies have proposed how protein folding might affect molecular evolution (2-8), and there is growing evidence that folding pathways and their associated kinetics and energetics are evolutionarily constrained. To date, however, there is little experimental evidence detailing how folding properties have changed throughout evolution. Are there trends in the folding mechanism or rates? Which aspects of the folding mechanism have been conserved, and how have they played a role in the evolution of modern-day homologs? We might naively expect folding to optimize, so that modern proteins generally fold faster than their ancestors. Or perhaps the energetics of the folding landscape evolved to avoid kinetic traps or misfolded states. If maintaining the folded state is important for fitness, then we might expect an improvement in kinetic stability over time, although a folded state that is too stable might be detrimental for conformational dynamics. These insights, and others, are critical for our und...

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De Novo Evolutionary Emergence of a Symmetrical Protein Is Shaped by Folding Constraints

Cited by 94 publications

References 39 publications

The case for defined protein folding pathways

The case for defined protein folding pathways

New Insights into Molecular Organization of Human Neuraminidase-1: Transmembrane Topology and Dimerization Ability

Evolutionary trend toward kinetic stability in the folding trajectory of RNases H

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