The Role of Conformational Dynamics and Allostery in Modulating Protein Evolution

2020 ◽  
Vol 49 (1) ◽  
pp. 267-288 ◽  
Author(s):  
Paul Campitelli ◽  
Tushar Modi ◽  
Sudhir Kumar ◽  
S. Banu Ozkan
Keyword(s):  
Protein Evolution ◽  
Environmental Changes ◽  
Conformational Dynamics ◽  
Amino Acid Level ◽  
Single Amino Acid ◽  
Dynamic Coupling ◽  
Coupling Index ◽  
A Site ◽  
Flexibility Index

Advances in sequencing techniques and statistical methods have made it possible not only to predict sequences of ancestral proteins but also to identify thousands of mutations in the human exome, some of which are disease associated. These developments have motivated numerous theories and raised many questions regarding the fundamental principles behind protein evolution, which have been traditionally investigated horizontally using the tip of the phylogenetic tree through comparative studies of extant proteins within a family. In this article, we review a vertical comparison of the modern and resurrected ancestral proteins. We focus mainly on the dynamical properties responsible for a protein's ability to adapt new functions in response to environmental changes. Using the Dynamic Flexibility Index and the Dynamic Coupling Index to quantify the relative flexibility and dynamic coupling at a site-specific, single-amino-acid level, we provide evidence that the migration of hinges, which are often functionally critical rigid sites, is a mechanism through which proteins can rapidly evolve. Additionally, we show that disease-associated mutations in proteins often result in flexibility changes even at positions distal from mutational sites, particularly in the modulation of active site dynamics.

scholarly journals Senescence and entrenchment in evolution of amino acid sites

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
A. V. Stolyarova ◽  
E. Nabieva ◽  
V. V. Ptushenko ◽  
A. V. Favorov ◽  
A. V. Popova ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Adaptive Evolution ◽  
Protein Evolution ◽  
Environmental Changes ◽  
Acid Sites ◽  
Analytical Modelling ◽  
Site Change ◽  
A Site ◽  
Positively Selected Sites

Abstract Amino acid propensities at a site change in the course of protein evolution. This may happen for two reasons. Changes may be triggered by substitutions at epistatically interacting sites elsewhere in the genome. Alternatively, they may arise due to environmental changes that are external to the genome. Here, we design a framework for distinguishing between these alternatives. Using analytical modelling and simulations, we show that they cause opposite dynamics of the fitness of the allele currently occupying the site: it tends to increase with the time since its origin due to epistasis (“entrenchment”), but to decrease due to random environmental fluctuations (“senescence”). By analysing the genomes of vertebrates and insects, we show that the amino acids originating at negatively selected sites experience strong entrenchment. By contrast, the amino acids originating at positively selected sites experience senescence. We propose that senescence of the current allele is a cause of adaptive evolution.

scholarly journals Mutations Utilize Dynamic Allostery to Confer Resistance in TEM-1 β-lactamase

2018 ◽  
Vol 19 (12) ◽  
pp. 3808 ◽  
Author(s):  
Tushar Modi ◽  
S. Ozkan
Keyword(s):  
Active Site ◽  
Active Sites ◽  
Critical Role ◽  
Conformational Dynamics ◽  
Driver Mutations ◽  
Common Mechanism ◽  
Dynamic Coupling ◽  
Long Distance ◽  
Coupling Index ◽  
High Dynamic

β-lactamases are enzymes produced by bacteria to hydrolyze β-lactam antibiotics as a common mechanism of resistance. Evolution in such enzymes has been rendering a wide variety of antibiotics impotent, therefore posing a major threat. Clinical and in vitro studies of evolution in TEM-1 β-lactamase have revealed a large number of single point mutations that are responsible for driving resistance to antibiotics and/or inhibitors. The distal locations of these mutations from the active sites suggest that these allosterically modulate the antibiotic resistance. We investigated the effects of resistance driver mutations on the conformational dynamics of the enzyme to provide insights about the mechanism of their long-distance interactions. Through all-atom molecular dynamics (MD) simulations, we obtained the dynamic flexibility profiles of the variants and compared those with that of the wild type TEM-1. While the mutational sites in the variants did not have any direct van der Waals interactions with the active site position S70 and E166, we observed a change in the flexibility of these sites, which play a very critical role in hydrolysis. Such long distance dynamic interactions were further confirmed by dynamic coupling index (DCI) analysis as the sites involved in resistance driving mutations exhibited high dynamic coupling with the active sites. A more exhaustive dynamic analysis, using a selection pressure for ampicillin and cefotaxime resistance on all possible types of substitutions in the amino acid sequence of TEM-1, further demonstrated the observed mechanism. Mutational positions that play a crucial role for the emergence of resistance to new antibiotics exhibited high dynamic coupling with the active site irrespective of their locations. These dynamically coupled positions were neither particularly rigid nor particularly flexible, making them more evolvable positions. Nature utilizes these sites to modulate the dynamics of the catalytic sites instead of mutating the highly rigid positions around the catalytic site.

scholarly journals Senescence and entrenchment in evolution of amino acid sites

2019 ◽  
Author(s):  
A. V. Stolyarova ◽  
E. Nabieva ◽  
V. V. Ptushenko ◽  
A. V. Favorov ◽  
A. V. Popova ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Adaptive Evolution ◽  
Protein Evolution ◽  
Similar Pattern ◽  
Environmental Changes ◽  
Acid Sites ◽  
Phylogenetic Distribution ◽  
A Site ◽  
Positively Selected Sites

AbstractAmino acid propensities at a site change in the course of protein evolution. This may happen for two reasons. Changes may be triggered by substitutions at epistatically interacting sites elsewhere in the genome; alternatively, they may arise due to environmental changes that are external to the genome. Here, we design a framework for distinguishing between these alternatives. Using analytical modelling and simulations, we show that they cause opposite dynamics of the fitness of the allele currently occupying the site: its fitness tends to increase with the time since its origin due to epistasis (“entrenchment”), but to decrease due to random environmental fluctuations (“senescence”). We analyse the phylogenetic distribution of substitutions in nuclear genomes, and show that among the amino acids originating at negatively selected sites of vertebrates, nearly all experience strong entrenchment. By contrast, among the amino acids originating at positively selected sites, 18% experience senescence. A similar pattern is observed in phylogenies of insects. We propose that senescence of the current allele is a cause of adaptive evolution.

scholarly journals Bacterial ribosome conformational dynamics during translation termination and rescue

2017 ◽  
Author(s):  
◽  
Widler Casy
Keyword(s):  
Stop Codon ◽  
Translation Termination ◽  
Conformational Dynamics ◽  
Class I ◽  
Translation Inhibition ◽  
Release Factors ◽  
Bacterial Ribosome ◽  
A Site ◽  
Hydrolysis Of

Hydrolysis of polypeptide from the ribosome is a critical step that must occur prior to the ribosome recycling phase of translation. Inability of cells to do so can result in translation inhibition and eventually leading to cell death. In bacteria, class one release factors bind to the ribosome to catalyze the release of the mature polypeptide during translation termination. However, in the event of ribosome stalling as a result of mRNA truncation, ribosome rescue factors bind to the ribosome to catalyze the release of the growing polypeptide from the stalled complex. This rescue process is then followed by ribosome recycling. Here we employ smFRET to study the effects of the class I release factors, RF1 and RF2, and an alternative release factor known as YaeJ on the conformational dynamics of the ribosome following hydrolysis of peptidyl tRNAs. Further, we investigated the role of A-site mRNA on the global conformation of the ribosome. Our results demonstrate that upon binding to their cognate stop codon, the class I release factors stabilize ribosome complexes in the non-rotated state. Similarly, binding of YaeJ to complexes that are assembled on truncated mRNAs resulted in ribosomes that occupy primarily the non-rotated state. We also observe that absence of mRNA in the A-site induces a hyper-rotated conformation between the two subunits. Together, these findings further characterize the interactions between these different ligands and the bacterial ribosome. In addition, these results suggest that stabilization of the ribosome in the non-rotated state is critical for priming the ribosome for the recycling phase of translation.

The Return of Alsace to France, 1918-1939

2018 ◽  
Author(s):  
Alison Carrol
Keyword(s):  
National Policy ◽  
Third Republic ◽  
French Society ◽  
German Empire ◽  
Cross Border ◽  
The First World War ◽  
German Speaking ◽  
A Site ◽  
First World

In 1918 the end of the First World War triggered the return of Alsace to France after almost fifty years of annexation into the German Empire. Enthusiastic crowds in Paris and Alsace celebrated the homecoming of the so-called lost province, but return proved far less straightforward than anticipated. The region’s German-speaking population demonstrated strong commitment to local cultures and institutions, as well as their own visions of return to France. As a result, the following two decades saw politicians, administrators, industrialists, cultural elites, and others grapple with the question of how to make Alsace French again. The answer did not prove straightforward; differences of opinion emerged both inside and outside the region, and reintegration became a fiercely contested process that remained incomplete when war broke out in 1939. The Return of Alsace to France examines this story. Drawing upon national, regional, and local archives, it follows the difficult process of Alsace’s reintegration into French society, culture, political and economic systems, and legislative and administrative institutions. It connects the microhistory of the region with the macro levels of national policy, international relations, and transnational networks, and with the cross-border flows of ideas, goods, people, and cultural products that shaped daily life in Alsace. Revealing Alsace to be a site of exchange between a range of interest groups with different visions of the region’s future, this book underlines the role of regional populations and cross-border interactions in forging the French Third Republic.

RNA secondary structure dependence in METTL3–METTL14 mRNA methylation is modulated by the N-terminal domain of METTL3

2020 ◽  
Vol 402 (1) ◽  
pp. 89-98
Author(s):  
Nathalie Meiser ◽  
Nicole Mench ◽  
Martin Hengesbach
Keyword(s):  
Secondary Structure ◽  
Rna Binding ◽  
Specific Protein ◽  
Structure Dependence ◽  
Terminal Domain ◽  
Methylation Assay ◽  
A Site ◽  
Methylation Activity

AbstractN6-methyladenosine (m6A) is the most abundant modification in mRNA. The core of the human N6-methyltransferase complex (MTC) is formed by a heterodimer consisting of METTL3 and METTL14, which specifically catalyzes m6A formation within an RRACH sequence context. Using recombinant proteins in a site-specific methylation assay that allows determination of quantitative methylation yields, our results show that this complex methylates its target RNAs not only sequence but also secondary structure dependent. Furthermore, we demonstrate the role of specific protein domains on both RNA binding and substrate turnover, focusing on postulated RNA binding elements. Our results show that one zinc finger motif within the complex is sufficient to bind RNA, however, both zinc fingers are required for methylation activity. We show that the N-terminal domain of METTL3 alters the secondary structure dependence of methylation yields. Our results demonstrate that a cooperative effect of all RNA-binding elements in the METTL3–METTL14 complex is required for efficient catalysis, and that binding of further proteins affecting the NTD of METTL3 may regulate substrate specificity.

scholarly journals Tethering-induced destabilization and ATP-binding for tandem RRM domains of ALS-causing TDP-43 and hnRNPA1

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mei Dang ◽  
Yifan Li ◽  
Jianxing Song
Keyword(s):  
Conformational Dynamics ◽  
Md Simulations ◽  
Atp Binding ◽  
Rna Recognition Motif ◽  
Rna Recognition ◽  
Nucleic Acid Binding ◽  
General Role ◽  
Nmr Characterization ◽  
Lateral Sclerosis

AbstractTDP-43 and hnRNPA1 contain tandemly-tethered RNA-recognition-motif (RRM) domains, which not only functionally bind an array of nucleic acids, but also participate in aggregation/fibrillation, a pathological hallmark of various human diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), alzheimer's disease (AD) and Multisystem proteinopathy (MSP). Here, by DSF, NMR and MD simulations we systematically characterized stability, ATP-binding and conformational dynamics of TDP-43 and hnRNPA1 RRM domains in both tethered and isolated forms. The results reveal three key findings: (1) upon tethering TDP-43 RRM domains become dramatically coupled and destabilized with Tm reduced to only 49 °C. (2) ATP specifically binds TDP-43 and hnRNPA1 RRM domains, in which ATP occupies the similar pockets within the conserved nucleic-acid-binding surfaces, with the affinity slightly higher to the tethered than isolated forms. (3) MD simulations indicate that the tethered RRM domains of TDP-43 and hnRNPA1 have higher conformational dynamics than the isolated forms. Two RRM domains become coupled as shown by NMR characterization and analysis of inter-domain correlation motions. The study explains the long-standing puzzle that the tethered TDP-43 RRM1–RRM2 is particularly prone to aggregation/fibrillation, and underscores the general role of ATP in inhibiting aggregation/fibrillation of RRM-containing proteins. The results also rationalize the observation that the risk of aggregation-causing diseases increases with aging.

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