scholarly journals Aggregation is a Context-Dependent Constraint on Protein Evolution

2021 ◽  
Vol 8 ◽  
Author(s):  
Michele Monti ◽  
Alexandros Armaos ◽  
Marco Fantini ◽  
Annalisa Pastore ◽  
Gian Gaetano Tartaglia
Keyword(s):  
Molecular Evolution ◽  
Protein Evolution ◽  
Protein Function ◽  
Beta Lactamase ◽  
Data Set ◽  
Cellular Processes ◽  
Bacterial Enzyme ◽  
Rna Biogenesis ◽  
Context Dependent

Solubility is a requirement for many cellular processes. Loss of solubility and aggregation can lead to the partial or complete abrogation of protein function. Thus, understanding the relationship between protein evolution and aggregation is an important goal. Here, we analysed two deep mutational scanning experiments to investigate the role of protein aggregation in molecular evolution. In one data set, mutants of a protein involved in RNA biogenesis and processing, human TAR DNA binding protein 43 (TDP-43), were expressed in S. cerevisiae. In the other data set, mutants of a bacterial enzyme that controls resistance to penicillins and cephalosporins, TEM-1 beta-lactamase, were expressed in E. coli under the selective pressure of an antibiotic treatment. We found that aggregation differentiates the effects of mutations in the two different cellular contexts. Specifically, aggregation was found to be associated with increased cell fitness in the case of TDP-43 mutations, as it protects the host from aberrant interactions. By contrast, in the case of TEM-1 beta-lactamase mutations, aggregation is linked to a decreased cell fitness due to inactivation of protein function. Our study shows that aggregation is an important context-dependent constraint of molecular evolution and opens up new avenues to investigate the role of aggregation in the cell.

scholarly journals Aggregation is a context-dependent constraint on protein evolution

2021 ◽  
Author(s):  
Michele Monti ◽  
Alexandros Armaos ◽  
Marco Fantini ◽  
Annalisa Pastore ◽  
Gian Gaetano Tartaglia
Keyword(s):  
Protein Evolution ◽  
Protein Function ◽  
Beta Lactamase ◽  
Data Set ◽  
Cellular Processes ◽  
Bacterial Enzyme ◽  
Rna Biogenesis ◽  
Context Dependent ◽  
The Relationship

Solubility is a requirement for many cellular processes. Loss of solubility and aggregation can lead to the partial or complete abrogation of protein function. Thus, understanding the relationship between protein evolution and aggregation is an important goal. Here, we analysed two deep mutational scanning experiments to investigate the role of protein aggregation in molecular evolution.In one data set, mutants of a protein involved in RNA biogenesis and processing, human TAR DNA binding protein 43 (TDP-43), were expressed inS. cerevisiae. In the other data set, mutants of a bacterial enzyme that controls resistance to penicillins and cephalosporins, TEM-1 beta-lactamase, were expressed inE. coli under the selective pressure of an antibiotic treatment. We found that aggregation differentiates the effects of mutations in the two different cellular contexts. Specifically, aggregation was found to be associated with increased cell fitness in the case of TDP-43 mutations, as it protects the host from aberrant interactions. By contrast, in the case of TEM-1 beta-lactamase mutations, aggregation is linked to a decreased cell fitness due to inactivation of protein function.Our study shows that aggregation is an important context-dependent constraint of molecular evolution and opens up new avenues to investigate the role of aggregation in different cellular contexts-

scholarly journals Trimethyllysine: From Carnitine Biosynthesis to Epigenetics

2020 ◽  
Vol 21 (24) ◽  
pp. 9451
Author(s):  
Marijn N. Maas ◽  
Jordi C. J. Hintzen ◽  
Miriam R. B. Porzberg ◽  
Jasmin Mecinović
Keyword(s):  
Protein Function ◽  
Genetic Disorders ◽  
Enzymatic Reactions ◽  
Lysine Methylation ◽  
Nucleosome Assembly ◽  
Cellular Processes ◽  
Subsequent Effect ◽  
Control Protein ◽  
Epigenetic Processes

Trimethyllysine is an important post-translationally modified amino acid with functions in the carnitine biosynthesis and regulation of key epigenetic processes. Protein lysine methyltransferases and demethylases dynamically control protein lysine methylation, with each state of methylation changing the biophysical properties of lysine and the subsequent effect on protein function, in particular histone proteins and their central role in epigenetics. Epigenetic reader domain proteins can distinguish between different lysine methylation states and initiate downstream cellular processes upon recognition. Dysregulation of protein methylation is linked to various diseases, including cancer, inflammation, and genetic disorders. In this review, we cover biomolecular studies on the role of trimethyllysine in carnitine biosynthesis, different enzymatic reactions involved in the synthesis and removal of trimethyllysine, trimethyllysine recognition by reader proteins, and the role of trimethyllysine on the nucleosome assembly.

Why there is more to protein evolution than protein function: splicing, nucleosomes and dual-coding sequence

2009 ◽  
Vol 37 (4) ◽  
pp. 756-761 ◽  
Author(s):  
Tobias Warnecke ◽  
Claudia C. Weber ◽  
Laurence D. Hurst
Keyword(s):  
Amino Acid ◽  
Protein Evolution ◽  
Protein Function ◽  
Dual Coding ◽  
Splice Enhancer ◽  
Dna And Rna ◽  
Rates Of Evolution ◽  
Exonic Splice ◽  
Production History

There is considerable variation in the rate at which different proteins evolve. Why is this? Classically, it has been considered that the density of functionally important sites must predict rates of protein evolution. Likewise, amino acid choice is usually assumed to reflect optimal protein function. In the present article, we briefly review evidence suggesting that this protein function-centred view is too simplistic. In particular, we concentrate on how selection acting during the protein's production history can also affect protein evolutionary rates and amino acid choice. Exploring the role of selection at the DNA and RNA level, we specifically address how the need (i) to specify exonic splice enhancer motifs in pre-mRNA, and (ii) to ensure nucleosome positioning on DNA have an impact on amino acid choice and rates of evolution. For both, we review evidence that sequence affected by more than one coding demand is particularly constrained. Strikingly, in mammals, splicing-related constraints are quantitatively as important as expression parameters in predicting rates of protein evolution. These results indicate that there is substantially more to protein evolution than protein functional constraints.

scholarly journals Ubiquitin-Specific Proteases: Players in Cancer Cellular Processes

2021 ◽  
Vol 14 (9) ◽  
pp. 848
Author(s):  
Lucas Cruz ◽  
Paula Soares ◽  
Marcelo Correia
Keyword(s):  
Protein Function ◽  
Deubiquitinating Enzymes ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Cellular Targets ◽  
Cellular Processes ◽  
Protein Ubiquitination ◽  
Damage Repair ◽  
Ubiquitin Molecule

Ubiquitination represents a post-translational modification (PTM) essential for the maintenance of cellular homeostasis. Ubiquitination is involved in the regulation of protein function, localization and turnover through the attachment of a ubiquitin molecule(s) to a target protein. Ubiquitination can be reversed through the action of deubiquitinating enzymes (DUBs). The DUB enzymes have the ability to remove the mono- or poly-ubiquitination signals and are involved in the maturation, recycling, editing and rearrangement of ubiquitin(s). Ubiquitin-specific proteases (USPs) are the biggest family of DUBs, responsible for numerous cellular functions through interactions with different cellular targets. Over the past few years, several studies have focused on the role of USPs in carcinogenesis, which has led to an increasing development of therapies based on USP inhibitors. In this review, we intend to describe different cellular functions, such as the cell cycle, DNA damage repair, chromatin remodeling and several signaling pathways, in which USPs are involved in the development or progression of cancer. In addition, we describe existing therapies that target the inhibition of USPs.

scholarly journals AML1/ETO and its function as a regulator of gene transcription via epigenetic mechanisms

Oncogene ◽  
2021 ◽  
Author(s):  
Kai Rejeski ◽  
Jesús Duque-Afonso ◽  
Michael Lübbert
Keyword(s):  
Gene Transcription ◽  
Protein Function ◽  
Structural Changes ◽  
Target Genes ◽  
Chromosomal Translocation ◽  
Global Changes ◽  
Cellular Processes ◽  
Genetic Landscape ◽  
Specific Impact

AbstractThe chromosomal translocation t(8;21) and the resulting oncofusion gene AML1/ETO have long served as a prototypical genetic lesion to model and understand leukemogenesis. In this review, we describe the wide-ranging role of AML1/ETO in AML leukemogenesis, with a particular focus on the aberrant epigenetic regulation of gene transcription driven by this AML-defining mutation. We begin by analyzing how structural changes secondary to distinct genomic breakpoints and splice changes, as well as posttranscriptional modifications, influence AML1/ETO protein function. Next, we characterize how AML1/ETO recruits chromatin-modifying enzymes to target genes and how the oncofusion protein alters chromatin marks, transcription factor binding, and gene expression. We explore the specific impact of these global changes in the epigenetic network facilitated by the AML1/ETO oncofusion on cellular processes and leukemic growth. Furthermore, we define the genetic landscape of AML1/ETO-positive AML, presenting the current literature concerning the incidence of cooperating mutations in genes such as KIT, FLT3, and NRAS. Finally, we outline how alterations in transcriptional regulation patterns create potential vulnerabilities that may be exploited by epigenetically active agents and other therapeutics.

scholarly journals The evolution and engineering of enzyme activity through tuning conformational landscapes

2021 ◽  
Vol 34 ◽  
Author(s):  
Adam M Damry ◽  
Colin J Jackson
Keyword(s):  
Structural Biology ◽  
Protein Evolution ◽  
Protein Function ◽  
Conformational Sampling ◽  
Conformational Substates ◽  
Evolutionary Trajectories ◽  
Conformational Landscape ◽  
Enzyme Functions ◽  
Insight Into

Abstract Proteins are dynamic molecules whose structures consist of an ensemble of conformational states. Dynamics contribute to protein function and a link to protein evolution has begun to emerge. This increased appreciation for the evolutionary impact of conformational sampling has grown from our developing structural biology capabilities and the exploration of directed evolution approaches, which have allowed evolutionary trajectories to be mapped. Recent studies have provided empirical examples of how proteins can evolve via conformational landscape alterations. Moreover, minor conformational substates have been shown to be involved in the emergence of new enzyme functions as they can become enriched through evolution. The role of remote mutations in stabilizing new active site geometries has also granted insight into the molecular basis underpinning poorly understood epistatic effects that guide protein evolution. Finally, we discuss how the growth of our understanding of remote mutations is beginning to refine our approach to engineering enzymes.

scholarly journals The Role of Deubiquitinases in Oncovirus and Host Interactions

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Yueshuo Li ◽  
Feng Shi ◽  
Jianmin Hu ◽  
Longlong Xie ◽  
Ann M. Bode ◽  
...  
Keyword(s):  
Life Cycle ◽  
Signaling Pathways ◽  
Protein Function ◽  
Deubiquitinating Enzymes ◽  
Antiviral Signaling ◽  
Host Interactions ◽  
Cellular Processes ◽  
Ubiquitin System ◽  
Almost All

Infection-related cancer comprises one-sixth of the global cancer burden. Oncoviruses can directly or indirectly contribute to tumorigenesis. Ubiquitination is a dynamic and reversible posttranslational modification that participates in almost all cellular processes. Hijacking of the ubiquitin system by viruses continues to emerge as a central theme around the viral life cycle. Deubiquitinating enzymes (DUBs) maintain ubiquitin homeostasis by removing ubiquitin modifications from target proteins, thereby altering protein function, stability, and signaling pathways, as well as acting as key mediators between the virus and its host. In this review, we focus on the multiple functions of DUBs in RIG-I-like receptors (RLRs) and stimulator of interferon genes (STING)-mediated antiviral signaling pathways, oncoviruses regulation of NF-κB activation, oncoviral life cycle, and the potential of DUB inhibitors as therapeutic strategies.

Role of small nuclear RNAs in eukaryotic gene expression

2013 ◽  
Vol 54 ◽  
pp. 79-90 ◽  
Author(s):  
Saba Valadkhan ◽  
Lalith S. Gunawardane
Keyword(s):  
Gene Expression ◽  
Protein Interactions ◽  
Rna Stability ◽  
Splice Sites ◽  
Branch Site ◽  
Small Nuclear Rnas ◽  
Eukaryotic Gene Expression ◽  
Eukaryotic Gene ◽  
Rna Biogenesis

Eukaryotic cells contain small, highly abundant, nuclear-localized non-coding RNAs [snRNAs (small nuclear RNAs)] which play important roles in splicing of introns from primary genomic transcripts. Through a combination of RNA–RNA and RNA–protein interactions, two of the snRNPs, U1 and U2, recognize the splice sites and the branch site of introns. A complex remodelling of RNA–RNA and protein-based interactions follows, resulting in the assembly of catalytically competent spliceosomes, in which the snRNAs and their bound proteins play central roles. This process involves formation of extensive base-pairing interactions between U2 and U6, U6 and the 5′ splice site, and U5 and the exonic sequences immediately adjacent to the 5′ and 3′ splice sites. Thus RNA–RNA interactions involving U2, U5 and U6 help position the reacting groups of the first and second steps of splicing. In addition, U6 is also thought to participate in formation of the spliceosomal active site. Furthermore, emerging evidence suggests additional roles for snRNAs in regulation of various aspects of RNA biogenesis, from transcription to polyadenylation and RNA stability. These snRNP-mediated regulatory roles probably serve to ensure the co-ordination of the different processes involved in biogenesis of RNAs and point to the central importance of snRNAs in eukaryotic gene expression.

Forming Impressions of Personality

2014 ◽  
Vol 45 (3) ◽  
pp. 153-163 ◽  
Author(s):  
Sanne Nauts ◽  
Oliver Langner ◽  
Inge Huijsmans ◽  
Roos Vonk ◽  
Daniël H. J. Wigboldus
Keyword(s):  
Impression Formation ◽  
Context Dependent

Asch’s seminal research on “Forming Impressions of Personality” (1946) has widely been cited as providing evidence for a primacy-of-warmth effect, suggesting that warmth-related judgments have a stronger influence on impressions of personality than competence-related judgments (e.g., Fiske, Cuddy, & Glick, 2007 ; Wojciszke, 2005 ). Because this effect does not fit with Asch’s Gestalt-view on impression formation and does not readily follow from the data presented in his original paper, the goal of the present study was to critically examine and replicate the studies of Asch’s paper that are most relevant to the primacy-of-warmth effect. We found no evidence for a primacy-of-warmth effect. Instead, the role of warmth was highly context-dependent, and competence was at least as important in shaping impressions as warmth.

Exchange Spin Coupling from Gaussian Process Regression

2020 ◽  
Author(s):  
Marc Philipp Bahlke ◽  
Natnael Mogos ◽  
Jonny Proppe ◽  
Carmen Herrmann
Keyword(s):  
Machine Learning ◽  
Gaussian Process ◽  
Gaussian Process Regression ◽  
Molecular Magnets ◽  
Molecular Structures ◽  
Spin Coupling ◽  
Structure Property ◽  
Data Set ◽  
Uncertainty Estimates

Heisenberg exchange spin coupling between metal centers is essential for describing and understanding the electronic structure of many molecular catalysts, metalloenzymes, and molecular magnets for potential application in information technology. We explore the machine-learnability of exchange spin coupling, which has not been studied yet. We employ Gaussian process regression since it can potentially deal with small training sets (as likely associated with the rather complex molecular structures required for exploring spin coupling) and since it provides uncertainty estimates (“error bars”) along with predicted values. We compare a range of descriptors and kernels for 257 small dicopper complexes and find that a simple descriptor based on chemical intuition, consisting only of copper-bridge angles and copper-copper distances, clearly outperforms several more sophisticated descriptors when it comes to extrapolating towards larger experimentally relevant complexes. Exchange spin coupling is similarly easy to learn as the polarizability, while learning dipole moments is much harder. The strength of the sophisticated descriptors lies in their ability to linearize structure-property relationships, to the point that a simple linear ridge regression performs just as well as the kernel-based machine-learning model for our small dicopper data set. The superior extrapolation performance of the simple descriptor is unique to exchange spin coupling, reinforcing the crucial role of choosing a suitable descriptor, and highlighting the interesting question of the role of chemical intuition vs. systematic or automated selection of features for machine learning in chemistry and material science.

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