scholarly journals Molecular Chaperones Accelerate the Evolution of Their Protein Clients in Yeast

2019 ◽  
Vol 11 (8) ◽  
pp. 2360-2375 ◽  
Author(s):  
David Alvarez-Ponce ◽  
José Aguilar-Rodríguez ◽  
Mario A Fares
Keyword(s):  
Protein Stability ◽  
Time Scales ◽  
Protein Evolution ◽  
Protein Interactions ◽  
Molecular Chaperones ◽  
Interaction Network ◽  
Evolutionary Divergence ◽  
Evolutionary Time ◽  
Genes Encoding ◽  
Client Proteins

Abstract Protein stability is a major constraint on protein evolution. Molecular chaperones, also known as heat-shock proteins, can relax this constraint and promote protein evolution by diminishing the deleterious effect of mutations on protein stability and folding. This effect, however, has only been stablished for a few chaperones. Here, we use a comprehensive chaperone–protein interaction network to study the effect of all yeast chaperones on the evolution of their protein substrates, that is, their clients. In particular, we analyze how yeast chaperones affect the evolutionary rates of their clients at two very different evolutionary time scales. We first study the effect of chaperone-mediated folding on protein evolution over the evolutionary divergence of Saccharomyces cerevisiae and S. paradoxus. We then test whether yeast chaperones have left a similar signature on the patterns of standing genetic variation found in modern wild and domesticated strains of S. cerevisiae. We find that genes encoding chaperone clients have diverged faster than genes encoding non-client proteins when controlling for their number of protein–protein interactions. We also find that genes encoding client proteins have accumulated more intraspecific genetic diversity than those encoding non-client proteins. In a number of multivariate analyses, controlling by other well-known factors that affect protein evolution, we find that chaperone dependence explains the largest fraction of the observed variance in the rate of evolution at both evolutionary time scales. Chaperones affecting rates of protein evolution mostly belong to two major chaperone families: Hsp70s and Hsp90s. Our analyses show that protein chaperones, by virtue of their ability to buffer destabilizing mutations and their role in modulating protein genotype–phenotype maps, have a considerable accelerating effect on protein evolution.

scholarly journals Molecular chaperones accelerate the evolution of their protein clients in yeast

2019 ◽  
Author(s):  
David Alvarez-Ponce ◽  
José Aguilar-Rodríguez ◽  
Mario A. Fares
Keyword(s):  
Protein Stability ◽  
Time Scales ◽  
Protein Evolution ◽  
Protein Interactions ◽  
Molecular Chaperones ◽  
Interaction Network ◽  
Evolutionary Divergence ◽  
Evolutionary Time ◽  
Genes Encoding ◽  
Shock Proteins

ABSTRACTProtein stability is a major constraint on protein evolution. Molecular chaperones, also known as heat-shock proteins, can relax this constraint and promote protein evolution by diminishing the deleterious effect of mutations on protein stability and folding. This effect, however, has only been stablished for a few chaperones. Here, we use a comprehensive chaperone-protein interaction network to study the effect of all yeast chaperones on the evolution of their protein substrates, that is, their clients. In particular, we analyze how yeast chaperones affect the evolutionary rates of their clients at two very different evolutionary time scales. We first study the effect of chaperone-mediated folding on protein evolution over the evolutionary divergence of Saccharomyces cerevisiae and S. paradoxus. We then test whether yeast chaperones have left a similar signature on the patterns of standing genetic variation found in modern wild and domesticated strains of S. cerevisiae. We find that genes encoding chaperone clients have diverged faster than genes encoding nonclient proteins when controlling for their number of protein-protein interactions. We also find that genes encoding client proteins have accumulated more intra-specific genetic diversity than those encoding nonclient proteins. In a number of multivariate analyses, controlling by other well-known factors that affect protein evolution, we find that chaperone dependence explains the largest fraction of the observed variance in the rate of evolution at both evolutionary time scales. Chaperones affecting rates of protein evolution mostly belong to two major chaperone families: Hsp70s and Hsp90s. Our analyses show that protein chaperones, by virtue of their ability to buffer destabilizing mutations and their role in modulating protein genotype-phenotype maps, have a considerable accelerating effect on protein evolution.

scholarly journals Evolution of frustrated and stabilising contacts in reconstructed ancient proteins

2021 ◽  
Author(s):  
Martina Crippa ◽  
Damiano Andreghetti ◽  
Riccardo Capelli ◽  
Guido Tiana
Keyword(s):  
Amino Acids ◽  
Protein Stability ◽  
Interaction Network ◽  
Reconstruction Algorithm ◽  
Major Determinant ◽  
Evolutionary Time ◽  
Energetic Properties ◽  
Ancient Proteins ◽  
Evolutionary Fitness

AbstractEnergetic properties of a protein are a major determinant of its evolutionary fitness. Using a reconstruction algorithm, dating the reconstructed proteins and calculating the interaction network between their amino acids through a coevolutionary approach, we studied how the interactions that stabilise 890 proteins, belonging to five families, evolved for billions of years. In particular, we focused our attention on the network of most strongly attractive contacts and on that of poorly optimised, frustrated contacts. Our results support the idea that the cluster of most attractive interactions extends its size along evolutionary time, but from the data, we cannot conclude that protein stability or that the degree of frustration tends always to decrease.

scholarly journals The molecular chaperone DnaK accelerates protein evolution

2016 ◽  
Author(s):  
Jose Aguilar-Rodriguez ◽  
Beatriz Sabater-Munoz ◽  
Victor Berlanga ◽  
David Alvarez-Ponce ◽  
Andreas Wagner ◽  
...  
Keyword(s):  
Time Scales ◽  
Protein Evolution ◽  
Sequence Data ◽  
Evolutionary Rates ◽  
Evolutionary Time ◽  
Nucleotide Substitutions ◽  
Chaperone Dnak ◽  
Nucleotide Insertions ◽  
Shock Proteins ◽  
And Function

Molecular chaperones, also known as heat-shock proteins, refold misfolded proteins and help other proteins reach their native conformation. Thanks to these abilities, some chaperones, such as the Hsp90 protein or the chaperonin GroEL, can buffer the deleterious phenotypic effects of mutations that alter protein structure and function. Hsp70 chaperones use a chaperoning mechanism different from Hsp90 and GroEL, and it is not known whether they can also buffer mutations. Here, we show that they can. To this end, we performed a mutation accumulation experiment inEscherichia coli, followed by whole-genome resequencing. Our sequence data shows that overexpression of the Hsp70 chaperone DnaK increases the tolerance of its clients for nonsynonymous nucleotide substitutions and nucleotide insertions and deletions. We also show that this elevated mutational buffering on short evolutionary time scales translates into differences in evolutionary rates on intermediate and long evolutionary time scales. To this end, we compared the evolutionary rates of DnaK clients and nonclients using the genomes ofE. coli,Salmonella typhimurium, and 83 other gamma-proteobacterial species. We find that clients that interact strongly with DnaK evolve faster than weakly interacting clients. Our results imply that all three major chaperone classes can buffer mutations and affect protein evolution. They illustrate how an individual protein like a chaperone can have a disproportionate effect on proteome evolution.

Network Pharmacology Approach uncovering Pathways involved in targeting Hsp90 through Curcumin and Epigallocatechin to control Inflammation.

2019 ◽  
Vol 16 ◽  
Author(s):  
Umme Hani ◽  
Shivananda Kandagalla ◽  
B.S. Sharath ◽  
K Jyothsna. ◽  
H Manjunatha.
Keyword(s):  
Gene Ontology ◽  
Molecular Chaperones ◽  
Curcuma Longa ◽  
Interaction Network ◽  
Network Pharmacology ◽  
Heme Oxygenase 1 ◽  
Nrf2 Pathway ◽  
Functional Behavior ◽  
Inflammatory Proteins ◽  
Prime Target

: Hsp90 are molecular chaperones of chronic inflammatory proteins and have emerged as prime target for treatment of inflammation. Principal components from Curcuma longa and Camellia sinensis, Curcumin and EGC respectively possesses anti-inflammatory properties inhibiting cytokines responsible for inflammation. Both act on common pathways in upregulation of heme oxygenase 1 through Pkcδ-Nrf2 pathway and downregulation of Tlr4, which in turn suppress expression of Hsp90. Curcumin and EGC were also found to bind -N and -C terminal domain of Hsp90 respectively. Based on this, work was designed with network pharmacological approach. Hsp90 associated gene targets of Curcumin and EGC were collected from databases, and gene ontology studies were done. PPI were obtained from string database for specific genes involved in Pkcδ-Nrf2 and Tlr4 pathway. Protein interaction network was constructed by cytoscape, and networks of Hsp90, Curcumin and EGC were merged to get common genes involved in Pkcδ-Nrf2 and Tlr4 pathway. Cluego analysis was done for obtained common genes to identify functional behavior in human diseases. Main proteins involved were identified as key regulators in Pkcδ-Nrf2 and Tlr4 pathway for controlling expression of Hsp90 from Curcumin and EGC in inflammation. Docking was performed on main proteins, Hsp90, Pkcδ and Tlr4 with Curcumin and EGC, significant binding energy was obtained for docked complexes. Combinatorial effects of Curcumin and EGC were observed in Pkcδ-Nrf2 and Tlr4pathway. Present study is an attempt to unravel common pathways mediated in intervention of Curcumin and EGC for suppression of Hsp90 associated with inflammation.

scholarly journals Short loop functional commonality identified in leukaemia proteome highlights crucial protein sub-networks

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Sun Sook Chung ◽  
Joseph C F Ng ◽  
Anna Laddach ◽  
N Shaun B Thomas ◽  
Franca Fraternali
Keyword(s):  
Protein Interactions ◽  
Large Scale ◽  
Interaction Network ◽  
Protein Protein Interactions ◽  
Protein Protein Interaction ◽  
Ppi Networks ◽  
Short Loop ◽  
New Strategy ◽  
Loop Network ◽  
Protein Protein Interaction Network

Abstract Direct drug targeting of mutated proteins in cancer is not always possible and efficacy can be nullified by compensating protein–protein interactions (PPIs). Here, we establish an in silico pipeline to identify specific PPI sub-networks containing mutated proteins as potential targets, which we apply to mutation data of four different leukaemias. Our method is based on extracting cyclic interactions of a small number of proteins topologically and functionally linked in the Protein–Protein Interaction Network (PPIN), which we call short loop network motifs (SLM). We uncover a new property of PPINs named ‘short loop commonality’ to measure indirect PPIs occurring via common SLM interactions. This detects ‘modules’ of PPI networks enriched with annotated biological functions of proteins containing mutation hotspots, exemplified by FLT3 and other receptor tyrosine kinase proteins. We further identify functional dependency or mutual exclusivity of short loop commonality pairs in large-scale cellular CRISPR–Cas9 knockout screening data. Our pipeline provides a new strategy for identifying new therapeutic targets for drug discovery.

scholarly journals A unified resource and configurable model of the synapse proteome and its role in disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Oksana Sorokina ◽  
Colin Mclean ◽  
Mike D. R. Croning ◽  
Katharina F. Heil ◽  
Emilia Wysocka ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Synaptic Proteins ◽  
Protein Protein Interactions ◽  
Network Resource ◽  
Unique Protein ◽  
Co Morbidity ◽  
Genes Encoding ◽  
Protein Components ◽  
Accessible Format ◽  
Neuronal Disorders

AbstractGenes encoding synaptic proteins are highly associated with neuronal disorders many of which show clinical co-morbidity. We integrated 58 published synaptic proteomic datasets that describe over 8000 proteins and combined them with direct protein–protein interactions and functional metadata to build a network resource that reveals the shared and unique protein components that underpin multiple disorders. All the data are provided in a flexible and accessible format to encourage custom use.

scholarly journals Frequent assembly of chimeric complexes in the protein interaction network of an interspecies yeast hybrid

2020 ◽  
Author(s):  
Rohan Dandage ◽  
Caroline M Berger ◽  
Isabelle Gagnon-Arsenault ◽  
Kyung-Mee Moon ◽  
Richard Greg Stacey ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Molecular Level ◽  
Yeast Species ◽  
Protein Complexes ◽  
Mitochondrial Protein ◽  
Chimeric Protein ◽  
Interaction Network ◽  
Protein Protein Interactions ◽  
Extreme Phenotypes ◽  
Yeast Hybrid

Abstract Hybrids between species often show extreme phenotypes, including some that take place at the molecular level. In this study, we investigated the phenotypes of an interspecies diploid hybrid in terms of protein-protein interactions inferred from protein correlation profiling. We used two yeast species, Saccharomyces cerevisiae and Saccharomyces uvarum, which are interfertile, but yet have proteins diverged enough to be differentiated using mass spectrometry. Most of the protein-protein interactions are similar between hybrid and parents, and are consistent with the assembly of chimeric complexes, which we validated using an orthogonal approach for the prefoldin complex. We also identified instances of altered protein-protein interactions in the hybrid, for instance in complexes related to proteostasis and in mitochondrial protein complexes. Overall, this study uncovers the likely frequent occurrence of chimeric protein complexes with few exceptions, which may result from incompatibilities or imbalances between the parental proteins.

scholarly journals Basal Body Structures Differentially Affect Transcription of RpoN- and FliA-Dependent Flagellar Genes in Helicobacter pylori

2015 ◽  
Vol 197 (11) ◽  
pp. 1921-1930 ◽  
Author(s):  
Jennifer Tsang ◽  
Timothy R. Hoover
Keyword(s):  
Helicobacter Pylori ◽  
Basal Body ◽  
Protein Interactions ◽  
Transcript Levels ◽  
Content Type ◽  
Genes Encoding ◽  
H Pylori ◽  
Flagellar Biogenesis ◽  
Flagellar Genes

ABSTRACTFlagellar biogenesis inHelicobacter pyloriis regulated by a transcriptional hierarchy governed by three sigma factors, RpoD (σ80), RpoN (σ54), and FliA (σ28), that temporally coordinates gene expression with the assembly of the flagellum. Previous studies showed that loss of flagellar protein export apparatus components inhibits transcription of flagellar genes. The FlgS/FlgR two-component system activates transcription of RpoN-dependent genes though an unknown mechanism. To understand better the extent to which flagellar gene regulation is coupled to flagellar assembly, we disrupted flagellar biogenesis at various points and determined how these mutations affected transcription of RpoN-dependent (flaBandflgE) and FliA-dependent (flaA) genes. The MS ring (encoded byfliF) is one of the earliest flagellar structures assembled. Deletion offliFresulted in the elimination of RpoN-dependent transcripts and an ∼4-fold decrease inflaAtranscript levels. FliH is a cytoplasmic protein that functions with the C ring protein FliN to shuttle substrates to the export apparatus. Deletions offliHand genes encoding C ring components (fliMandfliY) decreased transcript levels offlaBandflgEbut had little or no effect on transcript levels offlaA. Transcript levels offlaBandflgEwere elevated in mutants where genes encoding rod proteins (fliEandflgBC) were deleted, while transcript levels offlaAwas reduced ∼2-fold in both mutants. We propose that FlgS responds to an assembly checkpoint associated with the export apparatus and that FliH and one or more C ring component assist FlgS in engaging this flagellar structure.IMPORTANCEThe mechanisms used by bacteria to couple transcription of flagellar genes with assembly of the flagellum are poorly understood. The results from this study identified components of theH. pyloriflagellar basal body that either positively or negatively affect expression of RpoN-dependent flagellar genes. Some of these basal body proteins may interact directly with regulatory proteins that control transcription of theH. pyloriRpoN regulon, a hypothesis that can be tested by examining protein-protein interactionsin vitro.

A guide-tag system controlling client enrichment into Y15 peptide-based granules for an in-cell protein recruitment assay

2021 ◽  
Author(s):  
Takayuki Miki ◽  
Masahiro Hashimoto ◽  
Taichi Nakai ◽  
Hisakazu Mihara
Keyword(s):  
Protein Interactions ◽  
Living Cells ◽  
The Self ◽  
Cell Protein ◽  
Protein Protein Interactions ◽  
Self Assembling ◽  
Client Proteins ◽  
Protein Recruitment ◽  
Peptide Tag

A series of guide-tags that can control the enrichment of client proteins into artificial scaffolds constituted by the self-assembling Y15 peptide tag facilitates the analysis of protein–protein interactions in living cells.

Genetic regulation of nitrogen metabolism in the fungi

1997 ◽  
Vol 61 (1) ◽  
pp. 17-32
Author(s):  
G A Marzluf
Keyword(s):  
Nitrogen Metabolism ◽  
Protein Interactions ◽  
Fungal Pathogens ◽  
Metabolic Regulation ◽  
Specific Binding ◽  
Genetic Regulation ◽  
Nitrogen Sources ◽  
Specific Protein ◽  
Genes Encoding ◽  
Gata Family

In the fungi, nitrogen metabolism is controlled by a complex genetic regulatory circuit which ensures the preferential use of primary nitrogen sources and also confers the ability to use many different secondary nitrogen sources when appropriate. Most structural genes encoding nitrogen catabolic enzymes are subject to nitrogen catabolite repression, mediated by positive-acting transcription factors of the GATA family of proteins. However, certain GATA family members, such as the yeast DAL80 factor, act negatively to repress gene expression. Selective expression of the genes which encode enzymes for the metabolism of secondary nitrogen sources is often achieved by induction, mediated by pathway-specific factors, many of which have a GAL4-like C6/Zn2 DNA binding domain. Regulation within the nitrogen circuit also involves specific protein-protein interactions, as exemplified by the specific binding of the negative-acting NMR protein with the positive-acting NIT2 protein of Neurospora crassa. Nitrogen metabolic regulation appears to play a significant role in the pathogenicity of certain animal and plant fungal pathogens.

Sign in / Sign up

Export Citation Format

Share Document