scholarly journals A shift in aggregation avoidance strategy marks a long-term direction to protein evolution

2017 ◽  
Author(s):  
S.G. Foy ◽  
B.A. Wilson ◽  
J. Bertram ◽  
M.H.J. Cordes ◽  
J. Masel
Keyword(s):  
Amino Acids ◽  
Common Ancestor ◽  
Gene Families ◽  
Protein Coding ◽  
Hydrophobic Residues ◽  
Extant Species ◽  
Aggregation Problem ◽  
Hydrophobic Amino Acids ◽  
Ancestral States

AbstractTo detect a direction to evolution, without the pitfalls of reconstructing ancestral states, we need to compare “more evolved” to “less evolved” entities. But because all extant species have the same common ancestor, none are chronologically more evolved than any other. However, different gene families were born at different times, allowing us to compare young protein-coding genes to those that are older and hence have been evolving for longer. To be retained during evolution, a protein must not only have a function, but must also avoid toxic dysfunction such as protein aggregation. There is conflict between the two requirements; hydrophobic amino acids form the cores of protein folds, but also promote aggregation. Young genes avoid strongly hydrophobic amino acids, which is presumably the simplest solution to the aggregation problem. Here we show that young genes’ few hydrophobic residues are clustered near one another along the primary sequence, presumably to assist folding. The higher aggregation risk created by the higher hydrophobicity of older genes is counteracted by more subtle effects in the ordering of the amino acids, including a reduction in the clustering of hydrophobic residues until they eventually become more interspersed than if distributed randomly. This interspersion has previously been reported to be a general property of proteins, but here we find that it is restricted to old genes. Quantitatively, the index of dispersion delineates a gradual trend, i.e. a decrease in the clustering of hydrophobic amino acids over billions of years.

scholarly journals Universal and taxon-specific trends in protein sequences as a function of age

2020 ◽  
Author(s):  
Jennifer E James ◽  
Sara M Willis ◽  
Paul G Nelson ◽  
Catherine Weibel ◽  
Luke J Kosinski ◽  
...  
Keyword(s):  
Common Ancestor ◽  
Young Animal ◽  
Structural Disorder ◽  
Last Universal Common Ancestor ◽  
Protein Coding ◽  
Universal Common Ancestor ◽  
Eukaryotic Species ◽  
Life On Earth ◽  
Hydrophobic Clustering

AbstractExtant protein-coding sequences span a huge range of ages, from those that emerged only recently in particular lineages, to those present in the last universal common ancestor. Because evolution has had less time to act on young sequences, there might be “phylostratigraphy” trends in any properties that evolve slowly with age. Indeed, a long-term reduction in hydrophobicity and in hydrophobic clustering has been found in previous, taxonomically restricted studies. Here we perform integrated phylostratigraphy across 435 fully sequenced and dated eukaryotic species, using sensitive HMM methods to detect homology of protein domains (which may vary in age within the same gene), and applying a variety of quality filters. We find that the reduction in hydrophobic clustering is universal across diverse lineages, showing limited sign of saturation. But the tendency for young domains to have higher protein structural disorder, driven primarily by more hydrophilic amino acids, is found only among young animal domains, and not young plant domains, nor ancient domains predating the existence of the last eukaryotic common ancestor. Among ancient domains, trends in amino acid composition reflect the order of recruitment into the genetic code, suggesting that events during the earliest stages of life on earth continue to have an impact on the composition of ancient sequences.

scholarly journals Role of conserved hydrophobic amino acids in androgen receptor AF-1 function

2003 ◽  
Vol 31 (3) ◽  
pp. 427-439 ◽  
Author(s):  
R Betney ◽  
IJ McEwan
Keyword(s):  
Amino Acids ◽  
Transcription Factor ◽  
Androgen Receptor ◽  
Gene Transcription ◽  
Hydrophobic Residues ◽  
Steroid Receptor Coactivator ◽  
Binding Interface ◽  
Hydrophobic Amino Acids

The intracellular androgen receptor (AR) is a ligand-activated transcription factor. Upon binding the steroids testosterone or dihydrotestosterone, the activated receptor translocates to the nucleus, binds to specific DNA response elements and interacts with the transcription machinery in order to regulate gene transcription. In the present study, we have described a highly conserved region (amino acids 224-258) within the AR AF-1 domain and have investigated the role of conserved bulky hydrophobic residues in gene regulation. Mutating pairs of residues (I229A/L236A; V240A/V242A; L251A/L254A) reduced transactivation activity by 25-40%. Mutating residues M244, L246 and V248 to alanines had a more dramatic affect on receptor activity, disrupting activity by at least 60%. The latter mutations also disrupted binding to the RNA polymerase-associated protein 74 subunit of the general transcription factor TFIIF. The protein conformation and stability of the mutant polypeptide in vitro was not significantly different from the wild type. None of the mutations tested disrupted binding of the AF-1 domain with the coactivator protein steroid receptor coactivator-1a. Thus we have concluded that conserved hydrophobic residues are important for receptor-dependent gene transcription and that M244, L246 and V248 are part of the binding interface for TFIIF.

scholarly journals Conformation-dependent influences of hydrophobic amino acids in two in-register parallel β-sheet amyloids, an α-synuclein amyloid and a local structural model of PrPSc

2019 ◽  
Author(s):  
Hiroki Otaki ◽  
Yuzuru Taguchi ◽  
Noriyuki Nishida
Keyword(s):  
Molecular Dynamics ◽  
Amino Acids ◽  
Prion Protein ◽  
Md Simulation ◽  
Structural Model ◽  
Prion Diseases ◽  
Md Simulations ◽  
Hydrophobic Residues ◽  
Prion Strains ◽  
Hydrophobic Amino Acids

AbstractPrions are pathogens that consist solely of abnormal isoforms of prion protein (PrPSc) without any genetic material. Therefore, they depend on purely protein-based mechanisms for diversification and maintenance of the pathogenetic information of prion strains. According to the protein-only hypothesis, the pathogenic properties of prions are determined by conformations of the constituent PrPSc, and alterations to even a single residue can drastically change the properties when the residue is located at a critical structural position of PrPSc. Interestingly, differences between polymorphic or species-specific residues responsible for the species/strain barriers are often caused by conservative replacements between hydrophobic amino acids. This implies that subtle differences among hydrophobic amino acids are significant for PrPSc structures. Specifically how the differences affect the structures is difficult to demonstrate due to the lack of detailed PrPSc structures. Here, we analyzed the influence of different hydrophobic residues on structures of an in-register parallel β-sheet amyloid of α-synuclein (αSyn) using molecular dynamics (MD) simulation, and applied the knowledge from the αSyn amyloid to design local structures of human PrPSc encompassing residues 107–143. The MD simulations of the αSyn amyloid revealed that methionine uniquely stabilized a U-shaped β-arch of the αSyn amyloid, whereas other hydrophobic amino acids destabilized the β-arch. Then, we assessed influence of the polymorphisms on the newly-designed model of PrPSc that are known to affect the clinical phenotypes of prion diseases. The MD simulations of the model also revealed unique effects of hydrophobic amino acids depending on regional structures. For example, G127V mutation that corresponds to a protective polymorphism against various human prion diseases greatly destabilized a U-shaped β-arch. Our study demonstrates specifically how and in what structures hydrophobic residues can exert unique effects on in-register parallel β-sheet amyloids and provides insights into the molecular mechanism of the strain diversity of prions and other pathogenic amyloids.Author SummaryPrions are unconventional pathogens that encode the pathogenic information in conformations of the constituent abnormal isoform of prion protein (PrPSc), independently of nucleotide genome. Therefore, conformational diversity of PrPSc underlies existence of many prion strains and species barriers of prions, although the conformations still remain undetermined. As prion/PrPSc propagates through refolding the host-encoded prion protein (PrPC) into the same conformation as itself, species barriers occur when the conformation of PrPSc is incompatible with the amino acid sequence of PrPC and the nascent PrPSc cannot stably maintain the structure. Interestingly, species barriers are often caused by a difference of a single hydrophobic residue. We investigated how the subtle differences between hydrophobic amino acids affect the structural stabilities of amyloids using molecular dynamics (MD) simulation of a newly designed local structural model of PrPSc, assuming that it has in-register parallel β-sheet structures. We have found that mutations equivalent to polymorphisms that cause barriers substantially affects the stabilities; for example, G127V mutation that makes the host resistant to various human prion diseases greatly destabilized the amyloid. The results support that PrPSc is an in-register parallel β-sheet amyloid and demonstrate the usefulness of MD simulation in investigation of species barriers of prions.

scholarly journals Substrate specificities of Escherichia coli ItaT that acetylates aminoacyl-tRNAs

2020 ◽  
Author(s):  
Chuqiao Zhang ◽  
Yuka Yashiro ◽  
Yuriko Sakaguchi ◽  
Tsutomu Suzuki ◽  
Kozo Tomita
Keyword(s):  
Escherichia Coli ◽  
Amino Acids ◽  
Amino Group ◽  
Hydrophobic Pocket ◽  
Hydrophobic Residues ◽  
Substrate Specificities ◽  
E Coli ◽  
Hydrophobic Amino Acids

Abstract Escherichia coli ItaT toxin reportedly acetylates the α-amino group of the aminoacyl-moiety of Ile-tRNAIle specifically, using acetyl-CoA as an acetyl donor, thereby inhibiting protein synthesis. The mechanism of the substrate specificity of ItaT had remained elusive. Here, we present functional and structural analyses of E. coli ItaT, which revealed the mechanism of ItaT recognition of specific aminoacyl-tRNAs for acetylation. In addition to Ile-tRNAIle, aminoacyl-tRNAs charged with hydrophobic residues, such as Val-tRNAVal and Met-tRNAMet, were acetylated by ItaT in vivo. Ile-tRNAIle, Val-tRNAVal and Met-tRNAMet were acetylated by ItaT in vitro, while aminoacyl-tRNAs charged with other hydrophobic residues, such as Ala-tRNAAla, Leu-tRNALeu and Phe-tRNAPhe, were less efficiently acetylated. A comparison of the structures of E. coli ItaT and the protein N-terminal acetyltransferase identified the hydrophobic residues in ItaT that possibly interact with the aminoacyl moiety of aminoacyl-tRNAs. Mutations of the hydrophobic residues of ItaT reduced the acetylation activity of ItaT toward Ile-tRNAIlein vitro, as well as the ItaT toxicity in vivo. Altogether, the size and shape of the hydrophobic pocket of ItaT are suitable for the accommodation of the specific aminoacyl-moieties of aminoacyl-tRNAs, and ItaT has broader specificity toward aminoacyl-tRNAs charged with certain hydrophobic amino acids.

scholarly journals Distribution of Charged and Hydrophobic Amino Acids on the Surfaces of Two Types of Beta-Fructosidase from Thermotoga Maritima

2020 ◽  
Vol 2 (1) ◽  
pp. 4
Author(s):  
Farkhat Sakibaev ◽  
Marina Holyavka ◽  
Victoria Koroleva ◽  
Valeriy Artyukhov
Keyword(s):  
Amino Acids ◽  
Enzyme Activity ◽  
Active Center ◽  
Active Site ◽  
Thermotoga Maritima ◽  
Significant Loss ◽  
Hydrophobic Residues ◽  
Charged Amino Acids ◽  
Hydrophobic Amino Acids

Thermotoga maritima beta-fructosidases are enzymes that release beta-D-fructose from sucrose, raffinose, and fructan polymers such as inulin. The surfaces of beta-fructosidases 1UYP and 1W2T from Thermotoga maritima were studied in this work. It was showed that amino acids are not distributed equally on the surfaces of the enzymes. Several clusters of charged and hydrophobic residues were detected at pH 7.0. Such clusters were detected by calculation of the distances between them. It was determined that on surfaces of beta-fructosidases PDB ID: 1UYP and PDB ID: 1W2T, 96% and 95% of charged amino acids and also 50% and 42% of hydrophobic amino acids form clusters, respectively. Six clusters of charged amino acids on the surface of beta-fructosidase 1UYP and five clusters on the surface of beta-fructosidase 1W2T were detected. The composition of such clusters is presented. Both types of beta-fructosidase have three clusters of hydrophobic amino acids on their surface. These facts should be considered when choosing immobilization conditions. It was shown that a charged matrix is more promising for the immobilization of beta-fructosidases 1UYP and 1W2T from Thermotoga maritima due to the possibility of binding without any significant loss of activity due to their overlapping active center. Hydrophobic carriers are less promising due to the probable active site overlap. Such binding may have a loss of enzyme activity as a result.

scholarly journals The transcriptional activator GCN4 contains multiple activation domains that are critically dependent on hydrophobic amino acids.

1995 ◽  
Vol 15 (3) ◽  
pp. 1220-1233 ◽  
Author(s):  
C M Drysdale ◽  
E Dueñas ◽  
B M Jackson ◽  
U Reusser ◽  
G H Braus ◽  
...  
Keyword(s):  
Amino Acids ◽  
Translational Control ◽  
Substantial Reduction ◽  
Transcriptional Activator ◽  
Full Length ◽  
Activation Domain ◽  
Hydrophobic Residues ◽  
Activation Domains ◽  
Hydrophobic Amino Acids ◽  
High Level

GCN4 is a transcriptional activator in the bZIP family that regulates amino acid biosynthetic genes in the yeast Saccharomyces cerevisiae. Previous work suggested that the principal activation domain of GCN4 is a highly acidic segment of approximately 40 amino acids located in the center of the protein. We conducted a mutational analysis of GCN4 with a single-copy allele expressed under the control of the native promoter and translational control elements. Our results indicate that GCN4 contains two activation domains of similar potency that can function independently to promote high-level transcription of the target genes HIS3 and HIS4. One of these domains is coincident with the acidic activation domain defined previously; the other extends over the N-terminal one-third of the protein. Both domains are partially dependent on the coactivator protein ADA2. Each domain appears to be composed of two or more small subdomains that have additive effects on transcription and that can cooperate in different combinations to promote high-level expression of HIS3 and HIS4. At least three of these subdomains are critically dependent on bulky hydrophobic amino acids for their function. Five of the important hydrophobic residues, Phe-97, Phe-98, Met-107, Tyr-110, and Leu-113, fall within a region of proposed sequence homology between GCN4 and the herpesvirus acidic activator VP16. The remaining three residues, Trp-120, Leu-123, and Phe-124, are highly conserved between GCN4 and its Neurospora counterpart, cpc-1. Because of the functional redundancy in the activation domain, mutations at positions 97 and 98 must be combined with mutations at positions 120 to 124 to observe a substantial reduction in activation by full-length GCN4, and substitution of all eight hydrophobic residues was required to inactivate full-length GCN4. These hydrophobic residues may mediate important interactions between GCN4 and one or more of its target proteins in the transcription initiation complex.

scholarly journals Phylogenomics of the Epigenetic Toolkit Reveals Punctate Retention of Genes across Eukaryotes

2020 ◽  
Vol 12 (12) ◽  
pp. 2196-2210
Author(s):  
Agnes K M Weiner ◽  
Mario A Cerón-Romero ◽  
Ying Yan ◽  
Laura A Katz
Keyword(s):  
Common Ancestor ◽  
Regulation Of Gene Expression ◽  
Rapid Evolution ◽  
Chromatin Modification ◽  
Gene Families ◽  
Testate Amoebae ◽  
Model Organisms ◽  
Last Eukaryotic Common Ancestor ◽  
Evolutionary Patterns ◽  
Protein Coding

Abstract Epigenetic processes in eukaryotes play important roles through regulation of gene expression, chromatin structure, and genome rearrangements. The roles of chromatin modification (e.g., DNA methylation and histone modification) and non-protein-coding RNAs have been well studied in animals and plants. With the exception of a few model organisms (e.g., Saccharomyces and Plasmodium), much less is known about epigenetic toolkits across the remainder of the eukaryotic tree of life. Even with limited data, previous work suggested the existence of an ancient epigenetic toolkit in the last eukaryotic common ancestor. We use PhyloToL, our taxon-rich phylogenomic pipeline, to detect homologs of epigenetic genes and evaluate their macroevolutionary patterns among eukaryotes. In addition to data from GenBank, we increase taxon sampling from understudied clades of SAR (Stramenopila, Alveolata, and Rhizaria) and Amoebozoa by adding new single-cell transcriptomes from ciliates, foraminifera, and testate amoebae. We focus on 118 gene families, 94 involved in chromatin modification and 24 involved in non-protein-coding RNA processes based on the epigenetics literature. Our results indicate 1) the presence of a large number of epigenetic gene families in the last eukaryotic common ancestor; 2) differential conservation among major eukaryotic clades, with a notable paucity of genes within Excavata; and 3) punctate distribution of epigenetic gene families between species consistent with rapid evolution leading to gene loss. Together these data demonstrate the power of taxon-rich phylogenomic studies for illuminating evolutionary patterns at scales of >1 billion years of evolution and suggest that macroevolutionary phenomena, such as genome conflict, have shaped the evolution of the eukaryotic epigenetic toolkit.

Long term dietary intake of aromatic amino acids are associated with leptin gene expression in adipose tissues of non-diabetic adults

2018 ◽  
Author(s):  
Golaleh Asghari ◽  
Emad Yuzbashian ◽  
Maryam Zarkesh ◽  
Parvin Mirmiran ◽  
Mehdi Hedayati ◽  
...  
Keyword(s):  
Gene Expression ◽  
Amino Acids ◽  
Dietary Intake ◽  
Aromatic Amino Acids ◽  
Adipose Tissues

13C nuclear magnetic resonance study of cyclodipeptides containing 13C enriched hydrophobic amino acids

1980 ◽  
Vol 45 (2) ◽  
pp. 482-490 ◽  
Author(s):  
Jaroslav Vičar ◽  
François Piriou ◽  
Pierre Fromageot ◽  
Karel Bláha ◽  
Serge Fermandjian
Keyword(s):  
Amino Acids ◽  
Nuclear Magnetic Resonance ◽  
Nuclear Magnetic Resonance Study ◽  
Coupling Constants ◽  
Side Chain ◽  
Amino Acid Residues ◽  
Magnetic Resonance Study ◽  
Side Chain Conformation ◽  
13C Nuclear Magnetic Resonance ◽  
Hydrophobic Amino Acids

The diastereoisomeric pairs of cyclodipeptides cis- and trans-cyclo(Ala-Ala), cyclo(Ala-Phe), cyclo(Val-Val) and cyclo(Leu-Leu) containing 85% 13C enriched amino-acid residues were synthesized and their 13C-13C coupling constants were measured. The combination of 13C-13C and 1H-1H coupling constants enabled to estimate unequivocally the side chain conformation of the valine and leucine residues.

scholarly journals Long-term Diet Quality and Gut Microbiome Functionality: A Prospective, Shotgun Metagenomic Study among Urban Chinese Adults

2021 ◽  
Vol 5 (4) ◽  
Author(s):  
Danxia Yu ◽  
Yaohua Yang ◽  
Jirong Long ◽  
Wanghong Xu ◽  
Qiuyin Cai ◽  
...  
Keyword(s):  
Diet Quality ◽  
Gut Microbiome ◽  
Metabolic Pathways ◽  
Gene Families ◽  
Diet Group ◽  
Healthy Diet ◽  
Chinese Adults ◽  
Α Diversity ◽  
Unhealthy Diet

ABSTRACT Background Diet is known to affect human gut microbiome composition; yet, how diet affects gut microbiome functionality remains unclear. Objective We compared the diversity and abundance/presence of fecal microbiome metabolic pathways among individuals according to their long-term diet quality. Methods In 2 longitudinal cohorts, we assessed participants’ usual diets via repeated surveys during 1996–2011 and collected a stool sample in 2015–2018. Participants who maintained a healthy or unhealthy diet (i.e., stayed in the highest or lowest quintile of a healthy diet score throughout follow-up) were selected. Participants were excluded if they reported a history of cancer, cardiovascular disease, diabetes, or hypertension; had diarrhea or constipation in the last 7 d; or used antibiotics in the last 6 mo before stool collection. Functional profiling of shotgun metagenomics was performed using HUMAnN2. Associations of dietary variables and 420 microbial metabolic pathways were evaluated via multivariable-adjusted linear or logistic regression models. Results We included 144 adults (mean age = 64 y; 55% female); 66 had an unhealthy diet and 78 maintained a healthy diet. The healthy diet group had higher Shannon α-diversity indexes of microbial gene families and metabolic pathways (both P < 0.02), whereas β-diversity, as evaluated by Bray-Curtis distance, did not differ between groups (both P > 0.50). At P < 0.01 [false discovery rate (FDR) <0.15], the healthy diet group showed enriched pathways for vitamin and carrier biosynthesis (e.g., tetrahydrofolate, acetyl-CoA, and l-methionine) and tricarboxylic acid (TCA) cycle, and increased degradation (or reduced biosynthesis) of certain sugars [e.g., cytidine monophosphate (CMP)-legionaminate, deoxythymidine diphosphate (dTDP)-l-rhamnose, and sucrose], nucleotides, 4-aminobutanoate, methylglyoxal, sulfate, and aromatic compounds (e.g., catechol and toluene). Meanwhile, several food groups were associated with the CMP-legionaminate biosynthesis pathway at FDR <0.05. Conclusions In a small longitudinal study of generally healthy, older Chinese adults, we found long-term healthy eating was associated with increased α-diversity of microbial gene families and metabolic pathways and altered symbiotic functions relevant to human nutrition and health.

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