Browse
Submit Data
Databases
API
Help

Dataset Information

15 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Quantifying evolutionary importance of protein sites: A Tale of two measures.

ABSTRACT: A key challenge in evolutionary biology is the accurate quantification of selective pressure on proteins and other biological macromolecules at single-site resolution. The evolutionary importance of a protein site under purifying selection is typically measured by the degree of conservation of the protein site itself. A possible alternative measure is the strength of the site-induced conservation gradient in the rest of the protein structure. However, the quantitative relationship between these two measures remains unknown. Here, we show that despite major differences, there is a strong linear relationship between the two measures such that more conserved protein sites also induce stronger conservation gradient in the rest of the protein. This linear relationship is universal as it holds for different types of proteins and functional sites in proteins. Our results show that the strong selective pressure acting on the functional site in general percolates through the rest of the protein via residue-residue contacts. Surprisingly however, catalytic sites in enzymes are the principal exception to this rule. Catalytic sites induce significantly stronger conservation gradients in the rest of the protein than expected from the degree of conservation of the site alone. The unique requirement for the active site to selectively stabilize the transition state of the catalyzed chemical reaction imposes additional selective constraints on the rest of the enzyme.

SUBMITTER: Sharir-Ivry A

PROVIDER: S-EPMC8026052 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Allelic association under map error and recombinational heterogeneity: a tale of two sites.

Project description:Recombination acts on the genetic map, not on the physical map. On the other hand, the physical map is usually more accurate. Choice of the genetic or physical map for positional cloning by allelic association depends on the goodness of fit of data to each map under an established model. Huntington disease illustrates the usual case in which the greater reliability of physical data outweighs recombinational heterogeneity. Hemochromatosis represents an exceptional case in which unrecognized recombinational heterogeneity retarded positional cloning for a decade. The Malecot model performs well for major genes, but no approach assuming either equilibrium or disequilibrium has been validated for oligogenes contributing to common disease. In this case of greatest interest, the power of allelic association relative to linkage is less clear than for major genes.

| S-EPMC21648 | biostudies-literature

A tale of two drug targets: the evolutionary history of BACE1 and BACE2.

Project description:The beta amyloid (APP) cleaving enzyme (BACE1) has been a drug target for Alzheimer's Disease (AD) since 1999 with lead inhibitors now entering clinical trials. In 2011, the paralog, BACE2, became a new target for type II diabetes (T2DM) having been identified as a TMEM27 secretase regulating pancreatic β cell function. However, the normal roles of both enzymes are unclear. This study outlines their evolutionary history and new opportunities for functional genomics. We identified 30 homologs (UrBACEs) in basal phyla including Placozoans, Cnidarians, Choanoflagellates, Porifera, Echinoderms, Annelids, Mollusks and Ascidians (but not Ecdysozoans). UrBACEs are predominantly single copy, show 35-45% protein sequence identity with mammalian BACE1, are ~100 residues longer than cathepsin paralogs with an aspartyl protease domain flanked by a signal peptide and a C-terminal transmembrane domain. While multiple paralogs in Trichoplax and Monosiga pre-date the nervous system, duplication of the UrBACE in fish gave rise to BACE1 and BACE2 in the vertebrate lineage. The latter evolved more rapidly as the former maintained the emergent neuronal role. In mammals, Ka/Ks for BACE2 is higher than BACE1 but low ratios for both suggest purifying selection. The 5' exons show higher Ka/Ks than the catalytic section. Model organism genomes show the absence of certain BACE human substrates when the UrBACE is present. Experiments could thus reveal undiscovered substrates and roles. The human protease double-target status means that evolutionary trajectories and functional shifts associated with different substrates will have implications for the development of clinical candidates for both AD and T2DM. A rational basis for inhibition specificity ratios and assessing target-related side effects will be facilitated by a more complete picture of BACE1 and BACE2 functions informed by their evolutionary context.

| S-EPMC3865767 | biostudies-literature

A Tale of Two Pandemics: Economic Inequality and Support for Containment Measures in Peru

Project description:Research suggests that the coronavirus pandemic disproportionately affected poor

| S-EPMC8361233 | biostudies-literature

A tale of two GTPases in cotranslational protein targeting.

Project description:Guanosine triphosphatases (GTPases) comprise a superfamily of proteins that provide molecular switches to regulate numerous cellular processes. The "GTPase switch" paradigm, in which a GTPase acts as a bimodal switch that is turned "on" and "off" by external regulatory factors, has been used to interpret the regulatory mechanism of many GTPases. Recent work on a pair of GTPases in the signal recognition particle (SRP) pathway has revealed a distinct mode of GTPase regulation. Instead of the classical GTPase switch, the two GTPases in the SRP and SRP receptor undergo a series of conformational changes during their dimerization and reciprocal activation. Each conformational rearrangement provides a point at which these GTPases can communicate with and respond to their upstream and downstream biological cues, thus ensuring the spatial and temporal precision of all the molecular events in the SRP pathway. We suggest that the SRP and SRP receptor represent an emerging class of "multistate" regulatory GTPases uniquely suited to provide exquisite control over complex cellular pathways that require multiple molecular events to occur in a highly coordinated fashion.

| S-EPMC3267943 | biostudies-literature

Quantifying the importance of protein conformation on ligand migration in myoglobin.

Project description:Myoglobin (Mb) is a model system for ligand binding and migration. The energy barriers (?G) for ligand migration in Mb have been studied in the past by experiment and theory and significant differences between different approaches were found. From experiment, it is known that Mb can assume a large number of conformational substates. In this work, these substates are investigated as a possible source of the differences in migration barriers. We show that the initial structure significantly affects the calculated ?G for a particular transition and that fluctuations in barrier heights ??G are of similar magnitude as the free energy barriers themselves. The sensitivity of ?G to the initial structure is compared to other sources of errors. Different protein structures can affect the calculated ?G by up to 4 kcal/mol, whereas differences between simple point charge models and more elaborate multipolar charge models for the CO-ligand are smaller by a factor of two. Analysis of the structural changes underlying the large effect of the conformational substate reveals the importance of coupling between protein and ligand motion for migration.

| S-EPMC3260668 | biostudies-literature

C.H. Waddington's differences with the creators of the modern evolutionary synthesis: a tale of two genes.

Project description:In 2011, Peterson suggested that the main reason why C.H. Waddington was essentially ignored by the framers of the modern evolutionary synthesis in the 1950s was because they were Cartesian reductionists and mathematical population geneticists while he was a Whiteheadian organicist and experimental geneticist who worked with Drosophila. This paper suggests a further reason that can only be seen now. The former defined genes and their alleles by their selectable phenotypes, essentially the Mendelian view, while Waddington defined a gene through its functional role as determined by genetic analysis, a view that foresaw the modern view that a gene is a DNA sequence with some function. The former were interested in selection, while Waddington focused on variation. The differences between the two views of a gene are briefly considered in the context of systems biology.

| S-EPMC5548827 | biostudies-other

Causes of evolutionary rate variation among protein sites.

Project description:It has long been recognized that certain sites within a protein, such as sites in the protein core or catalytic residues in enzymes, are evolutionarily more conserved than other sites. However, our understanding of rate variation among sites remains surprisingly limited. Recent progress to address this includes the development of a wide array of reliable methods to estimate site-specific substitution rates from sequence alignments. In addition, several molecular traits have been identified that correlate with site-specific mutation rates, and novel mechanistic biophysical models have been proposed to explain the observed correlations. Nonetheless, current models explain, at best, approximately 60% of the observed variance, highlighting the limitations of current methods and models and the need for new research directions.

| S-EPMC4724262 | biostudies-literature

The importance of making testable predictions: A cautionary tale.

Project description:We found a startling correlation (Pearson ρ > 0.97) between a single event in daily sea surface temperatures each spring, and peak fish egg abundance measurements the following summer, in 7 years of approximately weekly fish egg abundance data collected at Scripps Pier in La Jolla California. Even more surprising was that this event-based result persisted despite the large and variable number of fish species involved (up to 46), and the large and variable time interval between trigger and response (up to ~3 months). To mitigate potential over-fitting, we made an out-of-sample prediction beyond the publication process for the peak summer egg abundance observed at Scripps Pier in 2020 (available on bioRxiv). During peer-review, the prediction failed, and while it would be tempting to explain this away as a result of the record-breaking toxic algal bloom that occurred during the spring (9x higher concentration of dinoflagellates than ever previously recorded), a re-examination of our methodology revealed a potential source of over-fitting that had not been evaluated for robustness. This cautionary tale highlights the importance of testable true out-of-sample predictions of future values that cannot (even accidentally) be used in model fitting, and that can therefore catch model assumptions that may otherwise escape notice. We believe that this example can benefit the current push towards ecology as a predictive science and support the notion that predictions should live and die in the public domain, along with the models that made them.

| S-EPMC7723288 | biostudies-literature

A tale of two TUTases.

Project description:The insertion and deletion of U residues at specific sites in mRNAs in trypanosome mitochondria is thought to involve 3' terminal uridylyl transferase (TUTase) activity. TUTase activity is also required to create the nonencoded 3' oligo[U] tails of the transacting guide RNAs (gRNAs). We have described two TUTases, RET1 (RNA editing TUTase 1) and RET2 (RNA editing TUTase 2) as components of different editing complexes. Tandem affinity purification-tagged Trypanosoma brucei RET2 (TbRET2) was expressed and localized to the cytosol in Leishmania tarentolae cells by removing the mitochondrial signal sequence. Double-affinity isolation yielded tagged TbRET2, together with a few additional proteins. This material exhibits a U-specific transferase activity in which a single U is added to the 3' end of a single-stranded RNA, thereby confirming that RET2 is a 3' TUTase. We also found that RNA interference of RET2 expression in T. brucei inhibits in vitro U-insertion editing and has no effect on the length of the 3' oligo[U] tails of the gRNAs, whereas down-regulation of RET1 has a minor effect on in vitro U-insertion editing, but produces a decrease in the average length of the oligo[U] tails. This finding suggests that RET2 is responsible for U-insertions at editing sites and RET1 is involved in gRNA 3' end maturation, which is essential for creating functional gRNAs. From these results we have functionally relabeled the previously described TUT-II complex containing RET1 as the guide RNA processing complex.

| S-EPMC196853 | biostudies-other

COG3926 and COG5526: a tale of two new lysozyme-like protein families.

Project description:We have identified two new lysozyme-like protein families by using a combination of sequence similarity searches, domain architecture analysis, and structural predictions. First, the P5 protein from bacteriophage phi8, which belongs to COG3926 and Pfam family DUF847, is predicted to have a new lysozyme-like domain. This assignment is consistent with the lytic function of P5 proteins observed in several related double-stranded RNA bacteriophages. Domain architecture analysis reveals two lysozyme-associated transmembrane modules (LATM1 and LATM2) in a few COG3926/DUF847 members. LATM2 is also present in two proteins containing a peptidoglycan binding domain (PGB) and an N-terminal region that corresponds to COG5526 with uncharacterized function. Second, structure prediction and sequence analysis suggest that COG5526 represents another new lysozyme-like family. Our analysis offers fold and active-site assignments for COG3926/DUF847 and COG5526. The predicted enzymatic activity is consistent with an experimental study on the zliS gene product from Zymomonas mobilis, suggesting that bacterial COG3926/DUF847 members might be activators of macromolecular secretion.

| S-EPMC2253296 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data