scholarly journals PolyQ length co-evolution in neural proteins

2021 ◽  
Vol 3 (2) ◽  
Author(s):  
Serena Vaglietti ◽  
Ferdinando Fiumara
Keyword(s):  
Protein Function ◽  
Phenotypic Variability ◽  
Regulatory System ◽  
Length Variation ◽  
Interacting Proteins ◽  
Neuropsychiatric Disease ◽  
Interspecific Divergence ◽  
Polyq Protein ◽  
Related Proteins ◽  
Evolutionary Fitness

Abstract Intermolecular co-evolution optimizes physiological performance in functionally related proteins, ultimately increasing molecular co-adaptation and evolutionary fitness. Polyglutamine (polyQ) repeats, which are over-represented in nervous system-related proteins, are increasingly recognized as length-dependent regulators of protein function and interactions, and their length variation contributes to intraspecific phenotypic variability and interspecific divergence. However, it is unclear whether polyQ repeat lengths evolve independently in each protein or rather co-evolve across functionally related protein pairs and networks, as in an integrated regulatory system. To address this issue, we investigated here the length evolution and co-evolution of polyQ repeats in clusters of functionally related and physically interacting neural proteins in Primates. We observed function-/disease-related polyQ repeat enrichment and evolutionary hypervariability in specific neural protein clusters, particularly in the neurocognitive and neuropsychiatric domains. Notably, these analyses detected extensive patterns of intermolecular polyQ length co-evolution in pairs and clusters of functionally related, physically interacting proteins. Moreover, they revealed both direct and inverse polyQ length co-variation in protein pairs, together with complex patterns of coordinated repeat variation in entire polyQ protein sets. These findings uncover a whole system of co-evolving polyQ repeats in neural proteins with direct implications for understanding polyQ-dependent phenotypic variability, neurocognitive evolution and neuropsychiatric disease pathogenesis.

scholarly journals Cell Death Related Proteins Beyond Apoptosis in the CNS

2022 ◽  
Vol 9 ◽  
Author(s):  
Bazhena Bahatyrevich-Kharitonik ◽  
Rafael Medina-Guzman ◽  
Alicia Flores-Cortes ◽  
Marta García-Cruzado ◽  
Edel Kavanagh ◽  
...  
Keyword(s):  
Cell Death ◽  
Protein Function ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Original Function ◽  
New Concepts ◽  
Cytoskeleton Reorganization ◽  
Caspase Substrates ◽  
Cell Death Signaling ◽  
Related Proteins

Cell death related (CDR) proteins are a diverse group of proteins whose original function was ascribed to apoptotic cell death signaling. Recently, descriptions of non-apoptotic functions for CDR proteins have increased. In this minireview, we comment on recent studies of CDR proteins outside the field of apoptosis in the CNS, encompassing areas such as the inflammasome and non-apoptotic cell death, cytoskeleton reorganization, synaptic plasticity, mitophagy, neurodegeneration and calcium signaling among others. Furthermore, we discuss the evolution of proteomic techniques used to predict caspase substrates that could potentially explain their non-apoptotic roles. Finally, we address new concepts in the field of non-apoptotic functions of CDR proteins that require further research such the effect of sexual dimorphism on non-apoptotic CDR protein function and the emergence of zymogen-specific caspase functions.

scholarly journals Entropy, Fluctuations, and Disordered Proteins

Entropy ◽  
2019 ◽  
Vol 21 (8) ◽  
pp. 764 ◽  
Author(s):  
Eshel Faraggi ◽  
A. Keith Dunker ◽  
Robert L. Jernigan ◽  
Andrzej Kloczkowski
Keyword(s):  
Protein Function ◽  
Accessible Surface Area ◽  
Disordered Proteins ◽  
Dihedral Angles ◽  
Residue Type ◽  
Sequence Structure ◽  
Multiple Sequence ◽  
Accessible Surface ◽  
Positive Correlations ◽  
Related Proteins

Entropy should directly reflect the extent of disorder in proteins. By clustering structurally related proteins and studying the multiple-sequence-alignment of the sequences of these clusters, we were able to link between sequence, structure, and disorder information. We introduced several parameters as measures of fluctuations at a given MSA site and used these as representative of the sequence and structure entropy at that site. In general, we found a tendency for negative correlations between disorder and structure, and significant positive correlations between disorder and the fluctuations in the system. We also found evidence for residue-type conservation for those residues proximate to potentially disordered sites. Mutation at the disorder site itself appear to be allowed. In addition, we found positive correlation for disorder and accessible surface area, validating that disordered residues occur in exposed regions of proteins. Finally, we also found that fluctuations in the dihedral angles at the original mutated residue and disorder are positively correlated while dihedral angle fluctuations in spatially proximal residues are negatively correlated with disorder. Our results seem to indicate permissible variability in the disordered site, but greater rigidity in the parts of the protein with which the disordered site interacts. This is another indication that disordered residues are involved in protein function.

scholarly journals Multiple Rare Risk Coding Variants in Postsynaptic Density-Related Genes Associated With Schizophrenia Susceptibility

2020 ◽  
Vol 11 ◽  
Author(s):  
Tsung-Ming Hu ◽  
Ying-Chieh Wang ◽  
Chia-Liang Wu ◽  
Shih-Hsin Hsu ◽  
Hsin-Yao Tsai ◽  
...  
Keyword(s):  
Protein Function ◽  
Cultured Cells ◽  
Postsynaptic Density ◽  
Psychiatric History ◽  
Missense Mutations ◽  
Genes Encoding ◽  
Schizophrenic Patients ◽  
Synaptic Receptors ◽  
Related Proteins ◽  
Coding Variants

ObjectiveSchizophrenia is a chronic debilitating neurobiological disorder of aberrant synaptic connectivity and synaptogenesis. Postsynaptic density (PSD)–related proteins in N-methyl-D-aspartate receptor–postsynaptic signaling complexes are crucial to regulating the synaptic transmission and functions of various synaptic receptors. This study examined the role of PSD-related genes in susceptibility to schizophrenia.MethodsWe resequenced 18 genes encoding the disks large-associated protein (DLGAP), HOMER, neuroligin (NLGN), neurexin, and SH3 and multiple ankyrin repeat domains (SHANK) protein families in 98 schizophrenic patients with family psychiatric history using semiconductor sequencing. We analyzed the protein function of the identified rare schizophrenia-associated mutants via immunoblotting and immunocytochemistry.ResultsWe identified 50 missense heterozygous mutations in 98 schizophrenic patients with family psychiatric history, and in silico analysis revealed some as damaging or pathological to the protein function. Ten missense mutations were absent from the dbSNP database, the gnomAD (non-neuro) dataset, and 1,517 healthy controls from Taiwan BioBank. Immunoblotting revealed eight missense mutants with altered protein expressions in cultured cells compared with the wild type.ConclusionOur findings suggest that PSD-related genes, especially the NLGN, SHANK, and DLGAP families, harbor rare functional mutations that might alter protein expression in some patients with schizophrenia, supporting contributing rare coding variants into the genetic architecture of schizophrenia.

scholarly journals Sipl1 and Rbck1 Are Novel Eya1-Binding Proteins with a Role in Craniofacial Development

2010 ◽  
Vol 30 (24) ◽  
pp. 5764-5775 ◽  
Author(s):  
Kathrin Landgraf ◽  
Frank Bollig ◽  
Mark-Oliver Trowe ◽  
Birgit Besenbeck ◽  
Christina Ebert ◽  
...  
Keyword(s):  
Branchial Arch ◽  
Craniofacial Development ◽  
Interacting Proteins ◽  
Rt Pcr ◽  
Interacting Protein ◽  
Eyes Absent ◽  
Mechanistic Insight ◽  
Interaction Partners ◽  
Related Proteins

ABSTRACT The eyes absent 1 protein (Eya1) plays an essential role in the development of various organs in both invertebrates and vertebrates. Mutations in the human EYA1 gene are linked to BOR (branchio-oto-renal) syndrome, characterized by kidney defects, hearing loss, and branchial arch anomalies. For a better understanding of Eya1's function, we have set out to identify new Eya1-interacting proteins. Here we report the identification of the related proteins Sipl1 (Shank-interacting protein-like 1) and Rbck1 (RBCC protein interacting with PKC1) as novel interaction partners of Eya1. We confirmed the interactions by glutathione S-transferase (GST) pulldown analysis and coimmunoprecipitation. A first mechanistic insight is provided by the demonstration that Sipl1 and Rbck1 enhance the function of Eya proteins to act as coactivators for the Six transcription factors. Using reverse transcriptase PCR (RT-PCR) and in situ hybridization, we show that Sipl1 and Rbck1 are coexpressed with Eya1 in several organs during embryogenesis of both the mouse and zebrafish. By morpholino-mediated knockdown, we demonstrate that the Sipl1 and Rbck1 orthologs are involved in different aspects of zebrafish development. In particular, knockdown of one Sipl1 ortholog as well as one Rbck1 ortholog led to a BOR syndrome-like phenotype, with characteristic defects in ear and branchial arch formation.

scholarly journals Interactions between two fission yeast serine/arginine-rich proteins and their modulation by phosphorylation

2002 ◽  
Vol 368 (2) ◽  
pp. 527-534 ◽  
Author(s):  
Zhaohua TANG ◽  
Norbert F. KÄUFER ◽  
Ren-Jang LIN
Keyword(s):  
Alternative Splicing ◽  
Protein Phosphorylation ◽  
Fission Yeast ◽  
Protein Function ◽  
Sr Proteins ◽  
Specific Protein ◽  
Glutathione S Transferase ◽  
Sr Protein ◽  
Random Screen ◽  
Related Proteins

The unexpected low number of genes in the human genome has triggered increasing attention to alternative pre-mRNA splicing, and serine/arginine-rich (SR) proteins have been correlated with the complex alternative splicing that is a characteristic of metazoans. SR proteins interact with RNA and splicing protein factors, and they also undergo reversible phosphorylation, thereby regulating constitutive and alternative splicing in mammals and Drosophila. However, it is not clear whether the features of SR proteins and alternative splicing are present in simple and genetically tractable organisms, such as yeasts. In the present study, we show that the SR-like proteins Srp1 and Srp2, found in the fission yeast Schizosaccharomyces pombe, interact with each other and the interaction is modulated by protein phosphorylation. By using Srp1 as bait in a yeast two-hybrid analysis, we specifically isolated Srp2 from a random screen. This Srp interaction was confirmed by a glutathione-S-transferase pull-down assay. We also found that the Srp1—Srp2 complex was phosphorylated at a reduced efficiency by a fission yeast SR-specific kinase, Dis1-suppression kinase (Dsk1). Conversely, Dsk1-mediated phosphorylation inhibited the formation of the Srp complex. These findings offer the first example in fission yeast for interactions between SR-related proteins and the modulation of the interactions by specific protein phosphorylation, suggesting that a mammalian-like SR protein function may exist in fission yeast.

CAVITY SCALING: AUTOMATED REFINEMENT OF CAVITY-AWARE MOTIFS IN PROTEIN FUNCTION PREDICTION

2007 ◽  
Vol 05 (02a) ◽  
pp. 353-382 ◽  
Author(s):  
BRIAN Y. CHEN ◽  
DREW H. BRYANT ◽  
VIACHESLAV Y. FOFANOV ◽  
DAVID M. KRISTENSEN ◽  
AMANDA E. CRUESS ◽  
...  
Keyword(s):  
Open Problem ◽  
Protein Function ◽  
Protein Function Prediction ◽  
Function Prediction ◽  
High Impact ◽  
Optimal Placement ◽  
Chemical Similarity ◽  
Functional Sites ◽  
Comparison Algorithms ◽  
Related Proteins

Algorithms for geometric and chemical comparison of protein substructure can be useful for many applications in protein function prediction. These motif matching algorithms identify matches of geometric and chemical similarity between well-studied functional sites, motifs, and substructures of functionally uncharacterized proteins, targets. For the purpose of function prediction, the accuracy of motif matching algorithms can be evaluated with the number of statistically significant matches to functionally related proteins, true positives (TPs), and the number of statistically insignificant matches to functionally unrelated proteins, false positives (FPs). Our earlier work developed cavity-aware motifs which use motif points to represent functionally significant atoms and C-spheres to represent functionally significant volumes. We observed that cavity-aware motifs match significantly fewer FPs than matches containing only motif points. We also observed that high-impact C-spheres, which significantly contribute to the reduction of FPs, can be isolated automatically with a technique we call Cavity Scaling. This paper extends our earlier work by demonstrating that C-spheres can be used to accelerate point-based geometric and chemical comparison algorithms, maintaining accuracy while reducing runtime. We also demonstrate that the placement of C-spheres can significantly affect the number of TPs and FPs identified by a cavity-aware motif. While the optimal placement of C-spheres remains a diffcult open problem, we compared two logical placement strategies to better understand C-sphere placement.

scholarly journals Deep Annotation of Protein Function across Diverse Bacteria from Mutant Phenotypes

2016 ◽  
Author(s):  
Morgan N. Price ◽  
Kelly M. Wetmore ◽  
R. Jordan Waters ◽  
Mark Callaghan ◽  
Jayashree Ray ◽  
...  
Keyword(s):  
Protein Function ◽  
Large Scale ◽  
Hypothetical Proteins ◽  
Data Set ◽  
Protein Coding ◽  
Bacterial Proteins ◽  
Genome Wide ◽  
Protein Functions ◽  
Mutant Phenotypes ◽  
Related Proteins

SummaryThe function of nearly half of all protein-coding genes identified in bacterial genomes remains unknown. To systematically explore the functions of these proteins, we generated saturated transposon mutant libraries from 25 diverse bacteria and we assayed mutant phenotypes across hundreds of distinct conditions. From 3,903 genome-wide mutant fitness assays, we obtained 14.9 million gene phenotype measurements and we identified a mutant phenotype for 8,487 proteins with previously unknown functions. The majority of these hypothetical proteins (57%) had phenotypes that were either specific to a few conditions or were similar to that of another gene, thus enabling us to make informed predictions of protein function. For 1,914 of these hypothetical proteins, the functional associations are conserved across related proteins from different bacteria, which confirms that these associations are genuine. This comprehensive catalogue of experimentally-annotated protein functions also enables the targeted exploration of specific biological processes. For example, sensitivity to a DNA-damaging agent revealed 28 known families of DNA repair proteins and 11 putative novel families. Across all sequenced bacteria, 14% of proteins that lack detailed annotations have an ortholog with a functional association in our data set. Our study demonstrates the utility and scalability of high-throughput genetics for large-scale annotation of bacterial proteins and provides a vast compendium of experimentally-determined protein functions across diverse bacteria.

scholarly journals Evolutionary adaptability linked to length variation in short genic tandem repeats

2018 ◽  
Author(s):  
William B Reinar ◽  
Jonfinn B Knutsen ◽  
Sissel Jentoft ◽  
Ole K Tørresen ◽  
Melinka A Butenko ◽  
...  
Keyword(s):  
Protein Function ◽  
Tandem Repeats ◽  
Phenotypic Traits ◽  
Length Variation ◽  
Interaction Sites ◽  
Genome Wide ◽  
Mutational Hotspots ◽  
Intergenic Regions ◽  
Gene Expression Levels

AbstractThere is increasing evidence that short tandem repeats (STRs) – mutational hotspots present in genes and in intergenic regions throughout most genomes – may influence gene and protein function and consequently affect the phenotype of an organism. However, the overall importance of STRs and their standing genetic variation within a population, e.g. if and how they facilitate evolutionary change and local adaptation, is still debated. Through genome-wide characterization of STRs in over a thousand wild Arabidopsis thaliana accessions we demonstrate that STRs display significant variation in length across the species’ geographical distribution. We find that length variants are correlated with environmental conditions, key adaptive phenotypic traits as well as gene expression levels. Further, we show that coding STRs are overrepresented in putative protein interaction sites. Taken together, our results suggest that these hypervariable loci play a major role in facilitating adaptation in plants, and due to the ubiquitous presence of STRs throughout the tree of life, similar roles in other organisms are likely.

scholarly journals Structural dynamics in the evolution of a bilobed protein scaffold

2021 ◽  
Vol 118 (49) ◽  
pp. e2026165118
Author(s):  
Giorgos Gouridis ◽  
Yusran A. Muthahari ◽  
Marijn de Boer ◽  
Douglas A. Griffith ◽  
Alexandra Tsirigotaki ◽  
...  
Keyword(s):  
Structural Dynamics ◽  
Single Molecule ◽  
Protein Function ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Divergent Evolution ◽  
Exchange Mass Spectrometry ◽  
Hydrogen Deuterium ◽  
Interdomain Interactions ◽  
Related Proteins

Novel biophysical tools allow the structural dynamics of proteins and the regulation of such dynamics by binding partners to be explored in unprecedented detail. Although this has provided critical insights into protein function, the means by which structural dynamics direct protein evolution remain poorly understood. Here, we investigated how proteins with a bilobed structure, composed of two related domains from the periplasmic-binding protein–like II domain family, have undergone divergent evolution, leading to adaptation of their structural dynamics. We performed a structural analysis on ∼600 bilobed proteins with a common primordial structural core, which we complemented with biophysical studies to explore the structural dynamics of selected examples by single-molecule Förster resonance energy transfer and Hydrogen–Deuterium exchange mass spectrometry. We show that evolutionary modifications of the structural core, largely at its termini, enable distinct structural dynamics, allowing the diversification of these proteins into transcription factors, enzymes, and extracytoplasmic transport-related proteins. Structural embellishments of the core created interdomain interactions that stabilized structural states, reshaping the active site geometry, and ultimately altered substrate specificity. Our findings reveal an as-yet-unrecognized mechanism for the emergence of functional promiscuity during long periods of evolution and are applicable to a large number of domain architectures.

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