Changes In Protein Function Research Articles

Binding of the commonly used antioxidants (quercetin, resveratrol, and dihydrolipoic acid) to major circulating proteins - spectroscopic and in silico docking and molecular dynamic simulation studies.

Poor bioavailability and reduced stability are the main drawbacks to efficiently utilizing many naturally occurring antioxidants, so their binding to circulatory proteins is essential. This work investigated whether major human circulatory proteins, besides albumin, including transferrin, alpha-2-macroglobulin, and fibrinogen, bind widely consumed antioxidants and food supplements, including quercetin, trans-resveratrol, and dihydrolipoic acid, thus filling the gap of detailed pharmacokinetic properties of these food supplements. Detailed examination of the protein structural and functional changes that occur upon ligand binding was analyzed by spectroscopic methods and in silico docking and molecular dynamic simulation studies on the model that consists of the protein/antioxidant pair with the highest affinity constant. It was found that alpha-2-macroglobulin binds trans-resveratrol with the highest affinity (Ka of 4.5 x 104 M-1). In silico results revealed four potential binding sites between trans-resveratrol and alpha-2-macroglobulin, with hydrogen bonds being crucial for binding, while other observed interactions (primarily aromatic interactions) are of secondary importance. The binding of trans-resveratrol to alpha-2-macroglobulin leads to mutual protection of both molecules from oxidative stress and significantly increased hidrosolubility of resveratrol, both of which could serve to increase the bioavailability and bioactivity of resveratrol in circulation.

Rapid Microwave Fixation of the Brain Reveals Seasonal Changes in the Phosphoproteome of Hibernating Thirteen-Lined Ground Squirrels.

Hibernating mammals such as the thirteen-lined ground squirrel (Ictidomys tridecemlineatus) experience significant reductions in oxidative metabolism and body temperature when entering a state known as torpor. Animals entering or exiting torpor do not experience permanent loss of brain function or other injuries, and the processes that enable such neuroprotection are not well understood. To gain insight into changes in protein function that occur in the dramatically different physiological states of hibernation, we performed quantitative phosphoproteomics experiments on thirteen-lined ground squirrels that are summer-active, winter-torpid, and spring-active. An important aspect of our approach was the use of focused microwave irradiation of the brain to sacrifice the animals and rapidly inactivate phosphatases and kinases to preserve the native phosphoproteome. Overall, our results showed pronounced changes in phosphorylated proteins for the transitions into and out of torpor, including proteins involved in gene expression, DNA maintenance and repair, cellular plasticity, and human disease. In contrast, the transition between the active states showed minimal changes. This study offers valuable insight into the global changes in brain phosphorylation in hibernating mammals, the results of which may be relevant to future therapeutic strategies for brain injury.

DNA nanodevice for analysis of force-activated protein extension and interactions.

Force-induced changes in protein structure and function mediate cellular responses to mechanical stresses. Existing methods to study protein conformation under mechanical force are incompatible with biochemical and structural analysis. Taking advantage of DNA nanotechnology, including the well-defined geometry of DNA origami and programmable mechanics of DNA hairpins, we built a nanodevice to apply controlled forces to proteins. This device was used to study the R1-R2 segment of the talin1 rod domain as a model protein, which comprises two alpha-helical bundles that reversibly unfold under tension to expose binding sites for the cytoskeletal protein vinculin. Electron microscopy confirmed tension-dependent protein extension while biochemical analysis demonstrated enhanced vinculin binding under tension. The device could also be used in pull down assays with cell lysates, which identified filamins as novel tension-dependent talin binders. The DNA nanodevice is thus a valuable addition to the molecular toolbox for studying mechanosensitive proteins.

Recent advances in noncoding RNA modifications of gastrointestinal cancer.

Elucidating the mechanisms underlying cancer development and proliferation is important for the development of therapeutic methods for the complete cure of cancer. In particular, the identification of diagnostic markers for early detection and new therapeutic strategies for refractory gastrointestinal cancers are needed. Various abnormal phenomena occur in cancer cells, such as functional changes of proteins, led by genomic mutations, and changes in gene expression due to dysregulation of epigenetic regulation. This is no exception for noncoding RNA (ncRNA), which do not encode proteins. Recent reports have revealed that microRNA (miRNA), long noncoding RNA (lncRNA), and circular RNA (circRNA) are deeply involved in cancer progression. These ncRNAs have attracted attention as gene expression regulatory molecules. Recent advances in technology have made it possible not only to read DNA and RNA sequences but also to study the modification state of each base. In particular, comprehensive analysis of N6-methyladenosine (m6A) has been performed by many research groups, with multiple studies reporting that m6A modifications of specific genes are associated with cancer progression. Based on the above, this review examines how ncRNA modifications are related to cancer progression in gastrointestinal cancers such as colorectal and pancreatic cancer. We also discuss enzyme inhibitors that have been reported to have drug discovery potential targeting m6A modifications. By utilizing the new perspective of ncRNA modification, we may be able to accumulate knowledge on the molecular biology of cancer and contribute to human health through diagnosis and treatment.

Structural changes and functional characteristics of common vetch isolate proteins altered by different pH-shifting treatments

To investigate protein structure and functional changes, common vetch protein isolate (CVPI) during pH-shifting were performed. Results showed secondary and tertiary structures of CVPI were improved during these treatments compared with the pH 7.0. Scanning electron microscopy showed the microstructure was changed from lamellar to spherical granular and rod-like structure during pH - shifting. Under 8 pH treatments (pH 2.0, 3.0, 12.0, 2.0 → 7.0, 3.0 → 7.0, 12.0 → 7.0, 11.0 → 9.0 and 11.0 → 7.0), the average particle sizes were smaller and from 82 to 146 nm. Under 8 pH treatments (pH 2.0, 3.0, 11.0, 12.0, 11.0 → 9.0, 11.0 → 7.0,12.0 → 9.0 and 12.0 → 7.0), the protein solubility was higher and from 63 to 86 %. Under 3 pH treatments (pH 2.0, 11.0 and 12.0), the emulsion activity index and emulsion stability index was higher and from 40 to 60 m2/g and from 54 to 97 min. Under 5 pH treatments (pH 2.0, 12.0, 11.0 → 9.0, 12.0 → 9.0 and 12.0 → 7.0), the foaming capacity and foaming stability was higher and from 145 to 185 % and from 67 to 82 %. Therefore, the pH – shifting treatment gave the CVPI improved characteristics in structural and functional properties.

SUMOylation of Warts kinase promotes neural stem cell reactivation

A delicate balance between neural stem cell (NSC) quiescence and proliferation is important for adult neurogenesis and homeostasis. Small ubiquitin-related modifier (SUMO)-dependent post-translational modifications cause rapid and reversible changes in protein functions. However, the role of the SUMO pathway during NSC reactivation and brain development is not established. Here, we show that the key components of the SUMO pathway play an important role in NSC reactivation and brain development in Drosophila. Depletion of SUMO/Smt3 or SUMO conjugating enzyme Ubc9 results in notable defects in NSC reactivation and brain development, while their overexpression leads to premature NSC reactivation. Smt3 protein levels increase with NSC reactivation, which is promoted by the Ser/Thr kinase Akt. Warts/Lats, the core protein kinase of the Hippo pathway, can undergo SUMO- and Ubc9-dependent SUMOylation at Lys766. This modification attenuates Wts phosphorylation by Hippo, leading to the inhibition of the Hippo pathway, and consequently, initiation of NSC reactivation. Moreover, inhibiting Hippo pathway effectively restores the NSC reactivation defects induced by SUMO pathway inhibition. Overall, our study uncovered an important role for the SUMO-Hippo pathway during Drosophila NSC reactivation and brain development.

Deubiquitinases in skeletal muscle-the underappreciated side of the ubiquitination coin.

Ubiquitination is a posttranslational modification that plays important roles in regulating protein stability, function, localization, and protein-protein interactions. Proteins are ubiquitinated via a process involving specific E1 activating enzymes, E2 conjugating enzymes, and E3 ligases. Simultaneously, protein ubiquitination is opposed by deubiquitinating enzymes (DUBs). DUB-mediated deubiquitination can change protein function or fate and recycle ubiquitin to maintain the free ubiquitin pool. Approximately 100 DUBs have been identified in the mammalian genome, and characterized into seven classes [ubiquitin-specific protease (USP), ovarian tumor proteases (OTU), ubiquitin C-terminal hydrolase (UCH), Machado-Josephin disease (MJD), JAB1/MPN/Mov34 metalloprotease (JAMM), Ub-containing novel DUB family (MINDY), and zinc finger containing ubiquitin peptidase (ZUP) classes]. Of these 100 DUBs, there has only been relatively limited investigation of 20 specifically in skeletal muscle cells, in vitro or in vivo, using overexpression, knockdown, and knockout models. To date, evidence indicates roles for individual DUBs in regulating aspects of myogenesis, protein turnover, muscle mass, and muscle metabolism. However, the exact mechanism by which these DUBs act (i.e., the specific targets of these DUBs and the type of ubiquitin chains they target) is still largely unknown, underscoring how little we know about DUBs in skeletal muscle. This review endeavors to comprehensively summarize the current state of knowledge of the function of DUBs in skeletal muscle and highlight the opportunities for gaining a greater understanding through further research into this important area of skeletal muscle and ubiquitin biology.

A Damaging COL6A3 Variant Alters the MIR31HG-Regulated Response of Chondrocytes in Neocartilage Organoids to Hyperphysiologic Mechanical Loading.

The pericellular matrix (PCM), with its hallmark proteins collagen type VI (COLVI) and fibronectin (FN), surrounds chondrocytes and is critical in transducing the biomechanical cues. To identify genetic variants that change protein function, exome sequencing is performed in a patient with symptomatic OA at multiple joint sites. A predicted damaging variant in COL6A3 is identified and introduced by CRISPR-Cas9 genome engineering in two established human induced pluripotent stem cell-derived in-vitro neocartilage organoid models. The downstream effects of the COL6A3 variant on the chondrocyte phenotypic state are studied by a multi-omics (mRNA and lncRNA) approach in interaction with hyper-physiological mechanical loading conditions. The damaging variant in COL6A3 results in significantly lower binding between the PCM proteins COLVI and FN and provokes an osteoarthritic chondrocyte state. By subsequently exposing the neocartilage organoids to hyperphysiological mechanical stress, it is demonstrated that the COL6A3 variant in chondrocytes abolishes the characteristic inflammatory signaling response after mechanical loading with PTGS2, PECAM1, and ADAMTS5, as central genes. Finally, by integrating epigenetic regulation, the lncRNA MIR31HG is identified as key regulator of the characteristic inflammatory signaling response to mechanical loading.

Beyond the genome: protecting the proteome may be the key to preventing skin aging.

Skin aging is associated with a progressive decline in physiological functions, skin cancers and, ultimately, death. It may be categorized as intrinsic or extrinsic, whereby intrinsic aging is attributed to chronological and genetic factors. At the molecular level, skin aging involves changes in protein conformation and function. The skin proteome changes constantly, mainly through carbonylation; an irreversible phenomenon leading to protein accumulation as toxic aggregates that impair cellular physiology and accelerate skin aging. This review details the central role of proteostasis during skin aging and why proteome protection may be a promising approach in mitigating skin aging. A comprehensive literature review of 87 articles focusing on the proteome, proteostasis, proteotoxicity, protein carbonylation, and the impact of the damaged proteome on aging, and in particular skin aging, was conducted. Skin aging is associated with deficiencies in the repair mechanisms of DNA, transcriptional control, mitochondrial function, cell cycle control, apoptosis, cellular metabolism, changes in hormonal levels secondary to toxicity of damaged proteins, and cell-to-cell communication for tissue homeostasis, which are largely controlled by proteins. In this context, a damaged proteome that leads to the loss of proteostasis may be considered as the first step in tissue aging. There is growing evidence that a healthy proteome plays a central role in skin and in maintaining healthy tissues, thus slowing down the process of skin aging. Hence, protecting the proteome against oxidative or other damage may be an appropriate strategy to prevent and delay skin aging.

Ion Signaling in Cell Motility and Development in Dictyostelium discoideum.

Cell-to-cell communication is fundamental to the organization and functionality of multicellular organisms. Intercellular signals orchestrate a variety of cellular responses, including gene expression and protein function changes, and contribute to the integrated functions of individual tissues. Dictyostelium discoideum is a model organism for cell-to-cell interactions mediated by chemical signals and multicellular formation mechanisms. Upon starvation, D. discoideum cells exhibit coordinated cell aggregation via cyclic adenosine 3',5'-monophosphate (cAMP) gradients and chemotaxis, which facilitates the unicellular-to-multicellular transition. During this process, the calcium signaling synchronizes with the cAMP signaling. The resulting multicellular body exhibits organized collective migration and ultimately forms a fruiting body. Various signaling molecules, such as ion signals, regulate the spatiotemporal differentiation patterns within multicellular bodies. Understanding cell-to-cell and ion signaling in Dictyostelium provides insight into general multicellular formation and differentiation processes. Exploring cell-to-cell and ion signaling enhances our understanding of the fundamental biological processes related to cell communication, coordination, and differentiation, with wide-ranging implications for developmental biology, evolutionary biology, biomedical research, and synthetic biology. In this review, I discuss the role of ion signaling in cell motility and development in D. discoideum.

Zero-shot prediction of mutation effects with multimodal deep representation learning guides protein engineering

Mutations in amino acid sequences can provoke changes in protein function. Accurate and unsupervised prediction of mutation effects is critical in biotechnology and biomedicine, but remains a fundamental challenge. To resolve this challenge, here we present Protein Mutational Effect Predictor (ProMEP), a general and multiple sequence alignment-free method that enables zero-shot prediction of mutation effects. A multimodal deep representation learning model embedded in ProMEP was developed to comprehensively learn both sequence and structure contexts from ~160 million proteins. ProMEP achieves state-of-the-art performance in mutational effect prediction and accomplishes a tremendous improvement in speed, enabling efficient and intelligent protein engineering. Specifically, ProMEP accurately forecasts mutational consequences on the gene-editing enzymes TnpB and TadA, and successfully guides the development of high-performance gene-editing tools with their engineered variants. The gene-editing efficiency of a 5-site mutant of TnpB reaches up to 74.04% (vs 24.66% for the wild type); and the base editing tool developed on the basis of a TadA 15-site mutant (in addition to the A106V/D108N double mutation that renders deoxyadenosine deaminase activity to TadA) exhibits an A-to-G conversion frequency of up to 77.27% (vs 69.80% for ABE8e, a previous TadA-based adenine base editor) with significantly reduced bystander and off-target effects compared to ABE8e. ProMEP not only showcases superior performance in predicting mutational effects on proteins but also demonstrates a great capability to guide protein engineering. Therefore, ProMEP enables efficient exploration of the gigantic protein space and facilitates practical design of proteins, thereby advancing studies in biomedicine and synthetic biology.

Nanoparticle-assisted tubulin assembly is environment dependent

Nanomaterials acquire a biomolecular corona upon introduction to biological media, leading to biological transformations such as changes in protein function, unmasking of epitopes, and protein fibrilization. Ex vivo studies to investigate the effect of nanoparticles on protein-protein interactions are typically performed in buffer and are rarely measured quantitatively in live cells. Here, we measure the differential effect of silica nanoparticles on protein association in vitro vs. in mammalian cells. BtubA and BtubB are a pair of bacterial tubulin proteins identified in Prosthecobacter strains that self-assemble like eukaryotic tubulin, first into dimers and then into microtubules in vitro or in vivo. Förster resonance energy transfer labeling of each of the Btub monomers with a donor (mEGFP) and acceptor (mRuby3) fluorescent protein provides a quantitative tool to measure their binding interactions in the presence of unfunctionalized silica nanoparticles in buffer and in cells using fluorescence spectroscopy and microscopy. We show that silica nanoparticles enhance BtubAB dimerization in buffer due to protein corona formation. However, these nanoparticles have little effect on bacterial tubulin self-assembly in the complex mammalian cellular environment. Thus, the effect of nanomaterials on protein-protein interactions may not be readily translated from the test tube to the cell in the absence of particle surface functionalization that can enable targeted protein-nanoparticle interactions to withstand competitive binding in the nanoparticle corona from other biomolecules.

Protein-Chlorogenic Acid Interactions: Mechanisms, Characteristics, and Potential Food Applications.

The interactions between proteins and chlorogenic acid (CGA) have gained significant attention in recent years, not only as a promising approach to modify the structural and techno-functional properties of proteins but also to enhance their bioactive potential in food systems. These interactions can be divided into covalent (chemical or irreversible) and non-covalent (physical or reversible) linkages. Mechanistically, CGA forms covalent bonds with nucleophilic amino acid residues of proteins by alkaline, free radical, and enzymatic approaches, leading to changes in protein structure and functionality, such as solubility, emulsification properties, and antioxidant activity. In addition, the protein-CGA complexes can be obtained by hydrogen bonds, hydrophobic and electrostatic interactions, and van der Waals forces, each offering unique advantages and outcomes. This review highlights the mechanism of these interactions and their importance in modifying the structural, functional, nutritional, and physiological attributes of animal- and plant-based proteins. Moreover, the potential applications of these protein-CGA conjugates/complexes are explored in various food systems, such as beverages, films and coatings, emulsion-based delivery systems, and so on. Overall, this literature review provides an in-depth overview of protein-CGA interactions, offering valuable insights for future research to develop novel protein-based food and non-food products with improved nutritional and functional characteristics.

A survey of the Sli gene in wild and cultivated potato.

Inbred-hybrid breeding of diploid potatoes necessitates breeding lines that are self-compatible. One way of incorporating self-compatibility into incompatible cultivated potato (Solanum tuberosum) germplasm is to introduce the S-locus inhibitor gene (Sli), which functions as a dominant inhibitor of gametophytic self-incompatibility. To learn more about Sli diversity and function in wild species relatives of cultivated potato, we obtained Sli gene sequences that extended from the 5'UTR to the 3'UTR from 133 individuals from 22 wild species relatives of potato and eight diverse cultivated potato clones. DNA sequence alignment and phylogenetic trees based on genomic and protein sequences show that there are two highly conserved groups of Sli sequences. DNA sequences in one group contain the 533 bp insertion upstream of the start codon identified previously in self-compatible potato. The second group lacks the insertion. Three diploid and four polyploid individuals of wild species collected from geographically disjointed localities contained Sli with the 533 bp insertion. For most of the wild species clones examined, however, Sli did not have the insertion. Phylogenetic analysis indicated that Sli sequences with the insertion, in wild species and in cultivated clones, trace back to a single origin. Some diploid wild potatoes that have Sli with the insertion were self-incompatible and some wild potatoes that lack the insertion were self-compatible. Although there is evidence of positive selection for some codon positions in Sli, there is no evidence of diversifying selection at the gene level. In silico analysis of Sli protein structure did not support the hypothesis that amino acid changes from wild-type (no insertion) to insertion-type account for changes in protein function. Our study demonstrated that genetic factors besides the Sli gene must be important for conditioning a switch in the mating system from self-incompatible to self-compatible in wild potatoes.

Accessory gland protein regulates pairing process and oviposition in the subterranean termite Reticulitermes chinensis after swarming.

Swarming and pairing behaviors are significant to population dispersal of termites. Tandem running is a key process in pairing behavior of dealates to find a mate. Succinylation can lead to significant changes in protein structure and function, which is widely involved in metabolism and behavior regulation in many organisms. However, whether succinylation modification regulates termites' tandem running is currently unknown. In this research, we performed quantitative modified proteomics of the subterranean termite Reticulitermes chinensis Snyder before and after alate swarming. The succinylation levels of accessory gland protein (ACP) were significantly altered after alate swarming. We found that ACP is enriched in male accessory gland and female oocytes of termites. The acetylation and succinylation sites of ACP affected tandem running of dealates. The transcriptome and metabolome analyses of alates injected with ACP and its mutant proteins showed that β-alanine metabolism pathway was the major downstream pathway of ACP. Silencing the significantly differentially expressed genes in the β-alanine metabolic pathway (acyl-CoA dehydrogenase, enoyl-CoA hydratase, 3-hydroxyisobutyrate dehydrogenase, methylmalonate-semialdehyde dehydrogenase) suppressed tandem running and altered oviposition of paired dealates. These findings demonstrate that protein translation modification is an important regulator of tandem running behavior of termites, which implies that the succinylation and acetylation modification sites of ACP could be potential targets for insecticide action. Our research offers a potential approach for developing novel dispersal inhibitors against social insect pests.

YabJ from Staphylococcus aureus entraps chlorides within its pocket

Chlorination is a potent disinfectant against various microorganisms, including bacteria and viruses, by inducing protein modifications and functional changes. Chlorine, in the form of sodium hypochlorite, stands out as the predominant sanitizer choice due to its cost-effectiveness and powerful antimicrobial properties. Upon exposure to chlorination, proteins undergo modifications, with amino acids experiencing alterations through the attachment of chloride or oxygen atoms. These modifications lead to shifts in protein function and the modulation of downstream signaling pathways, ultimately resulting in a bactericidal effect. However, certain survival proteins, such as chaperones or transcription factors, aid organisms in overcoming harsh chlorination conditions. The expression of YabJ, a highly conserved protein from Staphylococcus aureus, is regulated by a stress-activated sigma factor called sigma B (σB). This research revealed that S. aureus YabJ maintains its structural integrity even under intense chlorination conditions and harbors sodium hypochlorite molecules within its surface pocket. Notably, the pocket of S. aureus YabJ is primarily composed of amino acids less susceptible to chlorination-induced damage, rendering it resistant to such effects. This study elucidates how S. aureus YabJ evades the detrimental effects of chlorination and highlights its role in sequestering sodium hypochlorite within its structure. Consequently, this process enhances resilience and facilitates adaptation to challenging environmental conditions.

Advances in AI for Protein Structure Prediction: Implications for Cancer Drug Discovery and Development.

Recent advancements in AI-driven technologies, particularly in protein structure prediction, are significantly reshaping the landscape of drug discovery and development. This review focuses on the question of how these technological breakthroughs, exemplified by AlphaFold2, are revolutionizing our understanding of protein structure and function changes underlying cancer and improve our approaches to counter them. By enhancing the precision and speed at which drug targets are identified and drug candidates can be designed and optimized, these technologies are streamlining the entire drug development process. We explore the use of AlphaFold2 in cancer drug development, scrutinizing its efficacy, limitations, and potential challenges. We also compare AlphaFold2 with other algorithms like ESMFold, explaining the diverse methodologies employed in this field and the practical effects of these differences for the application of specific algorithms. Additionally, we discuss the broader applications of these technologies, including the prediction of protein complex structures and the generative AI-driven design of novel proteins.

Network integration of thermal proteome profiling with multi-omics data decodes PARP inhibition

Complex disease phenotypes often span multiple molecular processes. Functional characterization of these processes can shed light on disease mechanisms and drug effects. Thermal Proteome Profiling (TPP) is a mass-spectrometry (MS) based technique assessing changes in thermal protein stability that can serve as proxies of functional protein changes. These unique insights of TPP can complement those obtained by other omics technologies. Here, we show how TPP can be integrated with phosphoproteomics and transcriptomics in a network-based approach using COSMOS, a multi-omics integration framework, to provide an integrated view of transcription factors, kinases and proteins with altered thermal stability. This allowed us to recover consequences of Poly (ADP-ribose) polymerase (PARP) inhibition in ovarian cancer cells on cell cycle and DNA damage response as well as interferon and hippo signaling. We found that TPP offers a complementary perspective to other omics data modalities, and that its integration allowed us to obtain a more complete molecular overview of PARP inhibition. We anticipate that this strategy can be used to integrate functional proteomics with other omics to study molecular processes.

MISSENSE MUTATIONS IN THE IRAK1 GENE ARE ASSOCIATED WITH AN INCREASED RISK OF SYSTEMIC LUPUS ERYTHEMATOSUS

Single nucleotide polymorphisms (SNPs) are the most common form of genetic variation in humans. Missense SNPs can change protein structure and function. This study aimed to determine missense SNPs of the IRAK1 gene that can affect the amino acid sequence and lead to changes in protein structure and function, as well as their relationship as a risk factor for SLE. In this in silico method, several bioinformatics tools have been used to identify missense SNPs, including their properties and impacts, as well as their interaction networks with proteins. The tools used were PolyPhenv2, SIFT, PhD-SNP, PROVEAN, SNAP, Panthers, I-Mutant 3.0, and GeneMania. Four missense SNPs, rs11465830, rs1059702, rs1059703, and 10127175, were obtained from the NCBI SNP database. The SIFT test results showed that all the SNPs were tolerant. In the test results obtained using PolyPhen, the four SNPs were benign. The results of the probe test indicated that the four SNPs were neutral. When tested with SNAP, one SNP was neutral, and three others had an impact. In the PhD-SNP test, all SNPs were neutral. In the panther test, all SNPs were benign. The I-mutant assay showed that the four SNPs could decrease protein stability. Tests with GeneMania have reported that most interactions between genes were between IRAK1 and MYD88, and physical interactions were the most dominant form of interaction. Conclusion. rs10127175, rs11465830, rs1059702, and rs1059703 are missense SNPs in IRAK1, which can disrupt protein stability and be a risk factor for SLE. Keywords: IRAK1, SNP, Missense, Systemic Lupus Erythematosus

Ecologically mediated differences in electric organ discharge drive evolution in a sodium channel gene in South American electric fishes.

Active electroreception-the ability to detect objects and communicate with conspecifics via the detection and generation of electric organ discharges (EODs)-has evolved convergently in several fish lineages. South American electric fishes (Gymnotiformes) are a highly species-rich group, possibly in part due to evolution of an electric organ (EO) that can produce diverse EODs. Neofunctionalization of a voltage-gated sodium channel gene accompanied the evolution of electrogenic tissue from muscle and resulted in a novel gene (scn4aa) uniquely expressed in the EO. Here, we investigate the link between variation in scn4aa and differences in EOD waveform. We combine gymnotiform scn4aa sequences encoding the C-terminus of the Nav1.4a protein, with biogeographic data and EOD recordings to test whether physiological transitions among EOD types accompany differential selection pressures on scn4aa. We found positive selection on scn4aa coincided with shifts in EOD types. Species that evolved in the absence of predators, which likely selected for reduced EOD complexity, exhibited increased scn4aa evolutionary rates. We model mutations in the protein that may underlie changes in protein function and discuss our findings in the context of gymnotiform signalling ecology. Together, this work sheds light on the selective forces underpinning major evolutionary transitions in electric signal production.