Biology subjects

Amat, S.

Publications and source records attributed to Amat, S..

12 recordsLinked to original sources

bioRxiv2026

Microbial Biogeography Across the Bovine Body: A Meta-analysis of 27 Anatomical Niches

Cattle harbor diverse bacterial communities across the gastrointestinal, respiratory, reproductive, mammary and other anatomical systems, but body-wide microbial biogeography remains poorly defined. To address this knowledge gap, we conducted a meta-analysis of publicly available bovine 16S rRNA gene amplicon sequencing data from 5,637 samples from 47 studies across six geographic regions and 27 anatomical sample types. Bacterial community structure differed significantly among sample types (PERMANOVA, R2 = 0.245, P = 0.0001), indicating spatial organization of bacterial communities across the bovine body, although study-level effects also contributed substantially to community variation. Communities were generally more similar within than between anatomical systems. Bacterial richness, diversity, taxonomic composition, and indicator taxa varied among sample types, with gastrointestinal, mammary-associated, ocular, and hoof microbiota exhibiting greater diversity than microbiota from liver, joint, and several reproductive samples. Distinct bacterial communities characterized the gastrointestinal, respiratory, reproductive, and mammary systems, as well as other anatomical sites. Despite these differences, several bacterial taxa were shared across multiple anatomical niches, particularly among male and female reproductive sites and among mammary-associated niches. This study provides a comprehensive body-wide characterization of bacterial biogeography in cattle and establishes a baseline for future studies of bovine microbial ecology and host-microbiome interactions.

microbiology↗

bioRxiv2026

Comparative Genomics of Bovine and Human Fusobacterium necrophorum Strains Reveal Subspecies- and Host-associated Differences in Virulence and Antimicrobial Resistance

Fusobacterium necrophorum (FN) is an important opportunistic pathogen implicated in necrotizing infections, including liver abscesses, calf diphtheria, metritis, and foot rot in cattle, and tonsillopharyngitis in humans. However, FN also exists as a commensal member of the bovine reproductive microbiota with potential negative, as in metritis, and even positive associations with pregnancy outcomes. The genomic features that enable FN to colonize diverse hosts and anatomical niches as either a commensal or a pathogen is poorly understood. We addressed these knowledge gaps by performing comparative genomic analysis of 137 FN strains (80 newly sequenced, 57 publicly available) from clinical and non-clinical sources across human and bovine hosts. We investigated the pangenome structure, virulence gene repertoire, antimicrobial resistance genes (ARG) prevalence, as well as host-and subspecies-associated genomic signatures of two FN subspecies: subsp. necrophorum (FNN) and subsp. funduliforme (FNF). Comparative genomics revealed an open pangenome with high accessory diversity, and phylogenetic analysis separated the strains into two distinct subspecies clades. Functional profiling revealed substantial metabolic divergence between subspecies, with FNN showing higher prevalence of carbohydrate transport systems and advanced glycation-related pathways, while FNF showed enrichment in threonate metabolism and hemolysin-related systems. Virulence gene analysis identified 84 variants across multiple functional categories with subspecies- and host-specific distributions. Antimicrobial resistance genes, primarily tetracycline resistance genes [tet(O), tet(M), tet(40)] and the macrolide resistance gene erm(B), were detected in 22.6% of strains, with higher prevalence in bovine than human strains. Overall, our results suggest that pathogenic potential of FN appears to be determined by the interplay between an open pangenome, subspecies-specific metabolic and virulence repertoires, host-associated adaptation, and niche specialization. IMPORTANCEFusobacterium necrophorum, comprising two subspecies, necrophorum (FNN) and funduliforme (FNF), is a major pathogen in cattle and humans, yet it also occurs as a commensal inhabitant in healthy cattle, particularly in the rumen, hindgut, semen, and the female reproductive tract. However, emerging evidence indicates it also occurs as a non-clinical inhabitant, particularly in the bovine reproductive tract, where it may be associated with improved pregnancy outcomes. We conducted a comparative genomic analysis of 137 F. necrophorum strains, including FNN (n = 12) and FNF (n = 125), sourced from humans (n=53) and cattle (n=84) across seven anatomical niches spanning both healthy and diseased sources. We identified subspecies- and host-specific metabolic pathways, antimicrobial resistance profiles, and distinct virulence gene distributions that underpin the ecological versatility of Fusobacterium necrophorum. Overall, these findings provide a genomic framework for understanding its host adaptation and niche specialization across bovine and human hosts.

microbiology↗

bioRxiv2026

Vaginal and uterine microbiomes in beef cattle at artificial insemination and associations with pregnancy outcomes

The female reproductive tract harbors complex microbial communities that may influence reproductive success. In previous work using 16S rRNA gene sequencing, we identified bacterial taxa in the vagina and uterus of beef cattle associated with pregnancy outcomes, but taxonomic resolution and functional inference was limited. Here we used shotgun metagenomic sequencing to characterize the taxonomic composition, functional potential, and antimicrobial resistome of vaginal and uterine microbiomes at the time of artificial insemination (AI) in cows that subsequently became pregnant or remained open. Vaginal (pregnant n = 54; open n = 7) and uterine (pregnant, n = 41; open, n = 9) samples were collected prior to AI. Microbial community structure did not differ between pregnancy outcome groups in either anatomical site (PERMANOVA; P > 0.05). However, cows that remained open showed significantly greater species-level richness and diversity in the vaginal microbiome (P < 0.05). No diversity differences were observed in the uterine microbiome. In contrast, significant differences were detected between anatomical sites, with distinct dominant taxa and functional profiles. Vaginal microbiomes were enriched in pathways related to genetic information processing, whereas uterine microbiomes exhibited greater representation of metabolic pathways. A total of 105 ARGs spanning 11 antimicrobial classes were identified, with tetracycline resistance genes [tet(Q), tet(W), and tet(M)] predominating, and blaTEM-116 more abundant in the uterine microbiome. Overall, while vaginal and uterine microbiomes were compositionally and functionally distinct, no robust pregnancy-associated taxonomic or functional signatures were detected, likely reflecting limited statistical power and challenges inherent to low-biomass metagenomic datasets. IMPORTANCEUnderstanding the role of the reproductive tract microbiome in fertility could improve reproductive efficiency in cattle. We used shotgun metagenomic sequencing to characterize the taxonomic composition, functional potential, and antimicrobial resistome of vaginal and uterine microbiomes at the time of artificial insemination in cows that subsequently became pregnant or remained open. Using paired samples from the same animals, we directly compared microbial communities between the upper and lower reproductive tract to identify shared and site-specific features. Although no distinct microbial signatures associated with pregnancy outcomes were detected, this may reflect limited statistical power and low microbial biomass inherent to these samples. Despite these challenges, our study provides high-resolution insights into the composition, functional potential, and resistome of bovine reproductive microbiomes and highlights important technical considerations for studying low-biomass microbial ecosystems.

microbiology↗

bioRxiv2025

Optimizing bacteriophage screening and isolation methods for microbial samples derived from different body sites of cattle

Bacteriophages are gaining increased research attention as alternatives to antibiotics and microbiome manipulation tools to enhance feed efficiency and animal health in cattle. However, challenges associated with phage specificity, microbial ecosystem variations, and the absence of effective screening methods have hindered harnessing the power of phage application in cattle. The objectives of this study were to (i) optimize phage screening method for microbial samples obtained from different cattle body sites, (ii) isolate lytic phages against key bovine pathogens and commensal bacteria, and (iii) characterize the isolated phages and their bacterial hosts. A total of 1,214 samples from different cattle body sites (n = 1194) and environmental sources were screened using 13 phage detection methods, including one high-throughput approach. Eighty-three phages were isolated, primarily from ruminal fluid (59), feces (15), vaginal (7) and nasopharyngeal swabs (1), and fetal ruminal fluid (1). The bacterial hosts inhibited by these phages were from 29 genera, with Bacillus (34), Escherichia/Shigella (8), Shouchella (5), Corynebacterium (4), and Lysinibacillus (4) being the most common. No phages were identified against bovine pathogens including Trueperella pyogenes, Mannheimia haemolytica, Pasteurella multocida, or Moraxella bovis. Method 12 demonstrated the highest efficiency in phage recovery, particularly from ruminal samples. The isolation of phages against commensal bacteria from the gastrointestinal, reproductive, and respiratory tracts, and fetal gut highlights their potential for microbiome modulation to improve cattle health and feed efficiency. These findings underscore the need for further research into pathogen-targeting phage isolation in cattle. ImportanceBacteriophage application holds a promising potential for improving feed efficiency and reducing enteric methane emissions and fighting against antimicrobial resistant bacterial pathogens in cattle. In the present study, we optimized a bacteriophage screening and isolation method that could be used to isolate bacteriophages against commensal bacteria from the ruminal, respiratory and reproductive tract microbiota in cattle. We isolated 83 phages that are lytic to bacterial species originating from rumen, vagina, nasopharynx of healthy adult cattle, as well as the intestinal tract of 6-month-old calf fetus. Overall, our study provides an important basis for the development of bacteriophage-based interventions to modulate ruminal, reproductive and respiratory tract microbiomes and thereby improve animal health and feed efficiency while reducing methane emissions in cattle.

microbiology↗

bioRxiv2024

Fusobacterium necrophorum and Fusobacterium varium are commensal members of the bovine reproductive microbiota and may colonize calf prenatally

Fusobacterium necrophorum is an important pathogen associated with several infectious diseases in cattle. However, recent sequencing-based studies have indicated that F. necrophorum is positively associated with pregnancy in beef cows and that Fusobacterium is the most abundant genus in the bull seminal microbiota, suggesting the potential role of Fusobacterium in reproductive health and fertility. Here, we performed a comprehensive screening to 1) determine whether Fusobacterium necrophorum (subspecies necrophorum [FNN] and funduliforme [FNF]), and Fusobacterium varium (FV) are part of the commensal members of the reproductive microbiota in cattle; 2) to explore whether these Fusobacterium spp. are colonized in calf prenatally. For this, we screened 11 different sample types including bovine and ram semen, bovine vaginal and uterine swabs, and bull fecal samples, as well as samples from 180- and 260-days old calf fetuses and their respective dams using both quantitative PCR (514 samples) and targeted culturing (499 samples). By qPCR, all the targeted Fusobacterium spp. were detected across all sample types, with FNF being the highly prevalent in the bull semen (66.7%) and maternal ruminal fluids (87.1%), which was confirmed by culturing. All the targeted Fusobacterium were identified in vaginal and uterine (3.1%-9.4%) as well as placental caruncles, and fetal fluids, ruminal and meconium samples (2.7% - 26.3%) by qPCR and were not isolated by culture method. Overall, our results suggest that F. necrophorum is a commensal member of healthy male reproductive microbiota, and that FNF, FNN and FV are present in bovine vagino-uterine microbiota, and calf intestine prenatally.

microbiology↗

bioRxiv2024

Genomic and metabolic characterization of Trueperella pyogenes isolated from domestic and wild animals

Trueperella pyogenes is an important bacterial pathogen implicated in infections such as mastitis, metritis, pneumonia, and liver abscesses in both domestic and wild animals as well as endocarditis and prosthetic joint infections in humans. Understanding the genomic and metabolic features that enable T. pyogenes to colonize different anatomical sites within a host and its inter-kingdom transmission and survival is important for the effective control of this pathogen. We employed whole genome sequencing, phenotype microarrays, and antimicrobial susceptibility testing to identify genomic, metabolic and phenotypic features as well as antimicrobial resistance (AMR) genes in T. pyogenes recovered from different livestock, companion and wildlife animals. For comparative genomic analysis, 83 T. pyogenes genomes, including 60 isolated in the current study and 23 publicly available genomes were evaluated. These genomes represented T. pyogenes strains originated from 16 different body sites of 11 different animal hosts (e.g. bovine, swine, ovine, cervid, bison, equine, chamois, feline). Additionally, 49 T. pyogenes isolates (bovine, ovine, deer, swine and feline) were evaluated for phenotypic antimicrobial resistance using disk diffusion, and for metabolic profiling using the Biology GENIII MicroPlates. We identified that T. pyogenes strains are not host- or body site-specific. The presence of conserved virulence genes (plo and fimA), as well as genotypic and phenotypic AMR may contribute to T. pyogeness ability to cause infections in livestock, wildlife, and pets. Most of the tested isolates metabolized diverse carbon sources and chemical compounds, suggesting that this metabolic versatility may contribute to T. pyogenes survival, competitive advantage, and pathogenic potential. ImportanceTrueperella pyogenes is an important animal pathogen with zoonotic potential, posing a significant health concern to both animals and humans due to its ability to cause infections across different animal host species and tissues. Current understanding of this pathogens adaptability and survival mechanisms is limited. Here, we evaluated the genomic, virulence, metabolic, and antimicrobial resistance characteristics of T. pyogenes recovered from 16 different body sites of 11 different animal hosts (livestock, companion, and wild animals). We identified multiple antimicrobial resistance and virulence genes that may enable T. pyogenes for sustained infection and transmission. Additionally, T. pyogenes strains displayed metabolic versatility which could also contribute to its ability to thrive in diverse environments. Understanding the genomic and metabolic, and antimicrobial resistance characteristics that enable T. pyogenes to colonize different anatomical sites within a host and its transmission between different animal species is important for the effective control of this pathogen.

microbiology↗

bioRxiv2023

Sequencing and Culture-based Characterization of the Vaginal and Uterine Microbiota in Beef Cattle that Became Pregnant or Non-pregnant via Artificial Insemination

In this study, we evaluated the vaginal and uterine microbiota between beef cattle that became pregnant via artificial insemination (AI) and those that did not to identify microbial signature associated with pregnancy. We also characterized the culturable fraction of these microbiota using extensive culturing and screened some vaginal and uterine bacterial isolates for their antimicrobial resistance. For this, vaginal and uterine swabs from two cohorts of Angus-crossbred cattle: mature cows (vaginal and uterine; 27 open and 31 pregnant) and heifers (vaginal; 26 open and 33 pregnant) that were collected before AI were processed for microbiota assessment using 16S rRNA gene sequencing and culturing. Twenty-nine vaginal and uterine bacterial isolates were screened for resistance against 41 antibiotics. Sequencing results revealed 11 taxa that were more abundant in the vaginal samples from non-pregnant heifers compared to pregnant heifers. No differentially abundant taxa were detected in the vaginal samples from pregnant versus non-pregnant cows. Pregnant cows had a distinct uterine microbiota community structure (P = 0.008) and interaction network structure compared to non-pregnant cows. Twenty-eight differentially abundant uterine taxa were observed between the two groups. Community structure and diversity were different between the cow vagina and uterus. A total of 733 bacterial isolates were recovered from vaginal (512) and uterine (221) swabs under aerobic (83 different species) and anaerobic (69 species) culturing. Among these isolates were pathogenic species and those mostly susceptible to tested antibiotics. Overall, our results indicate that pregnancy-associated taxonomic signatures are present in the bovine uterine and vaginal microbiota. ImportanceEmerging evidence suggests that microbiome-targeted approaches may provide a novel opportunity to reduce the incidence of reproductive failures in cattle. To develop such microbiome-based strategies, one of the first logical steps is to identify reproductive microbiome features related to fertility, and isolate the pregnancy associated microbial species for developing a future bacterial consortium that could be administered before breeding to enhance pregnancy outcomes. Here, we characterized the vaginal and uterine microbiota in beef cattle that became pregnant or not via AI and identified some microbiota features associated with pregnancy. We compared similarities between vaginal and uterine microbiota, and between heifers and cows. Using extensive culturing, we provided new insights on the culturable fraction of the vaginal and uterine microbiota, and their antimicrobial resistance. Overall, our findings will serve as an important basis for future research aimed at harnessing the vaginal and uterine microbiome for improved cattle fertility.

microbiology↗

bioRxiv2023

Whole-body Microbiota of Newborn Calves and Their Response to Prenatal Vitamin and Mineral Supplementation

Here, we investigated whether initial microbial colonization at seven different anatomical locations in newborn calves and their blood cytokines are influenced by prenatal vitamin and mineral (VTM) supplementation. Samples were collected from the hoof, liver, lung, nasal cavity, eye, rumen (tissue and fluid), and vagina of beef calves that were born from dams that received diets with or without VTM supplementation throughout gestation (n=7/group). Calves were separated from their dams immediately after birth and fed colostrum and milk replacer until euthanasia at 30 h post-initial colostrum feeding. The microbiota of all samples was assessed using 16S rRNA gene sequencing and qPCR. 15 cytokines and chemokines were quantified in their serum. The hoof, ocular, liver, respiratory, and reproductive sites of newborn calves were colonized by site-specific microbiota that differed from that of the rumen (0.64 [≥] R2 [≥] 0.12, P [≤] 0.003). Only the ruminal fluid microbiota was differed by on prenatal VTM supplementation (P<0.01 Differences (P<0.05) were detected in microbial richness (vagina), diversity (ruminal tissue and fluid, eye), composition at the phylum and genus level (ruminal tissue and fluid, and vagina), and total bacterial abundance (ocular and vagina) between VTM and control calves. The cytokine IP-10 was higher (P=0.02) in VTM calves. Overall, our results suggest that despite immediate separation from the dam upon birth, whole-body of 32-h old calves are colonized by relatively rich, diverse and site-specific bacterial communities, and that initial microbial colonization of the rumen, vagina and oculus seem to be influenced by the prenatal VTM supplementation. IMPORTANCEIncreased appreciation of maternal nutrition and microbiomes involvement in developmental programming and evidence supporting in utero microbial colonization highlight that maternal nutrition factors could impact offspring microbial colonization. Here, we investigated whether initial microbial colonization in any of 7 different anatomical sites of newborn calves was influenced by maternal vitamin and mineral (VTM) supplementation. We identified changes in ruminal, vaginal, and ocular microbiota in newborn calves in response to prenatal VTM supplementation. We provided a "holistic" view on the whole-body calf microbiota. Our data was obtained from calves of the same sex and age, and who were immediately separated from dams, and hence provides novel insights on taxonomic composition of initial bacterial microbiota colonization in those anatomical sites examined. Combined, this study provides direction for future work targeting the manipulation of early life microbiome via alteration of maternal nutrition and harnessing early life microbiota for improved cattle health and production.

microbiology↗

bioRxiv2022

A Single Intranasal Dose of Bacterial Therapeutics to Calves Confers Longitudinal Modulation of the Nasopharyngeal Microbiota

To address the emergence of antimicrobial-resistant pathogens in livestock, microbiome-based strategies are increasingly being sought to reduce antimicrobial use. Here, we describe the intranasal application of bacterial therapeutics (BTs) for mitigating bovine respiratory disease (BRD) and used structural equation modeling to investigate the causal networks after BT application. Beef cattle received i) an intranasal cocktail of previously characterized BT strains, ii) an injection of metaphylactic antimicrobial (tulathromycin), or iii) intranasal saline. Despite being transient colonizers, inoculated BT strains induced longitudinal modulation of the nasopharyngeal bacterial microbiota while showing no adverse effect on animal health. The BT-mediated changes in bacteria included reduced diversity and richness and strengthened cooperative and competitive interactions. In contrast, tulathromycin increased bacterial diversity and antibiotic resistance, and disrupted bacterial interactions. Overall, a single intranasal dose of BTs can modulate the bovine respiratory microbiota, highlighting that microbiome-based strategies have the potential in being utilized to mitigate BRD in feedlot cattle.

microbiology↗

bioRxiv2021

Characterization of the microbiota associated with 12-week-old bovine fetuses exposed to divergent in utero nutrition

A recent study reported the existence of a diverse microbiota in 5-to-7-month-old calf fetuses, suggesting that colonization of the bovine gut with so-called "pioneer" microbiota may begin during mid-gestation. In the present study, we investigated 1) the presence of microbiota in bovine fetuses at early gestation (12 weeks), and 2) whether the fetal microbiota is influenced by the maternal rate of gain or dietary supplementation with vitamins and minerals (VTM) during early gestation. Amniotic and allantoic fluids, and intestinal and placental (cotyledon) tissue samples obtained from fetuses (n = 33) on day 83 of gestation were processed for the assessment of fetal microbiota using 16S rRNA gene sequencing. The sequencing results revealed that a diverse and complex microbial community was present in each of these fetal compartments evaluated. Allantoic and amniotic fluids, and fetal intestinal and placenta microbiota each had distinctly different (0.047 [≥] R2 [≥] 0.019, P [≤] 0.031) microbial community structures. Allantoic fluid had a greater (P < 0.05) microbial richness (number of OTUs) (Mean 122) compared to amniotic fluid (84), intestine (63) and placenta (66). Microbial diversity (Shannon index) was similar for the intestinal and placental samples, and both were less diverse compared with fetal fluid microbiota (P < 0.05). Thirty-nine different archaeal and bacterial phyla were detected across all fetal samples, with Proteobacteria (55%), Firmicutes (16.2%), Acidobacteriota (13.6%) and Bacteroidota (5%) predominating. Among the 20 most relatively abundant bacterial genera, Acidovorax, Acinetobacter, Brucella, Corynebacterium, Enterococcus, Exiguobacterium and Stenotrophomonas differed by fetal sample type (P < 0.05). A total of 55 taxa were shared among the four different microbial communities. qPCR of bacteria in the intestine and placenta samples as well as scanning electron microscopy imaging of fetal fluids provided additional evidence for the presence of a microbiota in these samples. Minor effects of maternal rate of gain and VTM supplementation, and their interactions on microbial richness and composition were detected. Overall, the results of this study indicate that colonization with pioneer microbiota may occur during early gestation in bovine fetuses, and that that the maternal nutritional regime during gestation may influence the early fetal microbiota.

microbiology↗

bioRxiv2021

The nasopharyngeal, ruminal, and vaginal microbiota and the core taxa shared across these microbiomes in virgin yearling heifers exposed to divergent in utero nutrition during their first trimester of gestation and in pregnant beef heifers in response to mineral supplementation

Emerging evidence has indicated that microbial transmission from the bovine dam to her fetus may take place before birth, and that the maternal microbiota during pregnancy modulates programming of fetal metabolic and nervous system development, highlighting the potential and extended role of the maternal microbiome in calf health and development. In the present study, we characterized the nasopharyngeal, ruminal and vaginal microbiota from two cohorts of beef heifers managed at the same location: 1) virgin yearling heifers (9 months old) born from dams received gestational diets which resulted in low (LG, n = 22) or medium (MG, n = 23) weight gain during the first 84 days of gestation; and 2) pregnant replacement heifers that received a vitamin and mineral supplement (VTM, n = 17) or not (Control, n = 15) during the first 6 months of gestation. Nasopharyngeal and vaginal swabs as well as ruminal fluid were collected from both cohorts and the microbiota of each sample was assessed using 16S rRNA gene sequencing. In addition to the comparison between treatment groups within each cohort, the similarity of the microbiota of the three sample types were evaluated, and shared taxa amongst these communities were identified. The bacterial genera present in the rumen and vagina that can influence methanogenic archaeal genera were predicted using a stepwise-selected generalized linear mixed model. No significant difference was observed in the alpha and beta diversity in any of the nasopharyngeal, ruminal and vaginal microbiota between LG and MG offspring virgin heifers, or between the control and VTM pregnant heifers (p > 0.05). Subtle compositional changes in the vaginal microbiota in yearling heifers, and in the nasopharyngeal and ruminal microbiota of pregnant heifers were detected in response to treatments. Forty-one archaeal and bacterial OTUs were shared by over 60% of all samples from both virgin and pregnant heifers. Two taxa within the Methanobrevibacter genus were identified as core taxa and this genus was more relatively abundant in pregnant heifers compared to virgin heifers. Among the 25 top genera, Prevotella and Prevotella UCG-003 (negative) and Christensenellaceae R-7 group (positive) were predicted to have a significant effect on ruminal Methanobrevibacter spp. The results of this study indicate that there is little impact of divergent gestational nutrition during the first trimester on the calf microbiome at 9 months postnatal, and that VTM supplementation during pregnancy may not alter the maternal microbiome. This study provides evidence that there are several microbial taxa, including methanogenic archaea, that are shared across the respiratory, gastrointestinal, and reproductive tracts, suggesting the need for a holistic evaluation of the bovine microbiota when considering potential maternal sources for seeding calves with pioneer microbiota.

microbiology↗

bioRxiv2020

Identification and Mechanistic Characterization of a Novel Peptide Inhibitor of Glycogen Synthase Kinase (GSK3) Derived from the Disrupted in Schizophrenia 1 (DISC1) Protein

Glycogen Synthase Kinase 3-beta (GSK3{beta}) is a critical regulator of several cellular pathways involved in neuroplasticity and is a potential target for neurotherapeutic development in the treatment of neuropsychiatric and neurodegenerative diseases. The majority of efforts to develop inhibitors of GSK3{beta} have been focused on developing small molecule inhibitors that compete with ATP through direct interaction with the ATP binding site. This strategy has presented selectivity challenges due to the evolutionary conservation of this domain within the kinome. The Disrupted in Schizophrenia (DISC1) protein, has previously been shown to bind and inhibit GSK3{beta} activity. Here, we report the characterization of a 44-mer peptide derived from human DISC1 (hDISCtide) that is sufficient to both bind and inhibit GSK3{beta} in a non-competitive mode that is distinct from classical ATP competitive inhibitors. Based on multiple independent biochemical and biophysical assays, we propose that hDISCtide interacts at two distinct regions of GSK3{beta}: an inhibitory region that partially overlaps with the binding site of FRATide, a well-known GSK3{beta} binding peptide, and a specific binding region that is unique to hDISCtide. Taken together, our findings present a novel avenue for developing a peptide-based selective inhibitor of GSK3{beta}.

neuroscience↗