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Uncovering new families and folds in the natural protein universe.
Durairaj, J, Waterhouse, AM, Mets, T, Brodiazhenko, T, Abdullah, M, Studer, G, Tauriello, G, Akdel, M, Andreeva, A, Bateman, A, et al
Nature. 2023;(7983):646-653
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Abstract
We are now entering a new era in protein sequence and structure annotation, with hundreds of millions of predicted protein structures made available through the AlphaFold database1. These models cover nearly all proteins that are known, including those challenging to annotate for function or putative biological role using standard homology-based approaches. In this study, we examine the extent to which the AlphaFold database has structurally illuminated this 'dark matter' of the natural protein universe at high predicted accuracy. We further describe the protein diversity that these models cover as an annotated interactive sequence similarity network, accessible at https://uniprot3d.org/atlas/AFDB90v4 . By searching for novelties from sequence, structure and semantic perspectives, we uncovered the β-flower fold, added several protein families to Pfam database2 and experimentally demonstrated that one of these belongs to a new superfamily of translation-targeting toxin-antitoxin systems, TumE-TumA. This work underscores the value of large-scale efforts in identifying, annotating and prioritizing new protein families. By leveraging the recent deep learning revolution in protein bioinformatics, we can now shed light into uncharted areas of the protein universe at an unprecedented scale, paving the way to innovations in life sciences and biotechnology.
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Structural validation and assessment of AlphaFold2 predictions for centrosomal and centriolar proteins and their complexes.
van Breugel, M, Rosa E Silva, I, Andreeva, A
Communications biology. 2022;(1):312
Abstract
Obtaining the high-resolution structures of proteins and their complexes is a crucial aspect of understanding the mechanisms of life. Experimental structure determination methods are time-consuming, expensive and cannot keep pace with the growing number of protein sequences available through genomic DNA sequencing. Thus, the ability to accurately predict the structure of proteins from their sequence is a holy grail of structural and computational biology that would remove a bottleneck in our efforts to understand as well as rationally engineer living systems. Recent advances in protein structure prediction, in particular the breakthrough with the AI-based tool AlphaFold2 (AF2), hold promise for achieving this goal, but the practical utility of AF2 remains to be explored. Focusing on proteins with essential roles in centrosome and centriole biogenesis, we demonstrate the quality and usability of the AF2 prediction models and we show that they can provide important insights into the modular organization of two key players in this process, CEP192 and CEP44. Furthermore, we used the AF2 algorithm to elucidate and then experimentally validate previously unknown prime features in the structure of TTBK2 bound to CEP164, as well as the Chibby1-FAM92A complex for which no structural information was available to date. These findings have important implications in understanding the regulation and function of these complexes. Finally, we also discuss some practical limitations of AF2 and anticipate the implications for future research approaches in the centriole/centrosome field.
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Effects of home confinement on mental health and lifestyle behaviours during the COVID-19 outbreak: insights from the ECLB-COVID19 multicentre study.
Ammar, A, Trabelsi, K, Brach, M, Chtourou, H, Boukhris, O, Masmoudi, L, Bouaziz, B, Bentlage, E, How, D, Ahmed, M, et al
Biology of sport. 2021;38(1):9-21
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Plain language summary
Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the respiratory syndrome coronavirus 2 (SARS-CoV-2). To curb the spread of the 2020 pandemic, social distancing, self-isolation and nationwide lockdown measures were put in place. These measures along with hygiene care are recognized as the most effective ways to curb the spread of disease. However; the weakening of social contacts can result in anxiety, frustration, panic attacks, loss or sudden increase of appetite, insomnia, depression, mood swings, delusions, fear, sleep disorders, and suicidal/domestic violence. The purpose of the study is to provide scientific data to help identify risk factors for the psychosocial strain during the COVID-19 outbreak. The study is an international cross-disciplinary online survey and was circulated in April 2020. 1047 replies were analysed from this preliminary phase. The results show a significant difference in all tested parameters and therefore reveal a large burden for mental wellbeing combined with a tendency towards an unhealthy lifestyle during, compared to before, the confinement enforced by the COVID-19 pandemic. These results highlight the importance for policy makers to consider strategies to promote wellbeing during future confinements.
Abstract
Although recognised as effective measures to curb the spread of the COVID-19 outbreak, social distancing and self-isolation have been suggested to generate a burden throughout the population. To provide scientific data to help identify risk factors for the psychosocial strain during the COVID-19 outbreak, an international cross-disciplinary online survey was circulated in April 2020. This report outlines the mental, emotional and behavioural consequences of COVID-19 home confinement. The ECLB-COVID19 electronic survey was designed by a steering group of multidisciplinary scientists, following a structured review of the literature. The survey was uploaded and shared on the Google online survey platform and was promoted by thirty-five research organizations from Europe, North Africa, Western Asia and the Americas. Questions were presented in a differential format with questions related to responses "before" and "during" the confinement period. 1047 replies (54% women) from Western Asia (36%), North Africa (40%), Europe (21%) and other continents (3%) were analysed. The COVID-19 home confinement evoked a negative effect on mental wellbeing and emotional status (P < 0.001; 0.43 ≤ d ≤ 0.65) with a greater proportion of individuals experiencing psychosocial and emotional disorders (+10% to +16.5%). These psychosocial tolls were associated with unhealthy lifestyle behaviours with a greater proportion of individuals experiencing (i) physical (+15.2%) and social (+71.2%) inactivity, (ii) poor sleep quality (+12.8%), (iii) unhealthy diet behaviours (+10%), and (iv) unemployment (6%). Conversely, participants demonstrated a greater use (+15%) of technology during the confinement period. These findings elucidate the risk of psychosocial strain during the COVID-19 home confinement period and provide a clear remit for the urgent implementation of technology-based intervention to foster an Active and Healthy Confinement Lifestyle AHCL).
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Relationship Between Vitamin D Status and Vitamin D Receptor Gene Polymorphisms With Markers of Metabolic Syndrome Among Adults.
Karonova, T, Grineva, E, Belyaeva, O, Bystrova, A, Jude, EB, Andreeva, A, Kostareva, A, Pludowski, P
Frontiers in endocrinology. 2018;:448
Abstract
Introduction: Recent studies have demonstrated that vitamin D deficiency contributes to the development of metabolic disorders, including obesity and type 2 diabetes mellitus (T2DM). Several vitamin D receptor (VDR) gene polymorphisms had been described to play a role in these conditions since vitamin D receptors were found in many tissues. The aim of this study was to assess the relationship between vitamin D status and VDR gene polymorphisms with metabolic syndrome (MS) parameters in Russian middle-aged women. Materials and Methods: A total of 697 women aged between 30 to 55 years were included in this cross-sectional study. Serum 25-hydroxyvitamin D (25(OH)D) level and four VDR gene polymorphisms rs1544410 (BsmI), rs7975232 (ApaI), rs731236 (TaqI), and rs2228570 (FokI) were measured. We applied the International Diabetes Federation (IDF) criteria to identify subjects with MS. Results: 9.3% of subjects had normal vitamin D level, while 90.7% were insufficient or deficient. Abdominal obesity (AO) was seen in 75.5%, impaired glucose tolerance (IGT) or T2DM was observed in 33.3%, reduced high-density lipoprotein cholesterol (HDL-C) level in 32.2% and hypertriglyceridemia in 23.4%. Serum 25(OH)D level in women with or without MS did not differ (48.6 ± 1.8 and 51.1 ± 1.5 nmol/l, p > 0.05). Subjects with vitamin D deficiency showed an increased risk of AO [CI 95% 2.23; 1.15-4.30] and low HDL-C [CI95% 2.60; 1.04-6.49] compared to subjects with normal 25(OH)D level. IGT and T2DM risk was increased only when 25(OH)D concentration was less than 39.0 nmol/l [CI 95% 7.17; 2.99-17.7], but risk of MS did not differ in normal vitamin D status subjects and insufficient/deficient ones (p > 0.05). T allele carriers (A) of rs7975232 had higher total cholesterol and low-density lipoprotein cholesterol levels compared with the GG (aa) genotypes. Similarly, GG (BB) genotype carriers of rs1544410 had higher triglyceride levels than subjects with A (b) allele carriers. However VDR gene polymorphisms did not seem to be associated with an increased risk of MS. Conclusions: Vitamin D deficiency, rs7975232, and rs1544410 VDR gene variants are associated with MS parameters in Russian middle-aged women.
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Serum 25(OH)D and adipokines levels in people with abdominal obesity.
Karonova, T, Belyaeva, O, Jude, EB, Tsiberkin, A, Andreeva, A, Grineva, E, Pludowski, P
The Journal of steroid biochemistry and molecular biology. 2018;:170-176
Abstract
Abdominal obesity is a risk factor for cardiovascular disease and diabetes mellitus and has been associated with vitamin D deficiency. Some studies have suggested an association between obesity and adipokine levels as well as low serum 25-hydroxyvitamin D (25(OH)D) level but the underlying mechanisms of the interlink between vitamin D status and serum leptin and adiponectin concentrations are still disputed. We included 435 residents (132 males) from St. Petersburg, Russia into this study. All subjects had physical examination and demographics noted. Blood was collected after an overnight fast and plasma glucose, insulin, serum lipids, 25(OH)D and adipokines (adiponectin and leptin) concentrations were determined at baseline in all participants. Abdominal obesity was diagnosed in 310 (71.3%) subjects (251 females and 59 males). Vitamin D insufficiency and deficiency were found in 314 (72.2%) subjects. Mean (95% CI) age, body mass index (BMI) and serum 25(OH)D for the cohort were 47.6±11.3years; 28.7±0.2kg/m2 and 62.5±24.3nmol/l respectively. Serum 25(OH)D level inversely correlated with body weight, waist circumference (WC) and BMI in females but not in males, was lower in diabetic than non-diabetic subjects, and was not significantly different in subjects with and without MetS. WC was positively correlated with leptin and negatively correlated with adiponectin. We found correlation between leptin and serum 25(OH)D level (r=-0.15, p=0.01) but this finding was a characteristic seen only in women. Our study showed a high prevalence of abdominal obesity, vitamin D deficiency and insufficiency in residents from North-West region of Russia, close association between adipokine (leptin, adiponectin) concentrations as well as vitamin D status and body composition (WC, BMI). However in our study the interlink between leptin level and 25(OH)D was found only in females. Further investigations are required to study the relationship between serum 25(OH)D level, obesity and serum adipokine levels.
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Crystal Structure of a Group I Energy Coupling Factor Vitamin Transporter S Component in Complex with Its Cognate Substrate.
Josts, I, Almeida Hernandez, Y, Andreeva, A, Tidow, H
Cell chemical biology. 2016;(7):827-836
Abstract
Energy coupling factor (ECF) transporters are responsible for the uptake of essential scarce nutrients in prokaryotes. This ATP-binding cassette transporter family comprises two subgroups that share a common architecture forming a tripartite membrane protein complex consisting of a translocation component and ATP hydrolyzing module and a substrate-capture (S) component. Here, we present the crystal structure of YkoE from Bacillus subtilis, the S component of the previously uncharacterized group I ECF transporter YkoEDC. Structural and biochemical analyses revealed the constituent residues of the thiamine-binding pocket as well as an unexpected mode of vitamin recognition. In addition, our experimental and bioinformatics data demonstrate major differences between YkoE and group II ECF transporters and indicate how group I vitamin transporter S components have diverged from other group I and group II ECF transporters.
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Evolution of protein fold in the presence of functional constraints.
Andreeva, A, Murzin, AG
Current opinion in structural biology. 2006;(3):399-408
Abstract
The functional requirement to form and maintain the active site structure probably exerts a strong selective pressure on a protein to adopt just one stable and evolutionarily conserved fold. Nonetheless, new evidence suggests the likelihood of protein fold being neither physically nor biologically invariant. Alternative folds discovered in several proteins are composed of constant and variable parts. The latter display context-dependent conformations and a tendency to form new oligomeric interfaces. In turn, oligomerisation mediates fold evolution without loss of protein function. Gene duplication breaks down homo-oligomeric symmetry and relieves the pressure to maintain the local architecture of redundant active sites; this can lead to further structural changes.