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1.
Front Immunol ; 15: 1368624, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38596677

RESUMO

Introduction: The immune systems of both the mother and the newborn face significant challenges during birth. Proper immune regulation after birth is essential for the survival of neonates. Numerous studies have demonstrated that the neonatal immune system is relatively immature, particularly in its adaptive arm, placing the primary responsibility for immune surveillance on innate immunity. Methods: Given the significant role of neutrophils in protecting the neonate after birth, we conducted a study investigating the properties of neutrophils in newborn cord blood using various methodological approaches. Results: Our findings demonstrate the presence of immature low-density neutrophils in the cord blood, which are likely responsible for the observed elevated expression of genes coding for proteins essential to antimicrobial response, including myeloperoxidase, neutrophils elastase, and defensins. Discussion: We propose that these cells function normally and support the protection of newborns early after birth. Furthermore, our results suggest that the mode of delivery might significantly influence the programming of neutrophil function. The presented findings emphasize the importance of distinct neutrophil subpopulations in neonatal immunity and their potential impact on early postnatal health.


Assuntos
Anti-Infecciosos , Neutrófilos , Recém-Nascido , Humanos , Sangue Fetal , Imunidade Inata , Proteínas/metabolismo , Anti-Infecciosos/metabolismo
2.
Nat Commun ; 15(1): 3244, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38622111

RESUMO

Proteins are molecular machines and to understand how they work, we need to understand how they move. New pump-probe time-resolved X-ray diffraction methods open up ways to initiate and observe protein motions with atomistic detail in crystals on biologically relevant timescales. However, practical limitations of these experiments demands parallel development of effective molecular dynamics approaches to accelerate progress and extract meaning. Here, we establish robust and accurate methods for simulating dynamics in protein crystals, a nontrivial process requiring careful attention to equilibration, environmental composition, and choice of force fields. With more than seven milliseconds of sampling of a single chain, we identify critical factors controlling agreement between simulation and experiments and show that simulated motions recapitulate ligand-induced conformational changes. This work enables a virtuous cycle between simulation and experiments for visualizing and understanding the basic functional motions of proteins.


Assuntos
Simulação de Dinâmica Molecular , Proteínas , Proteínas/metabolismo , Difração de Raios X , Conformação Proteica
3.
Nat Commun ; 15(1): 3129, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38605050

RESUMO

The essence of difference between hemostasis and thrombosis is that the clotting reaction is a highly fine-tuned process. Vascular protein disulfide isomerase (PDI) represents a critical mechanism regulating the functions of hemostatic proteins. Herein we show that histidine-rich glycoprotein (HRG) is a substrate of PDI. Reduction of HRG by PDI enhances the procoagulant and anticoagulant activities of HRG by neutralization of endothelial heparan sulfate (HS) and inhibition of factor XII (FXIIa) activity, respectively. Murine HRG deficiency (Hrg-/-) leads to delayed onset but enhanced formation of thrombus compared to WT. However, in the combined FXII deficiency (F12-/-) and HRG deficiency (by siRNA or Hrg-/-), there is further thrombosis reduction compared to F12-/- alone, confirming HRG's procoagulant activity independent of FXIIa. Mutation of target disulfides of PDI leads to a gain-of-function mutant of HRG that promotes its activities during coagulation. Thus, PDI-HRG pathway fine-tunes thrombosis by promoting its rapid initiation via neutralization of HS and preventing excessive propagation via inhibition of FXIIa.


Assuntos
Isomerases de Dissulfetos de Proteínas , Trombose , Animais , Camundongos , Isomerases de Dissulfetos de Proteínas/genética , Dissulfetos , Proteínas/metabolismo , Trombose/genética , Trombose/metabolismo , Heparitina Sulfato , Fator XII/metabolismo
4.
Commun Biol ; 7(1): 447, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38605212

RESUMO

Protein evolution is constrained by structure and function, creating patterns in residue conservation that are routinely exploited to predict structure and other features. Similar constraints should affect variation across individuals, but it is only with the growth of human population sequencing that this has been tested at scale. Now, human population constraint has established applications in pathogenicity prediction, but it has not yet been explored for structural inference. Here, we map 2.4 million population variants to 5885 protein families and quantify residue-level constraint with a new Missense Enrichment Score (MES). Analysis of 61,214 structures from the PDB spanning 3661 families shows that missense depleted sites are enriched in buried residues or those involved in small-molecule or protein binding. MES is complementary to evolutionary conservation and a combined analysis allows a new classification of residues according to a conservation plane. This approach finds functional residues that are evolutionarily diverse, which can be related to specificity, as well as family-wide conserved sites that are critical for folding or function. We also find a possible contrast between lethal and non-lethal pathogenic sites, and a surprising clinical variant hot spot at a subset of missense enriched positions.


Assuntos
Proteínas , Humanos , Domínios Proteicos , Proteínas/metabolismo , Ligação Proteica , Sequência de Bases
5.
Langmuir ; 40(15): 7781-7790, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38572817

RESUMO

The distinct features of nanoparticles have provided a vast opportunity of developing new diagnosis and therapy strategies for miscellaneous diseases. Although a few nanomedicines are available in the market or in the translation stage, many important issues are still unsolved. When entering the body, nanomaterials will be quickly coated by proteins from their surroundings, forming a corona on their surface, the so-called protein corona. Studies have shown that the protein corona has many important biological implications, particularly at the in vivo level. For example, they can promote the immune system to rapidly clear these outer materials and prevent nanoparticles from playing their designed role in therapy. In this Perspective, the available techniques for characterizing protein-nanoparticle interactions are critically summarized. Effects of nanoparticle properties and environmental factors on protein corona formation, which can further regulate the in vivo fate of nanoparticles, are highlighted and discussed. Moreover, recent progress on the biomedical application of protein corona-engineered nanoparticles is introduced, and future directions for this important yet challenging research area are also briefly discussed.


Assuntos
Nanopartículas , Coroa de Proteína , Coroa de Proteína/metabolismo , Nanopartículas/metabolismo , Proteínas/metabolismo , Nanomedicina , Ligação Proteica
6.
Signal Transduct Target Ther ; 9(1): 80, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38565536

RESUMO

RNA-binding proteins (RBPs)-RNA networks have contributed to cancer development. Circular RNAs (circRNAs) are considered as protein recruiters; nevertheless, the patterns of circRNA-protein interactions in colorectal cancer (CRC) are still lacking. Processing bodies (PBs) formed through liquid-liquid phase separation (LLPS) are membrane-less organelles (MLOs) consisting of RBPs and RNA. Previous evidence suggests a connection between PBs dynamics and cancer progression. Despite the increasingly acknowledged crucial role of RBPs and RNA in the accumulation and maintenance of MLOs, there remains a lack of specific research on the interactions between PBs-related RBPs and circRNAs in CRC. Herein, we identify that MEX-3 RNA binding family member A (MEX3A), frequently upregulated in CRC tissues, predicts poorer patient survival. Elevated MEX3A accelerates malignance and inhibits autophagy of CRC cells. Importantly, MEX3A undergoes intrinsically disordered regions (IDRs)-dependent LLPS in the cytoplasm. Specifically, circMPP6 acts as a scaffold to facilitate the interaction between MEX3A and PBs proteins. The MEX3A/circMPP6 complex modulates PBs dynamic and promotes UPF-mediated phosphodiesterase 5A (PDE5A) mRNA degradation, consequently leading to the aggressive properties of CRC cells. Clinically, CRC patients exhibiting high MEX3A expression and low PDE5A expression have the poorest overall survival. Our findings reveal a collaboration between MEX3A and circMPP6 in the regulation of mRNA decay through triggering the PBs aggregation, which provides prognostic markers and/or therapeutic targets for CRC.


Assuntos
Neoplasias Colorretais , RNA Circular , Humanos , Autofagia/genética , Neoplasias Colorretais/metabolismo , Família , Fosfoproteínas/metabolismo , Proteínas/metabolismo , RNA/genética , RNA Circular/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
7.
Sci Rep ; 14(1): 7736, 2024 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-38565583

RESUMO

Evolution shapes protein sequences for their functions. Here, we studied the moonlighting functions of the N-linked sequon NXS/T, where X is not P, in human nucleocytosolic proteins. By comparing membrane and secreted proteins in which sequons are well known for N-glycosylation, we discovered that cyto-sequons can participate in nucleic acid binding, particularly in zinc finger proteins. Our global studies further discovered that sequon occurrence is largely proportional to protein length. The contribution of sequons to protein functions, including both N-glycosylation and nucleic acid binding, can be regulated through their density as well as the biased usage between NXS and NXT. In proteins where other PTMs or structural features are rich, such as phosphorylation, transmembrane ɑ-helices, and disulfide bridges, sequon occurrence is scarce. The information acquired here should help understand the relationship between protein sequence and function and assist future protein design and engineering.


Assuntos
Ácidos Nucleicos , Proteínas , Humanos , Proteínas/metabolismo , Glicosilação , Sequência de Aminoácidos , Fosforilação , Ácidos Nucleicos/metabolismo
8.
Chem Biol Drug Des ; 103(4): e14515, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38570333

RESUMO

Neurodegenerative disorders are devastating disorders characterized by gradual loss of neurons and cognition or mobility impairment. The common pathological features of these diseases are associated with the accumulation of misfolded or aggregation of proteins. The pivotal roles of autophagy and proteostasis in maintaining cellular health and preventing the accumulation of misfolded proteins, which are associated with neurodegenerative diseases like Huntington's disease (HD), Alzheimer's disease (AD), and Parkinson's disease (PD). This article presents an in-depth examination of the interplay between autophagy and proteostasis, highlighting how these processes cooperatively contribute to cellular homeostasis and prevent pathogenic protein aggregate accumulation. Furthermore, the review emphasises the potential therapeutic implications of targeting autophagy and proteostasis to mitigate neurodegenerative diseases. While advancements in research hold promise for developing novel treatments, the article also addresses the challenges and complexities associated with modulating these intricate cellular pathways. Ultimately, advancing understanding of the underlying mechanism of autophagy and proteostasis in neurodegenerative disorders provides valuable insights into potential therapeutic avenues and future research directions.


Assuntos
Doença de Huntington , Doenças Neurodegenerativas , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Proteostase , Proteínas/metabolismo , Doença de Huntington/tratamento farmacológico , Doença de Huntington/metabolismo , Autofagia
9.
Methods Mol Biol ; 2797: 195-209, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38570461

RESUMO

Knowledge of how effectors interact with RAS GTPases is key to understanding how these switch-like proteins function in cells. Effectors bind specifically to GTP-loaded RAS using RAS association (RA) or RAS binding domains (RBDs) that show wide-ranging affinities and thermodynamic characteristics. Both normal development and RAS-induced tumorigenesis depend on multiple distinct effector proteins that are frequently co-expressed and co-localized, suggesting an antagonistic nature to signaling whereby multiple proteins compete for a limited pool of activated GTPase. NMR spectroscopy offers a powerful approach to multiplex effectors and/or regulatory enzymes and quantifies their interaction with RAS, expanding our biophysical and systems-level understanding of RAS signaling in a more integrated and physiologically relevant setting. Here we describe a method to directly quantitate GTPase binding to competing effectors, using wild-type KRAS complex with ARAF and PLCε1 as a model. Unlabeled RBD/RA domains are added simultaneously to isotopically labeled RAS, and peak intensities at chemical shifts characteristic of individually bound domains provide quantitation. Similar competition-based assays can be run with small molecule interactors, GEF/GAP domains, or regulatory enzymes that drive posttranslational modifications. Such efforts bring in vitro interaction experiments in line with more complex cellular environments.


Assuntos
Transdução de Sinais , Proteínas ras , Proteínas ras/metabolismo , Proteínas/metabolismo , Espectroscopia de Ressonância Magnética , Ligação Proteica
10.
Sci Rep ; 14(1): 7668, 2024 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-38561386

RESUMO

The phenylpyrazole insecticide fipronil has wide-ranging applications from agriculture to public health to control undesirable organisms. However, several studies have reported the residual environmental hazards of fipronil and demonstrated its harmful effects even in mammalian reproduction. Therefore, this study was conducted to demonstrate the mode of action of fipronil on mouse spermatozoa. We treated fipronil to spermatozoa and performed comprehensive function evaluations. Moreover, proteomic analyses were conducted to identify the alteration of protein expression levels in spermatozoa. Most of sperm motility and kinematic parameters and intracellular ATP levels were diminished, and the spontaneous acrosome reaction was promoted after treatment with fipronil. Proteomic analyses revealed altered expression levels of 14 proteins after treatment. These proteins have been reported to be associated with sperm-specific pathways, prominently the cytoskeleton of the sperm, "9 + 2" axoneme composition, metabolism, and fertility. Collectively, our results showed that fipronil alters sperm functional-related proteins and therefore influences male fertility. This study elucidates the possible reproductive toxic hazards associated with male infertility through aberrant suppression of sperm proteins.


Assuntos
Proteômica , Pirazóis , Sêmen , Masculino , Camundongos , Animais , Motilidade dos Espermatozoides , Espermatozoides/metabolismo , Proteínas/metabolismo , Mamíferos
11.
BMC Genomics ; 25(1): 324, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38561675

RESUMO

Lactococcus lactis is widely applied by the dairy industry for the fermentation of milk into products such as cheese. Adaptation of L. lactis to the dairy environment often depends on functions encoded by mobile genetic elements (MGEs) such as plasmids. Other L. lactis MGEs that contribute to industrially relevant traits like antimicrobial production and carbohydrate utilization capacities belong to the integrative conjugative elements (ICE). Here we investigate the prevalence of ICEs in L. lactis using an automated search engine that detects colocalized, ICE-associated core-functions (involved in conjugation or mobilization) in lactococcal genomes. This approach enabled the detection of 36 candidate-ICEs in 69 L. lactis genomes. By phylogenetic analysis of conserved protein functions encoded in all lactococcal ICEs, these 36 ICEs could be classified in three main ICE-families that encompass 7 distinguishable ICE-integrases and are characterized by apparent modular-exchangeability and plasticity. Finally, we demonstrate that phylogenetic analysis of the conjugation-associated VirB4 ATPase function differentiates ICE- and plasmid-derived conjugation systems, indicating that conjugal transfer of lactococcal ICEs and plasmids involves genetically distinct machineries. Our genomic analysis and sequence-based classification of lactococcal ICEs creates a comprehensive overview of the conserved functional repertoires encoded by this family of MGEs in L. lactis, which can facilitate the future exploitation of the functional traits they encode by ICE mobilization to appropriate starter culture strains.


Assuntos
Lactococcus lactis , Lactococcus lactis/genética , Filogenia , Plasmídeos/genética , Proteínas/metabolismo , Genoma , Conjugação Genética , Elementos de DNA Transponíveis
12.
Exp Biol Med (Maywood) ; 249: 10117, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38590360

RESUMO

The risk factors and causes of intracerebral hemorrhage (ICH) and the degree of functional recovery after ICH are distinct between young and elderly patients. The increasing incidence of ICH in young adults has become a concern; however, research on the molecules and pathways involved ICH in subjects of different ages is lacking. In this study, tandem mass tag (TMT)-based proteomics was utilized to examine the protein expression profiles of perihematomal tissue from young and aged mice 24 h after collagenase-induced ICH. Among the 5,129 quantified proteins, ICH induced 108 and 143 differentially expressed proteins (DEPs) in young and aged mice, respectively; specifically, there were 54 common DEPs, 54 unique DEPs in young mice and 89 unique DEPs in aged mice. In contrast, aging altered the expression of 58 proteins in the brain, resulting in 39 upregulated DEPs and 19 downregulated DEPs. Bioinformatics analysis indicated that ICH activated different proteins in complement pathways, coagulation cascades, the acute phase response, and the iron homeostasis signaling pathway in mice of both age groups. Protein-protein interaction (PPI) analysis and ingenuity pathway analysis (IPA) demonstrated that the unique DEPs in the young and aged mice were related to lipid metabolism and carbohydrate metabolism, respectively. Deeper paired-comparison analysis demonstrated that apolipoprotein M exhibited the most significant change in expression as a result of both aging and ICH. These results help illustrate age-related protein expression changes in the acute phase of ICH.


Assuntos
Hemorragia Cerebral , Proteômica , Idoso , Humanos , Camundongos , Animais , Proteômica/métodos , Hemorragia Cerebral/metabolismo , Encéfalo/metabolismo , Envelhecimento , Proteínas/metabolismo
13.
Nat Commun ; 15(1): 2875, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38570497

RESUMO

The characterization of protein-protein interactions (PPIs) is fundamental to the understanding of biochemical processes. Many methods have been established to identify and study direct PPIs; however, screening and investigating PPIs involving large or poorly soluble proteins remains challenging. Here, we introduce ReLo, a simple, rapid, and versatile cell culture-based method for detecting and investigating interactions in a cellular context. Our experiments demonstrate that ReLo specifically detects direct binary PPIs. Furthermore, we show that ReLo bridging experiments can also be used to determine the binding topology of subunits within multiprotein complexes. In addition, ReLo facilitates the identification of protein domains that mediate complex formation, allows screening for interfering point mutations, and it is sensitive to drugs that mediate or disrupt an interaction. In summary, ReLo is a simple and rapid alternative for the study of PPIs, especially when studying structurally complex proteins or when established methods fail.


Assuntos
Mapeamento de Interação de Proteínas , Proteínas , Mapeamento de Interação de Proteínas/métodos , Proteínas/metabolismo
14.
Biochem Biophys Res Commun ; 709: 149725, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38579617

RESUMO

Proteinoids are synthetic polymers that have structural similarities to natural proteins, and their formation is achieved through the application of heat to amino acid combinations in a dehydrated environment. The thermal proteins, initially synthesised by Sidney Fox during the 1960s, has the ability to undergo self-assembly, resulting in the formation of microspheres that resemble cells. These microspheres have fascinating biomimetic characteristics. In recent studies, substantial advancements have been made in elucidating the electrical signalling phenomena shown by proteinoids, hence showcasing their promising prospects in the field of neuro-inspired computing. This study demonstrates the advancement of experimental prototypes that employ proteinoids in the construction of fundamental neural network structures. The article provides an overview of significant achievements in proteinoid systems, such as the demonstration of electrical excitability, emulation of synaptic functions, capabilities in pattern recognition, and adaptability of network structures. This study examines the similarities and differences between proteinoid networks and spontaneous neural computation. We examine the persistent challenges associated with deciphering the underlying mechanisms of emergent proteinoid-based intelligence. Additionally, we explore the potential for developing bio-inspired computing systems using synthetic thermal proteins in forthcoming times. The results of this study offer a theoretical foundation for the advancement of adaptive, self-assembling electronic systems that operate using artificial bio-neural principles.


Assuntos
Aminoácidos , Proteínas , Proteínas/metabolismo , Temperatura Alta , Redes Neurais de Computação
15.
Mol Biol Cell ; 35(5): ar72, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38568782

RESUMO

Cilia generate three-dimensional waveforms required for cell motility and transport of fluid, mucus, and particles over the cell surface. This movement is driven by multiple dynein motors attached to nine outer doublet microtubules that form the axoneme. The outer and inner arm dyneins are organized into 96-nm repeats tandemly arrayed along the length of the doublets. Motility is regulated in part by projections from the two central pair microtubules that contact radial spokes located near the base of the inner dynein arms in each repeat. Although much is known about the structures and protein complexes within the axoneme, many questions remain about the regulatory mechanisms that allow the cilia to modify their waveforms in response to internal or external stimuli. Here, we used Chlamydomonas mbo (move backwards only) mutants with altered waveforms to identify at least two conserved proteins, MBO2/CCDC146 and FAP58/CCDC147, that form part of a L-shaped structure that varies between doublet microtubules. Comparative proteomics identified additional missing proteins that are altered in other motility mutants, revealing overlapping protein defects. Cryo-electron tomography and epitope tagging revealed that the L-shaped, MBO2/FAP58 structure interconnects inner dynein arms with multiple regulatory complexes, consistent with its function in modifying the ciliary waveform.


Assuntos
Axonema , Dineínas , Axonema/metabolismo , Dineínas/metabolismo , Microtúbulos/metabolismo , Cílios/metabolismo , Proteínas/metabolismo , Flagelos/metabolismo
16.
Food Chem Toxicol ; 187: 114638, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38582341

RESUMO

With a society increasingly demanding alternative protein food sources, new strategies for evaluating protein safety issues, such as allergenic potential, are needed. Large-scale and systemic studies on allergenic proteins are hindered by the limited and non-harmonized clinical information available for these substances in dedicated databases. A missing key information is that representing the symptomatology of the allergens, especially given in terms of standard vocabularies, that would allow connecting with other biomedical resources to carry out different studies related to human health. In this work, we have generated the first resource with a comprehensive annotation of allergens' symptomatology, using a text-mining approach that extracts significant co-mentions between these entities from the scientific literature (PubMed, ∼36 million abstracts). The method identifies statistically significant co-mentions between the textual descriptions of the two types of entities in the literature as indication of relationship. 1,180 clinical signs extracted from the Human Phenotype Ontology, the Medical Subject Heading terms of PubMed together with other allergen-specific symptoms, were linked to 1,036 unique allergens annotated in two main allergen-related public databases via 14,009 relationships. This novel resource, publicly available through an interactive web interface, could serve as a starting point for future manually curated compilation of allergen symptomatology.


Assuntos
Alérgenos , Mineração de Dados , Humanos , Mineração de Dados/métodos , Bases de Dados Factuais , Proteínas/metabolismo
17.
Skin Res Technol ; 30(4): e13708, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38634247

RESUMO

BACKGROUND: Reconstructed epidermis models, obtained from 3D keratinocytes culture, have gained significant prominence as prototypes for safety and efficacy testing in skin research. To effectively evaluate these models, it is essential to perform molecular and functional characterization. The skin's barrier function is one of the essential aspects of the epidermis that needs to be assessed. A noninvasive method is thus required for the evaluation of the skin barrier in these models. With this perspective, the aim of this feasibility study is to apply the speckle technique for the assessment of the skin barrier in the Reconstructed Human Epidermis (RHE). MATERIALS AND METHODS: Speckle analysis as well as Raman microspectroscopy were performed on RHE samples at two maturation days, D17 and D20. RESULTS: Between D17 and D20, our study showed an increase in various Raman parameters, including stratum corneum percentage, lateral lipid packing, lipid-to-protein ratio, and protein secondary structure. Furthermore, the degree of light polarization and the speckle grain size also increased over this period. CONCLUSION: The speckle technique proved to be effective for evaluating the skin barrier in Reconstructed Human Epidermis (RHE) models. Comparison with Raman validates this approach and provides comprehensive molecular and functional characterization of reconstructive skin models.


Assuntos
Epiderme , Pele , Humanos , Epiderme/metabolismo , Pele/química , Queratinócitos , Proteínas/metabolismo , Lipídeos/análise
18.
Elife ; 132024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38630609

RESUMO

Revealing protein binding sites with other molecules, such as nucleic acids, peptides, or small ligands, sheds light on disease mechanism elucidation and novel drug design. With the explosive growth of proteins in sequence databases, how to accurately and efficiently identify these binding sites from sequences becomes essential. However, current methods mostly rely on expensive multiple sequence alignments or experimental protein structures, limiting their genome-scale applications. Besides, these methods haven't fully explored the geometry of the protein structures. Here, we propose GPSite, a multi-task network for simultaneously predicting binding residues of DNA, RNA, peptide, protein, ATP, HEM, and metal ions on proteins. GPSite was trained on informative sequence embeddings and predicted structures from protein language models, while comprehensively extracting residual and relational geometric contexts in an end-to-end manner. Experiments demonstrate that GPSite substantially surpasses state-of-the-art sequence-based and structure-based approaches on various benchmark datasets, even when the structures are not well-predicted. The low computational cost of GPSite enables rapid genome-scale binding residue annotations for over 568,000 sequences, providing opportunities to unveil unexplored associations of binding sites with molecular functions, biological processes, and genetic variants. The GPSite webserver and annotation database can be freely accessed at https://bio-web1.nscc-gz.cn/app/GPSite.


Assuntos
Aprendizado Profundo , Ligação Proteica , Proteínas/metabolismo , Sítios de Ligação , Peptídeos/metabolismo
19.
Cell Death Dis ; 15(4): 244, 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38575607

RESUMO

The immunosuppressive microenvironment caused by several intrinsic and extrinsic mechanism has brought great challenges to the immunotherapy of pancreatic cancer. We identified GFPT2, the key enzyme in hexosamine biosynthesis pathway (HBP), as an immune-related prognostic gene in pancreatic cancer using transcriptome sequencing and further confirmed that GFPT2 promoted macrophage M2 polarization and malignant phenotype of pancreatic cancer. HBP is a glucose metabolism pathway leading to the generation of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), which is further utilized for protein O-GlcNAcylation. We confirmed GFPT2-mediated O-GlcNAcylation played an important role in regulating immune microenvironment. Through cellular proteomics, we identified IL-18 as a key downstream of GFPT2 in regulating the immune microenvironment. Through CO-IP and protein mass spectrum, we confirmed that YBX1 was O-GlcNAcylated and nuclear translocated by GFPT2-mediated O-GlcNAcylation. Then, YBX1 functioned as a transcription factor to promote IL-18 transcription. Our study elucidated the relationship between the metabolic pathway of HBP in cancer cells and the immune microenvironment, which might provide some insights into the combination therapy of HBP vulnerability and immunotherapy in pancreatic cancer.


Assuntos
Interleucina-18 , Neoplasias Pancreáticas , Humanos , Glicosilação , Interleucina-18/metabolismo , Neoplasias Pancreáticas/patologia , Proteínas/metabolismo , Vias Biossintéticas , Hexosaminas , Microambiente Tumoral , Proteína 1 de Ligação a Y-Box/metabolismo , Glutamina-Frutose-6-Fosfato Transaminase (Isomerizante)/genética
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