Base excision repair （BER） is an evolutionarily conserved process for maintaining genomic integrity by eliminating several dozen damaged （oxidized or aikylated） or inappropriate bases that are generated endogenous...Base excision repair （BER） is an evolutionarily conserved process for maintaining genomic integrity by eliminating several dozen damaged （oxidized or aikylated） or inappropriate bases that are generated endogenously or induced by genotoxicants, predominantly, reactive oxygen species （ROS）. BER involves 4-5 steps starting with base excision by a DNA glycosylase, followed by a common pathway usually involving an AP-endonuclease （APE） to generate 3＇ OH terminus at the damage site, followed by repair synthesis with a DNA polymerase and nick sealing by a DNA iigase. This pathway is also responsible for repairing DNA single-strand breaks with blocked termini directly generated by ROS. Nearly all glycosylases, far fewer than their substrate lesions particularly for oxidized bases, have broad and overlapping substrate range, and could serve as back-up enzymes in vivo. In contrast, mammalian cells encode only one APE, APEI, unlike two APEs in lower organisms. In spite of overall similarity, BER with distinct subpathways in the mammals is more complex than in E. coli. The glycosylases form complexes with downstream proteins to carry out efficient repair via distinct subpathways one of which, responsible for repair of strand breaks with 3＇ phosphate termini generated by the NEIL family glycosylases or by ROS, requires the phosphatase activity of polynucleotide kinase instead of APE1. Different complexes may utilize distinct DNA polymerases and iigases. Mammalian glycosylases have nonconserved extensions at one of the termini, dispensable for enzymatic activity but needed for interaction with other BER and non-BER proteins for complex formation and organeile targeting. The mammalian enzymes are sometimes covalently modified which may affect activity and complex formation. The focus of this review is on the early steps in mammalian BER for oxidized damage.展开更多
N^6-methyladenosine(m^6A)emerges as an important modification in eukaryotic mRNAs.m^6A has first been reported in 1974,and its functional significance in mammalian gene regulation and importance for proper development...N^6-methyladenosine(m^6A)emerges as an important modification in eukaryotic mRNAs.m^6A has first been reported in 1974,and its functional significance in mammalian gene regulation and importance for proper development have been well established.An arsenal of writer,eraser,and reader proteins accomplish deposition,removal,and interpretation of the m^6A mark,resulting in dynamic function.This led to the concept of an epitranscriptome,the compendium of RNA species with chemical modification ofthe nucleobases in the cell,in analogy to the epigenome.While m^6A has long been known to also exist in plant mRNAs,proteins involved in m^6A metabolism have only recently been detected by mutant analysis,homology search,and mRNA interactome capture in the reference plant Arabidopsis thaliana.Dysregulation ofthe m^6A modification causes severe developmental abnormalities of leaves and roots and altered timing of reproductive development.Furthermore,m^6A modification affects viral infection.Here,we discuss recent progress in identifying m^6A sites transcriptome-wide,in identifying the molecular players involved in writing,removing,and reading the mark,and in assigning functions to this RNA modification in 4.thaliana.We highlight similarities and differences to m^6A modification in mammals and provide an outlook on important questions that remain to be addressed.展开更多
The functional genes underlying phenotypic variation and their interactions represent“genetic mysteries”.Understanding and utilizing these genetic mysteries are key solutions for mitigating the current threats to ag...The functional genes underlying phenotypic variation and their interactions represent“genetic mysteries”.Understanding and utilizing these genetic mysteries are key solutions for mitigating the current threats to agriculture posed by population growth and individual food preferences.Due to advances in highthroughput multi-omics technologies,we are stepping into an Interactome Big Data era that is certain to revolutionize genetic research.In this article,we provide a brief overview of current strategies to explore genetic mysteries.We then introduce the methods for constructing and analyzing the Interactome Big Data and summarize currently available interactome resources.Next,we discuss how Interactome Big Data can be used as a versatile tool to dissect genetic mysteries.We propose an integrated strategy that could revolutionize genetic research by combining Interactome Big Data with machine learning,which involves mining information hidden in Big Data to identify the genetic models or networks that control various traits,and also provide a detailed procedure for systematic dissection of genetic mysteries,Finally,we discuss three promising future breeding strategies utilizing the Interactome Big Data to improve crop yields and quality.展开更多
The protein connector enhancer of kinase suppressor of Ras 2(CNKSR2),present in both the postsynaptic density and cytoplasm of neurons,is a scaffolding protein with several protein-binding domains.Variants of the CNKS...The protein connector enhancer of kinase suppressor of Ras 2(CNKSR2),present in both the postsynaptic density and cytoplasm of neurons,is a scaffolding protein with several protein-binding domains.Variants of the CNKSR2 gene have been implicated in neurodevelopmental disorders,particularly intellectual disability,although the precise mechanism involved has not yet been fully understood.Research has demonstrated that CNKSR2 plays a role in facilitating the localization of postsynaptic density protein complexes to the membrane,thereby influencing synaptic signaling and the morphogenesis of dendritic spines.However,the function of CNKSR2 in the cytoplasm remains to be elucidated.In this study,we used immunoprecipitation and high-resolution liquid chromatography-mass spectrometry to identify the interactors of CNKSR2.Through a combination of bioinformatic analysis and cytological experiments,we found that the CNKSR2 interactors were significantly enriched in the proteome of the centrosome.We also showed that CNKSR2 interacted with the microtubule protein DYNC1H1 and with the centrosome marker CEP290.Subsequent colocalization analysis confirmed the centrosomal localization of CNKSR2.When we downregulated CNKSR2 expression in mouse neuroblastoma cells(Neuro 2A),we observed significant changes in the expression of numerous centrosomal genes.This manipulation also affected centrosome-related functions,including cell size and shape,cell proliferation,and motility.Furthermore,we found that CNKSR2 interactors were highly enriched in de novo variants associated with intellectual disability and autism spectrum disorder.Our findings establish a connection between CNKSR2 and the centrosome,and offer new insights into the underlying mechanisms of neurodevelopmental disorders.展开更多
Tauopathies,diseases characterized by neuropathological aggregates of tau including Alzheimer's disease and subtypes of fro ntotemporal dementia,make up the vast majority of dementia cases.Although there have been...Tauopathies,diseases characterized by neuropathological aggregates of tau including Alzheimer's disease and subtypes of fro ntotemporal dementia,make up the vast majority of dementia cases.Although there have been recent developments in tauopathy biomarkers and disease-modifying treatments,ongoing progress is required to ensure these are effective,economical,and accessible for the globally ageing population.As such,continued identification of new potential drug targets and biomarkers is critical."Big data"studies,such as proteomics,can generate information on thousands of possible new targets for dementia diagnostics and therapeutics,but currently remain underutilized due to the lack of a clear process by which targets are selected for future drug development.In this review,we discuss current tauopathy biomarkers and therapeutics,and highlight areas in need of improvement,particularly when addressing the needs of frail,comorbid and cognitively impaired populations.We highlight biomarkers which have been developed from proteomic data,and outline possible future directions in this field.We propose new criteria by which potential targets in proteomics studies can be objectively ranked as favorable for drug development,and demonstrate its application to our group's recent tau interactome dataset as an example.展开更多
Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understan...Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.展开更多
Plant protein-protein interaction networks have not been identified by large-scale experiments. In order to better understand the protein interactions in rice, the Predicted Rice Interactome Network （PRIN; http：//bi...Plant protein-protein interaction networks have not been identified by large-scale experiments. In order to better understand the protein interactions in rice, the Predicted Rice Interactome Network （PRIN; http：//bis.zju.edu.cn/ prin/） presented 76,585 predicted interactions involving 5,049 rice proteins. After mapping genomic features of rice （GO annotation, subcellular localizationprediction, and gene expression）, we found that a well-annotated and biologically significant network is rich enough to capture many significant functional linkages within higher-order biological systems, such as pathways and biological processes. Furthermore, we took MADS-box do- main-containing proteins and circadian rhythm signaling pathways as examples to demonstrate that functional protein complexes and biological pathways could be effectively expanded in our predicted network. The expanded molecular network in PRIN has considerably improved the capability of these analyses to integrate existing knowledge and provide novel insights into the function and coordination of genes and gene networks.展开更多
The study of the neuron has always been a fundamental aspect when it came to studying mental illnesses such as autism and depression. The protein protocadherin-9 (PCDH9) is an important transmembrane protein in the de...The study of the neuron has always been a fundamental aspect when it came to studying mental illnesses such as autism and depression. The protein protocadherin-9 (PCDH9) is an important transmembrane protein in the development of the neuron synapse. Hence, research on its protein interactome is key to understanding its functionality and specific properties. A newly discovered biotin ligase, TurboID, is a proximity labeler that is designed to be able to label and observe transmembrane proteins, something that previous methods struggled with. The TurboID method is verified in HEK293T cells and primary cultured mouse cortical neurons. Results have proven the validity of the TurboID method in observing PCDH9-interacting proteins.展开更多
Background:Betel nut/areca nut/Areca catechu is one of the most commonly used psychoactive substance,and is also a major preventable cause of cancer.Unlike other psychoactive substances,such as nicotine,the mechanisms...Background:Betel nut/areca nut/Areca catechu is one of the most commonly used psychoactive substance,and is also a major preventable cause of cancer.Unlike other psychoactive substances,such as nicotine,the mechanisms underlying addiction to areca nuts and related oncogenesis remain elusive.Recent reports suggest a possible overlap in the mechanisms of action of nicotine and areca nuts in the human body.Thus,this study aimed to investigate the interactome of human proteins associated with areca nut exposure and the intricate similarities and differences in the effects of the two psychoactive substances on humans.Methods:A list of proteins associated with areca nut use was obtained from the available literature using terms from Medical Subject Headings(MeSH).Protein-protein interaction(PPI)networks and functional enrichment were analyzed.The results obtained for both psychoactive substances were compared.Results:Given the limited number of common proteins(36/226,16%)in the two sets,a substantial overlap(612/1176 nodes,52%)was observed in the PPI networks,as well as in Gene Ontology.Areca nuts mainly affect signaling pathways through three hub proteins(alpha serine/threonine-protein kinase,tumor protein 53,and interleukin-6),which are common to both psychoactive substances,as well as two unique hub proteins(epidermal growth factor receptor and master regulator of cell cycle entry and proliferative metabolism).Areca nut-related proteins are associated with unique pathways,such as extracellular matrix organization,lipid storage,and metabolism,which are not found in nicotine-associated proteins.Conclusions:Areca nuts affect regulatory mechanisms,leading to systemic toxicity and oncogenesis.Areca nuts also affect unique pathways that can be studied as potential markers of exposure,as well as targets for anticancer therapeutic agents.展开更多
With the awarding of the 2015 Nobel Prize in Physiology or Medicine to Chinese pharmacologist Tu Youyou,and the significant contributions of traditional Chinese medicine(TCM)for coronavirus disease 2019(COVID-19),TCM ...With the awarding of the 2015 Nobel Prize in Physiology or Medicine to Chinese pharmacologist Tu Youyou,and the significant contributions of traditional Chinese medicine(TCM)for coronavirus disease 2019(COVID-19),TCM has garnered increasing attention and interest globally.Although advanced research progress has been made in the efficacy research,mechanism elucidation and target prediction of TCM in recent years[1].展开更多
supported by the Earmarked Fund for Modern Agro-industry Technology Research System of China （CARS-36） from the Ministry of Agriculture of China;the National Natural Science Foundation of China （31572549）;the Nati...supported by the Earmarked Fund for Modern Agro-industry Technology Research System of China （CARS-36） from the Ministry of Agriculture of China;the National Natural Science Foundation of China （31572549）;the National Key Technology R＆D Program of China （2015BAD12B01-2） from the Ministry of Science and Technology of China展开更多
Objective: To explore the molecular-level mechanism on the hematopoiesis effect of Angelicae sinensis Radix(ASR) with systems-based interactome analysis. Methods: This systems-based interactome analysis was designed t...Objective: To explore the molecular-level mechanism on the hematopoiesis effect of Angelicae sinensis Radix(ASR) with systems-based interactome analysis. Methods: This systems-based interactome analysis was designed to enforce the workflow of "ASR(herb)→compound→target protein→internal protein actions→ending regulated protein for hematopoiesis". This workflow was deployed with restrictions on regulated proteins expresses in bone marrow and anemia disease and futher validated with experiments. Results: The hematopoiesis mechanism of ASR might be accomplished through regulating pathways of cell proliferation towards hemopoiesis with cross-talking agents of spleen tyrosine kinase(SYK), Janus kinase 2(JAK2), and interleukin-2-inducible T-cell kinase(ITK). The hematopoietic function of ASR was also validated by colonyforming assay performed on mice bone marrow cells. As a result, SYK, JAK2 and ITK were activated. Conclusion: This study provides a new approach to systematically study and predict the therapeutic mechanism for ASR based on interactome analysis towards biological process with experimental validations.展开更多
The 14-3-3 protein family is among the most extensively studied, yet still largely mysterious protein families in mammals to date. As they are well recognized for their roles in apoptosis, cell cycle regulation, and p...The 14-3-3 protein family is among the most extensively studied, yet still largely mysterious protein families in mammals to date. As they are well recognized for their roles in apoptosis, cell cycle regulation, and proliferation in healthy cells, aberrant 14-3-3 expression has unsurprisingly emerged as instrumentalin the development of many cancers and in prognosis. Interestingly, while the seven known 14-3-3 isoforms in humans have many similar functions across cell types, evidence of isoform-specific functions and localization has been observed in both healthy and diseased cells The strikingly high similarity among 14-3-3 isoforms has made it difficult to delineate isoform-specific functions and for isoform-specific targeting. Here, we review our knowledge of 14-3-3 interactome（s） generated by high- throughput techniques, bioinformatics, structural genomics and chemical genornics and point out that integrating the information with molecular dynamics （MD） simulations may bring us new opportunity to the design of isoform-specific inhibitors, which can not only be used as powerful research tools for delineating distinct interactomes of individual 14-3-3 isoforms, but also can serve as potential new anti-cancer drugs that selectively target aberrant 14-3-3 isoform.展开更多
The metabolic enzyme isocitrate dehydrogenase 1(IDH1)catalyzes the oxidative decarboxylation of isocitrate to a-ketoglutarate(a-KG).Its mutation often leads to aberrant gene expression in cancer.IDH1 was reported to b...The metabolic enzyme isocitrate dehydrogenase 1(IDH1)catalyzes the oxidative decarboxylation of isocitrate to a-ketoglutarate(a-KG).Its mutation often leads to aberrant gene expression in cancer.IDH1 was reported to bind thousands of RNA transcripts in a sequence-dependent manner;yet,the functional significance of this RNA-binding activity remains elusive.Here,we report that IDH1 promotes mRNA translation via direct associations with polysome mRNA and translation machinery.Comprehensive proteomic analysis in embryonic stem cells(ESCs)revealed strikingenrichmentof ribosomal proteins and translation regulators in IDH1-bound protein interactomes.We performed ribosomal profiling and analyzed mRNA transcripts that are associated with actively translating polysomes.Interestingly,knockout of IDH1 in ESCs led to significant downregulation of polysome-bound mRNA in IDH1 targets and subtle upregulation of ribosome densities at the start codon,indicating inefficient translation initiation upon loss of IDH1.Tethering IDH1 to a luciferase mRNA via the MS2-MBP system promotes luciferase translation,independently of the catalytic activity of IDH1.Intriguingly,IDH1 fails to enhance luciferase translation driven by an internal ribosome entry site.Together,these results reveal an unforeseen role of IDH1 in fine-tuning cap-dependent translation via the initiation step.展开更多
Background Spermatozoa interact with oviduct secretions before fertilization in vivo but the molecular players of this dialog and underlying dynamics remain largely unknown.Our objectives were to identify an exhaustiv...Background Spermatozoa interact with oviduct secretions before fertilization in vivo but the molecular players of this dialog and underlying dynamics remain largely unknown.Our objectives were to identify an exhaustive list of sperm-interacting proteins(SIPs)in the bovine oviduct fluid and to evaluate the impact of the oviduct anatomical region(isthmus vs.ampulla)and time relative to ovulation(pre-ovulatory vs.post-ovulatory)on SIPs number and abundance.Methods Pools of oviduct fluid(OF)from the pre-ovulatory ampulla,pre-ovulatory isthmus,post-ovulatory ampulla,and post-ovulatory isthmus in the side of ovulation were collected from the slaughterhouse.Frozen-thawed bull sperm were incubated with OF or phosphate-buffered saline(control)for 60 min at 38.5℃.After protein extraction and digestion,sperm and OF samples were analyzed by nanoLC-MS/MS and label-free protein quantification.Results A quantitative comparison between proteins identified in sperm and OF samples(2333 and 2471 proteins,respectively)allowed for the identification of 245 SIPs.The highest number(187)were found in the pre-ovulatory isthmus,i.e.,time and place of the sperm reservoir.In total,41 SIPs(17%)were differentially abundant between stages in a given region or between regions at a given stage and 76 SIPs(31%)were identified in only one region×stage condition.Functional analysis of SIPs predicted roles in cell response to stress,regulation of cell motility,fertilization,and early embryo development.Conclusion This study provides a comprehensive list of SIPs in the bovine oviduct and evidences dynamic spatiotemporal changes in sperm-oviduct interactions around ovulation time.Moreover,these data provide protein candidates to improve sperm conservation and in vitro fertilization media.展开更多
Interactions are the essence of all biomolecules because they cannot fulfill their roles without interacting with other molecules. Hence, mapping the interactions of biomolecules can be useful for understanding their ...Interactions are the essence of all biomolecules because they cannot fulfill their roles without interacting with other molecules. Hence, mapping the interactions of biomolecules can be useful for understanding their roles and functions. Furthermore, the development of molecular based systems biology requires an understanding of the biomolecular interactions. In recent years, the mapping of protein-protein interactions in different species has been reported, but few reports have focused on the large-scale mapping of protein-protein interactions in human. Here, we review the developments in protein interaction mapping and we discuss issues and strategies for the mapping of the human protein interactome.展开更多
文摘Base excision repair （BER） is an evolutionarily conserved process for maintaining genomic integrity by eliminating several dozen damaged （oxidized or aikylated） or inappropriate bases that are generated endogenously or induced by genotoxicants, predominantly, reactive oxygen species （ROS）. BER involves 4-5 steps starting with base excision by a DNA glycosylase, followed by a common pathway usually involving an AP-endonuclease （APE） to generate 3＇ OH terminus at the damage site, followed by repair synthesis with a DNA polymerase and nick sealing by a DNA iigase. This pathway is also responsible for repairing DNA single-strand breaks with blocked termini directly generated by ROS. Nearly all glycosylases, far fewer than their substrate lesions particularly for oxidized bases, have broad and overlapping substrate range, and could serve as back-up enzymes in vivo. In contrast, mammalian cells encode only one APE, APEI, unlike two APEs in lower organisms. In spite of overall similarity, BER with distinct subpathways in the mammals is more complex than in E. coli. The glycosylases form complexes with downstream proteins to carry out efficient repair via distinct subpathways one of which, responsible for repair of strand breaks with 3＇ phosphate termini generated by the NEIL family glycosylases or by ROS, requires the phosphatase activity of polynucleotide kinase instead of APE1. Different complexes may utilize distinct DNA polymerases and iigases. Mammalian glycosylases have nonconserved extensions at one of the termini, dispensable for enzymatic activity but needed for interaction with other BER and non-BER proteins for complex formation and organeile targeting. The mammalian enzymes are sometimes covalently modified which may affect activity and complex formation. The focus of this review is on the early steps in mammalian BER for oxidized damage.
文摘N^6-methyladenosine(m^6A)emerges as an important modification in eukaryotic mRNAs.m^6A has first been reported in 1974,and its functional significance in mammalian gene regulation and importance for proper development have been well established.An arsenal of writer,eraser,and reader proteins accomplish deposition,removal,and interpretation of the m^6A mark,resulting in dynamic function.This led to the concept of an epitranscriptome,the compendium of RNA species with chemical modification ofthe nucleobases in the cell,in analogy to the epigenome.While m^6A has long been known to also exist in plant mRNAs,proteins involved in m^6A metabolism have only recently been detected by mutant analysis,homology search,and mRNA interactome capture in the reference plant Arabidopsis thaliana.Dysregulation ofthe m^6A modification causes severe developmental abnormalities of leaves and roots and altered timing of reproductive development.Furthermore,m^6A modification affects viral infection.Here,we discuss recent progress in identifying m^6A sites transcriptome-wide,in identifying the molecular players involved in writing,removing,and reading the mark,and in assigning functions to this RNA modification in 4.thaliana.We highlight similarities and differences to m^6A modification in mammals and provide an outlook on important questions that remain to be addressed.
基金This research was supported by the National Natural Science Foundation of China(92035302,31922068)the Fundamental Research Funds for the Central Universities(ZK201908)+2 种基金the Fundamental Research Funds for the Central Universities(2662020ZKPY017)the Huazhong Agricultural University Scientific&Technological Self-innovation Foundation(2015R016)the China Postdoctoral Science Foundation(2019M662666).
文摘The functional genes underlying phenotypic variation and their interactions represent“genetic mysteries”.Understanding and utilizing these genetic mysteries are key solutions for mitigating the current threats to agriculture posed by population growth and individual food preferences.Due to advances in highthroughput multi-omics technologies,we are stepping into an Interactome Big Data era that is certain to revolutionize genetic research.In this article,we provide a brief overview of current strategies to explore genetic mysteries.We then introduce the methods for constructing and analyzing the Interactome Big Data and summarize currently available interactome resources.Next,we discuss how Interactome Big Data can be used as a versatile tool to dissect genetic mysteries.We propose an integrated strategy that could revolutionize genetic research by combining Interactome Big Data with machine learning,which involves mining information hidden in Big Data to identify the genetic models or networks that control various traits,and also provide a detailed procedure for systematic dissection of genetic mysteries,Finally,we discuss three promising future breeding strategies utilizing the Interactome Big Data to improve crop yields and quality.
基金supported by the National Nature Science Foundation of China,No.32101020(to JL)the Natural Science Foundation of Shandong Province,Nos.ZR2020MC071(to JL),ZR2023MH327(to HZ)+1 种基金the Integrated Project of Major Research Plan of National Natural Science Foundation of China,No.92249303(to PL)the Natural Science Foundation of Qingdao,No.23-2-1-193-zyyd-jch(to HZ)。
文摘The protein connector enhancer of kinase suppressor of Ras 2(CNKSR2),present in both the postsynaptic density and cytoplasm of neurons,is a scaffolding protein with several protein-binding domains.Variants of the CNKSR2 gene have been implicated in neurodevelopmental disorders,particularly intellectual disability,although the precise mechanism involved has not yet been fully understood.Research has demonstrated that CNKSR2 plays a role in facilitating the localization of postsynaptic density protein complexes to the membrane,thereby influencing synaptic signaling and the morphogenesis of dendritic spines.However,the function of CNKSR2 in the cytoplasm remains to be elucidated.In this study,we used immunoprecipitation and high-resolution liquid chromatography-mass spectrometry to identify the interactors of CNKSR2.Through a combination of bioinformatic analysis and cytological experiments,we found that the CNKSR2 interactors were significantly enriched in the proteome of the centrosome.We also showed that CNKSR2 interacted with the microtubule protein DYNC1H1 and with the centrosome marker CEP290.Subsequent colocalization analysis confirmed the centrosomal localization of CNKSR2.When we downregulated CNKSR2 expression in mouse neuroblastoma cells(Neuro 2A),we observed significant changes in the expression of numerous centrosomal genes.This manipulation also affected centrosome-related functions,including cell size and shape,cell proliferation,and motility.Furthermore,we found that CNKSR2 interactors were highly enriched in de novo variants associated with intellectual disability and autism spectrum disorder.Our findings establish a connection between CNKSR2 and the centrosome,and offer new insights into the underlying mechanisms of neurodevelopmental disorders.
基金supported by funding from the Bluesand Foundation,Alzheimer's Association(AARG-21-852072 and Bias Frangione Early Career Achievement Award)to EDan Australian Government Research Training Program scholarship and the University of Sydney's Brain and Mind Centre fellowship to AH。
文摘Tauopathies,diseases characterized by neuropathological aggregates of tau including Alzheimer's disease and subtypes of fro ntotemporal dementia,make up the vast majority of dementia cases.Although there have been recent developments in tauopathy biomarkers and disease-modifying treatments,ongoing progress is required to ensure these are effective,economical,and accessible for the globally ageing population.As such,continued identification of new potential drug targets and biomarkers is critical."Big data"studies,such as proteomics,can generate information on thousands of possible new targets for dementia diagnostics and therapeutics,but currently remain underutilized due to the lack of a clear process by which targets are selected for future drug development.In this review,we discuss current tauopathy biomarkers and therapeutics,and highlight areas in need of improvement,particularly when addressing the needs of frail,comorbid and cognitively impaired populations.We highlight biomarkers which have been developed from proteomic data,and outline possible future directions in this field.We propose new criteria by which potential targets in proteomics studies can be objectively ranked as favorable for drug development,and demonstrate its application to our group's recent tau interactome dataset as an example.
基金funded by NIH-NIA R01AG061708 (to PHO)Patrick Grange Memorial Foundation (to PHO)+1 种基金A Long Swim (to PHO)CureSPG4 Foundation (to PHO)。
文摘Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.
基金supported by the National Natural Science Foundation of China(Grant No.30771326,30971743,31050110121)the National Science and Technology Project of China(Grant No.2008AA10Z125,2008ZX08003-005,2009DFA32030)the Program for New Century Excellent Talents in University of China(Grant No.NCET-07-0740)
文摘Plant protein-protein interaction networks have not been identified by large-scale experiments. In order to better understand the protein interactions in rice, the Predicted Rice Interactome Network （PRIN; http：//bis.zju.edu.cn/ prin/） presented 76,585 predicted interactions involving 5,049 rice proteins. After mapping genomic features of rice （GO annotation, subcellular localizationprediction, and gene expression）, we found that a well-annotated and biologically significant network is rich enough to capture many significant functional linkages within higher-order biological systems, such as pathways and biological processes. Furthermore, we took MADS-box do- main-containing proteins and circadian rhythm signaling pathways as examples to demonstrate that functional protein complexes and biological pathways could be effectively expanded in our predicted network. The expanded molecular network in PRIN has considerably improved the capability of these analyses to integrate existing knowledge and provide novel insights into the function and coordination of genes and gene networks.
文摘The study of the neuron has always been a fundamental aspect when it came to studying mental illnesses such as autism and depression. The protein protocadherin-9 (PCDH9) is an important transmembrane protein in the development of the neuron synapse. Hence, research on its protein interactome is key to understanding its functionality and specific properties. A newly discovered biotin ligase, TurboID, is a proximity labeler that is designed to be able to label and observe transmembrane proteins, something that previous methods struggled with. The TurboID method is verified in HEK293T cells and primary cultured mouse cortical neurons. Results have proven the validity of the TurboID method in observing PCDH9-interacting proteins.
基金supported by intramural funding from the National Institute of Cancer Prevention and Research,Indian Council of Medical Research(No.NICPR/Anuj/intramural/2021/1).
文摘Background:Betel nut/areca nut/Areca catechu is one of the most commonly used psychoactive substance,and is also a major preventable cause of cancer.Unlike other psychoactive substances,such as nicotine,the mechanisms underlying addiction to areca nuts and related oncogenesis remain elusive.Recent reports suggest a possible overlap in the mechanisms of action of nicotine and areca nuts in the human body.Thus,this study aimed to investigate the interactome of human proteins associated with areca nut exposure and the intricate similarities and differences in the effects of the two psychoactive substances on humans.Methods:A list of proteins associated with areca nut use was obtained from the available literature using terms from Medical Subject Headings(MeSH).Protein-protein interaction(PPI)networks and functional enrichment were analyzed.The results obtained for both psychoactive substances were compared.Results:Given the limited number of common proteins(36/226,16%)in the two sets,a substantial overlap(612/1176 nodes,52%)was observed in the PPI networks,as well as in Gene Ontology.Areca nuts mainly affect signaling pathways through three hub proteins(alpha serine/threonine-protein kinase,tumor protein 53,and interleukin-6),which are common to both psychoactive substances,as well as two unique hub proteins(epidermal growth factor receptor and master regulator of cell cycle entry and proliferative metabolism).Areca nut-related proteins are associated with unique pathways,such as extracellular matrix organization,lipid storage,and metabolism,which are not found in nicotine-associated proteins.Conclusions:Areca nuts affect regulatory mechanisms,leading to systemic toxicity and oncogenesis.Areca nuts also affect unique pathways that can be studied as potential markers of exposure,as well as targets for anticancer therapeutic agents.
基金This work is supported by the“Pioneer”and“Leading Goose”R&D Program of Zhejiang(No.2024C03106)Ningbo Top Medical and Health Research Program(No.2022030309)。
文摘With the awarding of the 2015 Nobel Prize in Physiology or Medicine to Chinese pharmacologist Tu Youyou,and the significant contributions of traditional Chinese medicine(TCM)for coronavirus disease 2019(COVID-19),TCM has garnered increasing attention and interest globally.Although advanced research progress has been made in the efficacy research,mechanism elucidation and target prediction of TCM in recent years[1].
基金supported by the Earmarked Fund for Modern Agro-industry Technology Research System of China (CARS-36) from the Ministry of Agriculture of Chinathe National Natural Science Foundation of China (31572549)the National Key Technology R&D Program of China (2015BAD12B01-2) from the Ministry of Science and Technology of China
文摘supported by the Earmarked Fund for Modern Agro-industry Technology Research System of China （CARS-36） from the Ministry of Agriculture of China;the National Natural Science Foundation of China （31572549）;the National Key Technology R＆D Program of China （2015BAD12B01-2） from the Ministry of Science and Technology of China
文摘Objective: To explore the molecular-level mechanism on the hematopoiesis effect of Angelicae sinensis Radix(ASR) with systems-based interactome analysis. Methods: This systems-based interactome analysis was designed to enforce the workflow of "ASR(herb)→compound→target protein→internal protein actions→ending regulated protein for hematopoiesis". This workflow was deployed with restrictions on regulated proteins expresses in bone marrow and anemia disease and futher validated with experiments. Results: The hematopoiesis mechanism of ASR might be accomplished through regulating pathways of cell proliferation towards hemopoiesis with cross-talking agents of spleen tyrosine kinase(SYK), Janus kinase 2(JAK2), and interleukin-2-inducible T-cell kinase(ITK). The hematopoietic function of ASR was also validated by colonyforming assay performed on mice bone marrow cells. As a result, SYK, JAK2 and ITK were activated. Conclusion: This study provides a new approach to systematically study and predict the therapeutic mechanism for ASR based on interactome analysis towards biological process with experimental validations.
文摘The 14-3-3 protein family is among the most extensively studied, yet still largely mysterious protein families in mammals to date. As they are well recognized for their roles in apoptosis, cell cycle regulation, and proliferation in healthy cells, aberrant 14-3-3 expression has unsurprisingly emerged as instrumentalin the development of many cancers and in prognosis. Interestingly, while the seven known 14-3-3 isoforms in humans have many similar functions across cell types, evidence of isoform-specific functions and localization has been observed in both healthy and diseased cells The strikingly high similarity among 14-3-3 isoforms has made it difficult to delineate isoform-specific functions and for isoform-specific targeting. Here, we review our knowledge of 14-3-3 interactome（s） generated by high- throughput techniques, bioinformatics, structural genomics and chemical genornics and point out that integrating the information with molecular dynamics （MD） simulations may bring us new opportunity to the design of isoform-specific inhibitors, which can not only be used as powerful research tools for delineating distinct interactomes of individual 14-3-3 isoforms, but also can serve as potential new anti-cancer drugs that selectively target aberrant 14-3-3 isoform.
基金This work was supported in part by the National Natural Science Foundation of China(31471219 and 31630095)the National Basic Research Program of China(2017YFA0504204)the Center for Life Sciences at Tsinghua University.
文摘The metabolic enzyme isocitrate dehydrogenase 1(IDH1)catalyzes the oxidative decarboxylation of isocitrate to a-ketoglutarate(a-KG).Its mutation often leads to aberrant gene expression in cancer.IDH1 was reported to bind thousands of RNA transcripts in a sequence-dependent manner;yet,the functional significance of this RNA-binding activity remains elusive.Here,we report that IDH1 promotes mRNA translation via direct associations with polysome mRNA and translation machinery.Comprehensive proteomic analysis in embryonic stem cells(ESCs)revealed strikingenrichmentof ribosomal proteins and translation regulators in IDH1-bound protein interactomes.We performed ribosomal profiling and analyzed mRNA transcripts that are associated with actively translating polysomes.Interestingly,knockout of IDH1 in ESCs led to significant downregulation of polysome-bound mRNA in IDH1 targets and subtle upregulation of ribosome densities at the start codon,indicating inefficient translation initiation upon loss of IDH1.Tethering IDH1 to a luciferase mRNA via the MS2-MBP system promotes luciferase translation,independently of the catalytic activity of IDH1.Intriguingly,IDH1 fails to enhance luciferase translation driven by an internal ribosome entry site.Together,these results reveal an unforeseen role of IDH1 in fine-tuning cap-dependent translation via the initiation step.
基金funded by INRAE and Agence Nationale de la Recherche under the grant number ANR-18-CE92-0049supported by grants from Biogenouest+1 种基金Infrastructures en Biologie Santéet Agronomie (IBiSA)Conseil Régional de Bretagne awarded to Protim proteomics core facility。
文摘Background Spermatozoa interact with oviduct secretions before fertilization in vivo but the molecular players of this dialog and underlying dynamics remain largely unknown.Our objectives were to identify an exhaustive list of sperm-interacting proteins(SIPs)in the bovine oviduct fluid and to evaluate the impact of the oviduct anatomical region(isthmus vs.ampulla)and time relative to ovulation(pre-ovulatory vs.post-ovulatory)on SIPs number and abundance.Methods Pools of oviduct fluid(OF)from the pre-ovulatory ampulla,pre-ovulatory isthmus,post-ovulatory ampulla,and post-ovulatory isthmus in the side of ovulation were collected from the slaughterhouse.Frozen-thawed bull sperm were incubated with OF or phosphate-buffered saline(control)for 60 min at 38.5℃.After protein extraction and digestion,sperm and OF samples were analyzed by nanoLC-MS/MS and label-free protein quantification.Results A quantitative comparison between proteins identified in sperm and OF samples(2333 and 2471 proteins,respectively)allowed for the identification of 245 SIPs.The highest number(187)were found in the pre-ovulatory isthmus,i.e.,time and place of the sperm reservoir.In total,41 SIPs(17%)were differentially abundant between stages in a given region or between regions at a given stage and 76 SIPs(31%)were identified in only one region×stage condition.Functional analysis of SIPs predicted roles in cell response to stress,regulation of cell motility,fertilization,and early embryo development.Conclusion This study provides a comprehensive list of SIPs in the bovine oviduct and evidences dynamic spatiotemporal changes in sperm-oviduct interactions around ovulation time.Moreover,these data provide protein candidates to improve sperm conservation and in vitro fertilization media.
文摘Interactions are the essence of all biomolecules because they cannot fulfill their roles without interacting with other molecules. Hence, mapping the interactions of biomolecules can be useful for understanding their roles and functions. Furthermore, the development of molecular based systems biology requires an understanding of the biomolecular interactions. In recent years, the mapping of protein-protein interactions in different species has been reported, but few reports have focused on the large-scale mapping of protein-protein interactions in human. Here, we review the developments in protein interaction mapping and we discuss issues and strategies for the mapping of the human protein interactome.
