Pub Date : 2024-07-26DOI: 10.1016/j.sbi.2024.102893
Adrien Chauvier, Nils G. Walter
Riboswitches are specialized RNA structures that orchestrate gene expression in response to sensing specific metabolite or ion ligands, mostly in bacteria. Upon ligand binding, these conformationally dynamic RNA motifs undergo structural changes that control critical gene expression processes such as transcription termination and translation initiation, thereby enabling cellular homeostasis and adaptation. Because RNA folds rapidly and co-transcriptionally, riboswitches make use of the low complexity of RNA sequences to adopt alternative, transient conformations on the heels of the transcribing RNA polymerase (RNAP), resulting in kinetic partitioning that defines the regulatory outcome. This review summarizes single molecule microscopy evidence that has begun to unveil a sophisticated network of dynamic, kinetically balanced interactions between riboswitch architecture and the gene expression machinery that, together, integrate diverse cellular signals.
{"title":"Beyond ligand binding: Single molecule observation reveals how riboswitches integrate multiple signals to balance bacterial gene regulation","authors":"Adrien Chauvier, Nils G. Walter","doi":"10.1016/j.sbi.2024.102893","DOIUrl":"10.1016/j.sbi.2024.102893","url":null,"abstract":"<div><p>Riboswitches are specialized RNA structures that orchestrate gene expression in response to sensing specific metabolite or ion ligands, mostly in bacteria. Upon ligand binding, these conformationally dynamic RNA motifs undergo structural changes that control critical gene expression processes such as transcription termination and translation initiation, thereby enabling cellular homeostasis and adaptation. Because RNA folds rapidly and co-transcriptionally, riboswitches make use of the low complexity of RNA sequences to adopt alternative, transient conformations on the heels of the transcribing RNA polymerase (RNAP), resulting in kinetic partitioning that defines the regulatory outcome. This review summarizes single molecule microscopy evidence that has begun to unveil a sophisticated network of dynamic, kinetically balanced interactions between riboswitch architecture and the gene expression machinery that, together, integrate diverse cellular signals.</p></div>","PeriodicalId":10887,"journal":{"name":"Current opinion in structural biology","volume":"88 ","pages":"Article 102893"},"PeriodicalIF":6.1,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-25DOI: 10.1016/j.sbi.2024.102891
Katherine A. Davies , Peter E. Czabotar , James M. Murphy
Necroptosis is a lytic form of programmed cell death implicated in inflammatory pathologies, leading to intense interest in the underlying mechanisms and therapeutic prospects. Here, we review our current structural understanding of how the terminal executioner of the pathway, the dead kinase, mixed lineage kinase domain-like (MLKL), is converted from a dormant to killer form by the upstream regulatory kinase, RIPK3. RIPK3-mediated phosphorylation of MLKL's pseudokinase domain toggles a molecular switch that induces dissociation from a cytoplasmic platform, assembly of MLKL oligomers, and trafficking to the plasma membrane, where activated MLKL accumulates and permeabilises the lipid bilayer to induce cell death. We highlight gaps in mechanistic knowledge of MLKL's activation, how mechanisms diverge between species, and the power of modelling in advancing structural insights.
{"title":"Death at a funeral: Activation of the dead enzyme, MLKL, to kill cells by necroptosis","authors":"Katherine A. Davies , Peter E. Czabotar , James M. Murphy","doi":"10.1016/j.sbi.2024.102891","DOIUrl":"10.1016/j.sbi.2024.102891","url":null,"abstract":"<div><p>Necroptosis is a lytic form of programmed cell death implicated in inflammatory pathologies, leading to intense interest in the underlying mechanisms and therapeutic prospects. Here, we review our current structural understanding of how the terminal executioner of the pathway, the dead kinase, mixed lineage kinase domain-like (MLKL), is converted from a dormant to killer form by the upstream regulatory kinase, RIPK3. RIPK3-mediated phosphorylation of MLKL's pseudokinase domain toggles a molecular switch that induces dissociation from a cytoplasmic platform, assembly of MLKL oligomers, and trafficking to the plasma membrane, where activated MLKL accumulates and permeabilises the lipid bilayer to induce cell death. We highlight gaps in mechanistic knowledge of MLKL's activation, how mechanisms diverge between species, and the power of modelling in advancing structural insights.</p></div>","PeriodicalId":10887,"journal":{"name":"Current opinion in structural biology","volume":"88 ","pages":"Article 102891"},"PeriodicalIF":6.1,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0959440X24001180/pdfft?md5=6d931814dc4980e4f60216073440c7c3&pid=1-s2.0-S0959440X24001180-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141765711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-24DOI: 10.1016/j.sbi.2024.102884
Freddie J.O. Martin, Mònica Santiveri , Haidai Hu , Nicholas M.I. Taylor
Ion-driven membrane motors, essential across all domains of life, convert a gradient of ions across a membrane into rotational energy, facilitating diverse biological processes including ATP synthesis, substrate transport, and bacterial locomotion. Herein, we highlight recent structural advances in the understanding of two classes of ion-driven membrane motors: rotary ATPases and 5:2 motors. The recent structure of the human F-type ATP synthase is emphasised along with the gained structural insight into clinically relevant mutations. Furthermore, we highlight the diverse roles of 5:2 motors and recent mechanistic understanding gained through the resolution of ions in the structure of a sodium-driven motor, combining insights into potential unifying mechanisms of ion selectivity and rotational torque generation in the context of their function as part of complex biological systems.
离子驱动膜马达在生命的各个领域都是必不可少的,它能将膜上的离子梯度转化为旋转能量,促进包括 ATP 合成、底物运输和细菌运动在内的各种生物过程。在此,我们重点介绍在了解两类离子驱动膜马达(旋转 ATP 酶和 5:2 马达)方面取得的最新结构进展。我们重点介绍了人类 F 型 ATP 合成酶的最新结构,以及对临床相关突变的结构认识。此外,我们还强调了 5:2 马达的不同作用,以及通过解析钠驱动马达结构中的离子而获得的最新机理认识,结合作为复杂生物系统一部分的离子选择性和旋转力矩产生的潜在统一机理。
{"title":"Ion-driven rotary membrane motors: From structure to function","authors":"Freddie J.O. Martin, Mònica Santiveri , Haidai Hu , Nicholas M.I. Taylor","doi":"10.1016/j.sbi.2024.102884","DOIUrl":"10.1016/j.sbi.2024.102884","url":null,"abstract":"<div><p>Ion-driven membrane motors, essential across all domains of life, convert a gradient of ions across a membrane into rotational energy, facilitating diverse biological processes including ATP synthesis, substrate transport, and bacterial locomotion. Herein, we highlight recent structural advances in the understanding of two classes of ion-driven membrane motors: rotary ATPases and 5:2 motors. The recent structure of the human F-type ATP synthase is emphasised along with the gained structural insight into clinically relevant mutations. Furthermore, we highlight the diverse roles of 5:2 motors and recent mechanistic understanding gained through the resolution of ions in the structure of a sodium-driven motor, combining insights into potential unifying mechanisms of ion selectivity and rotational torque generation in the context of their function as part of complex biological systems.</p></div>","PeriodicalId":10887,"journal":{"name":"Current opinion in structural biology","volume":"88 ","pages":"Article 102884"},"PeriodicalIF":6.1,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0959440X24001118/pdfft?md5=3d420fd977d0790fe93a91624256205e&pid=1-s2.0-S0959440X24001118-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141757607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-22DOI: 10.1016/j.sbi.2024.102890
Nancy R. Gough, Charalampos G. Kalodimos
Protein kinases are dynamic enzymes that display complex regulatory mechanisms. Although they possess a structurally conserved catalytic domain, significant conformational dynamics are evident both within a single kinase and across different kinases in the kinome. Here, we highlight methods for exploring this conformational space and its dynamics using kinase domains from ABL1 (Abelson kinase), PKA (protein kinase A), AurA (Aurora A), and PYK2 (proline-rich tyrosine kinase 2) as examples. Such experimental approaches combined with AI-driven methods, such as AlphaFold, will yield discoveries about kinase regulation, the catalytic process, substrate specificity, the effect of disease-associated mutations, as well as new opportunities for structure-based drug design.
{"title":"Exploring the conformational landscape of protein kinases","authors":"Nancy R. Gough, Charalampos G. Kalodimos","doi":"10.1016/j.sbi.2024.102890","DOIUrl":"10.1016/j.sbi.2024.102890","url":null,"abstract":"<div><p>Protein kinases are dynamic enzymes that display complex regulatory mechanisms. Although they possess a structurally conserved catalytic domain, significant conformational dynamics are evident both within a single kinase and across different kinases in the kinome. Here, we highlight methods for exploring this conformational space and its dynamics using kinase domains from ABL1 (Abelson kinase), PKA (protein kinase A), AurA (Aurora A), and PYK2 (proline-rich tyrosine kinase 2) as examples. Such experimental approaches combined with AI-driven methods, such as AlphaFold, will yield discoveries about kinase regulation, the catalytic process, substrate specificity, the effect of disease-associated mutations, as well as new opportunities for structure-based drug design.</p></div>","PeriodicalId":10887,"journal":{"name":"Current opinion in structural biology","volume":"88 ","pages":"Article 102890"},"PeriodicalIF":6.1,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141736724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-18DOI: 10.1016/j.sbi.2024.102878
Mark P. Foster, Matthew J. Benedek, Tyler D. Billings, Jonathan S. Montgomery
Cre recombinase is a phage-derived enzyme that has found utility for precise manipulation of DNA sequences. Cre recognizes and recombines pairs of loxP sequences characterized by an inverted repeat and asymmetric spacer. Cre cleaves and religates its DNA targets such that error-prone repair pathways are not required to generate intact DNA products. Major obstacles to broader applications are lack of knowledge of how Cre recognizes its targets, and how its activity is controlled. The picture emerging from high resolution methods is that the dynamic properties of both the enzyme and its DNA target are important determinants of its activity in both sequence recognition and DNA cleavage. Improved understanding of the role of dynamics in the key steps along the pathway of Cre-loxP recombination should significantly advance our ability to both redirect Cre to new sequences and to control its DNA cleavage activity in the test tube and in cells.
Cre 重组酶是一种源自噬菌体的酶,可用于精确操作 DNA 序列。Cre 能识别并重组以倒置重复和不对称间隔为特征的成对 loxP 序列。Cre 可裂解和重构其 DNA 目标,这样就不需要通过容易出错的修复途径来生成完整的 DNA 产物。更广泛应用的主要障碍是不了解 Cre 如何识别其靶标以及如何控制其活性。高分辨率方法得出的结论是,酶及其 DNA 靶标的动态特性是决定其序列识别和 DNA 切割活性的重要因素。进一步了解动态特性在 Cre-loxP 重组途径关键步骤中的作用,将大大提高我们在试管和细胞中将 Cre 重定向到新序列以及控制其 DNA 切裂活性的能力。
{"title":"Dynamics in Cre-loxP site-specific recombination","authors":"Mark P. Foster, Matthew J. Benedek, Tyler D. Billings, Jonathan S. Montgomery","doi":"10.1016/j.sbi.2024.102878","DOIUrl":"10.1016/j.sbi.2024.102878","url":null,"abstract":"<div><p>Cre recombinase is a phage-derived enzyme that has found utility for precise manipulation of DNA sequences. Cre recognizes and recombines pairs of <em>loxP</em> sequences characterized by an inverted repeat and asymmetric spacer. Cre cleaves and religates its DNA targets such that error-prone repair pathways are not required to generate intact DNA products. Major obstacles to broader applications are lack of knowledge of how Cre recognizes its targets, and how its activity is controlled. The picture emerging from high resolution methods is that the dynamic properties of both the enzyme and its DNA target are important determinants of its activity in both sequence recognition and DNA cleavage. Improved understanding of the role of dynamics in the key steps along the pathway of Cre-<em>loxP</em> recombination should significantly advance our ability to both redirect Cre to new sequences and to control its DNA cleavage activity in the test tube and in cells.</p></div>","PeriodicalId":10887,"journal":{"name":"Current opinion in structural biology","volume":"88 ","pages":"Article 102878"},"PeriodicalIF":6.1,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0959440X24001052/pdfft?md5=9e745023813d113b6de70407b1fbd474&pid=1-s2.0-S0959440X24001052-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141636510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-18DOI: 10.1016/j.sbi.2024.102887
Vytautas Gapsys , Wojciech Kopec , Dirk Matthes , Bert L. de Groot
The rapid advancement in computational power available for research offers to bring not only quantitative improvements, but also qualitative changes in the field of biomolecular simulation. Here, we review the state of biomolecular dynamics simulations at the threshold to exascale resources becoming available. Both developments in parallel and distributed computing will be discussed, providing a perspective on the state of the art of both. A main focus will be on obtaining binding and conformational free energies, with an outlook to macromolecular complexes and (sub)cellular assemblies.
{"title":"Biomolecular simulations at the exascale: From drug design to organelles and beyond","authors":"Vytautas Gapsys , Wojciech Kopec , Dirk Matthes , Bert L. de Groot","doi":"10.1016/j.sbi.2024.102887","DOIUrl":"10.1016/j.sbi.2024.102887","url":null,"abstract":"<div><p>The rapid advancement in computational power available for research offers to bring not only quantitative improvements, but also qualitative changes in the field of biomolecular simulation. Here, we review the state of biomolecular dynamics simulations at the threshold to exascale resources becoming available. Both developments in parallel and distributed computing will be discussed, providing a perspective on the state of the art of both. A main focus will be on obtaining binding and conformational free energies, with an outlook to macromolecular complexes and (sub)cellular assemblies.</p></div>","PeriodicalId":10887,"journal":{"name":"Current opinion in structural biology","volume":"88 ","pages":"Article 102887"},"PeriodicalIF":6.1,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0959440X24001143/pdfft?md5=2b578ad583b2ee9d85875c616c70f9c2&pid=1-s2.0-S0959440X24001143-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141636512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-17DOI: 10.1016/j.sbi.2024.102877
J. Winston Arney , Alain Laederach , Kevin M. Weeks
RNA molecules fold to form complex internal structures. Many of these RNA structures populate ensembles with rheostat-like properties, with each state having a distinct function. Until recently, analysis of RNA structures, especially within cells, was limited to modeling either a single averaged structure or computationally-modeled ensembles. These approaches obscure the intrinsic heterogeneity of many structured RNAs. Single-molecule correlated chemical probing (smCCP) strategies are now making it possible to measure and deconvolute RNA structure ensembles based on efficiently executed chemical probing experiments. Here, we provide an overview of fundamental single-molecule probing principles, review current ensemble deconvolution strategies, and discuss recent applications to diverse biological systems. smCCP is enabling a revolution in understanding how the plasticity of RNA structure is exploited in biological systems to respond to stimuli and alter gene function. The energetics of RNA ensembles are often subtle and a subset can likely be targeted to modulate disease-associated biological processes.
{"title":"Visualizing RNA structure ensembles by single-molecule correlated chemical probing","authors":"J. Winston Arney , Alain Laederach , Kevin M. Weeks","doi":"10.1016/j.sbi.2024.102877","DOIUrl":"10.1016/j.sbi.2024.102877","url":null,"abstract":"<div><p>RNA molecules fold to form complex internal structures. Many of these RNA structures populate ensembles with rheostat-like properties, with each state having a distinct function. Until recently, analysis of RNA structures, especially within cells, was limited to modeling either a single averaged structure or computationally-modeled ensembles. These approaches obscure the intrinsic heterogeneity of many structured RNAs. Single-molecule correlated chemical probing (smCCP) strategies are now making it possible to measure and deconvolute RNA structure ensembles based on efficiently executed chemical probing experiments. Here, we provide an overview of fundamental single-molecule probing principles, review current ensemble deconvolution strategies, and discuss recent applications to diverse biological systems. smCCP is enabling a revolution in understanding how the plasticity of RNA structure is exploited in biological systems to respond to stimuli and alter gene function. The energetics of RNA ensembles are often subtle and a subset can likely be targeted to modulate disease-associated biological processes.</p></div>","PeriodicalId":10887,"journal":{"name":"Current opinion in structural biology","volume":"88 ","pages":"Article 102877"},"PeriodicalIF":6.1,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141636511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-15DOI: 10.1016/j.sbi.2024.102879
Calvin P. Lin, Elizabeth A. Komives
The cellular process by which the protein ubiquitin (Ub) is covalently attached to a protein substrate involves Ub activating (E1s) and conjugating enzymes (E2s) that work together with a large variety of E3 ligases that impart substrate specificity. The largest family of E3s is the Cullin-RING ligase (CRL) family which utilizes a wide variety of substrate receptors, adapter proteins, and cooperating ligases. Cryo-electron microscopy (cryoEM) has revealed a wide variety of structures which suggest how Ub transfer occurs. Hydrogen deuterium exchange mass spectrometry (HDXMS) has revealed the role of dynamics and expanded our knowledge of how covalent NEDD8 modification (neddylation) activates the CRLs, particularly by facilitating cooperation with additional RING-between-RING ligases to transfer Ub.
{"title":"Diversity of structure and function in Cullin E3 ligases","authors":"Calvin P. Lin, Elizabeth A. Komives","doi":"10.1016/j.sbi.2024.102879","DOIUrl":"10.1016/j.sbi.2024.102879","url":null,"abstract":"<div><p>The cellular process by which the protein ubiquitin (Ub) is covalently attached to a protein substrate involves Ub activating (E1s) and conjugating enzymes (E2s) that work together with a large variety of E3 ligases that impart substrate specificity. The largest family of E3s is the Cullin-RING ligase (CRL) family which utilizes a wide variety of substrate receptors, adapter proteins, and cooperating ligases. Cryo-electron microscopy (cryoEM) has revealed a wide variety of structures which suggest how Ub transfer occurs. Hydrogen deuterium exchange mass spectrometry (HDXMS) has revealed the role of dynamics and expanded our knowledge of how covalent NEDD8 modification (neddylation) activates the CRLs, particularly by facilitating cooperation with additional RING-between-RING ligases to transfer Ub.</p></div>","PeriodicalId":10887,"journal":{"name":"Current opinion in structural biology","volume":"88 ","pages":"Article 102879"},"PeriodicalIF":6.1,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0959440X24001064/pdfft?md5=4d0108ead674eda244db07a4b0fdfd46&pid=1-s2.0-S0959440X24001064-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141623600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-13DOI: 10.1016/j.sbi.2024.102886
Souparna Chakrabarty , Shujuan Wang , Tanaya Roychowdhury , Stephen D. Ginsberg , Gabriela Chiosis
Protein-protein interactions (PPIs) play a crucial role in cellular function and disease manifestation, with dysfunctions in PPI networks providing a direct link between stressors and phenotype. The dysfunctional Protein-Protein Interactome (dfPPI) platform, formerly known as epichaperomics, is a newly developed chemoproteomic method aimed at detecting dynamic changes at the systems level in PPI networks under stressor-induced cellular perturbations within disease states. This review provides an overview of dfPPIs, emphasizing the novel methodology, data analytics, and applications in disease research. dfPPI has applications in cancer research, where it identifies dysfunctions integral to maintaining malignant phenotypes and discovers strategies to enhance the efficacy of current therapies. In neurodegenerative disorders, dfPPI uncovers critical dysfunctions in cellular processes and stressor-specific vulnerabilities. Challenges, including data complexity and the potential for integration with other omics datasets are discussed. The dfPPI platform is a potent tool for dissecting disease systems biology by directly informing on dysfunctions in PPI networks and holds promise for advancing disease identification and therapeutics.
蛋白质-蛋白质相互作用(PPI)在细胞功能和疾病表现中起着至关重要的作用,PPI网络的功能失调是应激源与表型之间的直接联系。功能失调蛋白-蛋白相互作用组(dfPPI)平台以前被称为外显子组学,是一种新开发的化学蛋白组学方法,旨在检测疾病状态下应激物诱导的细胞扰动在 PPI 网络系统水平上的动态变化。本综述概述了 dfPPI,强调了其新颖的方法、数据分析以及在疾病研究中的应用。dfPPI 在癌症研究中得到了应用,它能识别维持恶性表型不可或缺的功能障碍,并发现提高当前疗法疗效的策略。在神经退行性疾病中,dfPPI 发现了细胞过程中的关键功能障碍和压力特异性弱点。会上讨论了所面临的挑战,包括数据的复杂性以及与其他全息数据集整合的潜力。dfPPI 平台通过直接告知 PPI 网络中的功能障碍,是剖析疾病系统生物学的有力工具,有望推动疾病识别和治疗。
{"title":"Introducing dysfunctional Protein-Protein Interactome (dfPPI) – A platform for systems-level protein-protein interaction (PPI) dysfunction investigation in disease","authors":"Souparna Chakrabarty , Shujuan Wang , Tanaya Roychowdhury , Stephen D. Ginsberg , Gabriela Chiosis","doi":"10.1016/j.sbi.2024.102886","DOIUrl":"https://doi.org/10.1016/j.sbi.2024.102886","url":null,"abstract":"<div><p>Protein-protein interactions (PPIs) play a crucial role in cellular function and disease manifestation, with dysfunctions in PPI networks providing a direct link between stressors and phenotype. The dysfunctional Protein-Protein Interactome (dfPPI) platform, formerly known as epichaperomics, is a newly developed chemoproteomic method aimed at detecting dynamic changes at the systems level in PPI networks under stressor-induced cellular perturbations within disease states. This review provides an overview of dfPPIs, emphasizing the novel methodology, data analytics, and applications in disease research. dfPPI has applications in cancer research, where it identifies dysfunctions integral to maintaining malignant phenotypes and discovers strategies to enhance the efficacy of current therapies. In neurodegenerative disorders, dfPPI uncovers critical dysfunctions in cellular processes and stressor-specific vulnerabilities. Challenges, including data complexity and the potential for integration with other omics datasets are discussed. The dfPPI platform is a potent tool for dissecting disease systems biology by directly informing on dysfunctions in PPI networks and holds promise for advancing disease identification and therapeutics.</p></div>","PeriodicalId":10887,"journal":{"name":"Current opinion in structural biology","volume":"88 ","pages":"Article 102886"},"PeriodicalIF":6.1,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0959440X24001131/pdfft?md5=ce1626c6a05f554e967c55418222e73c&pid=1-s2.0-S0959440X24001131-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141606930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Adopting computational tools for analyzing extensive biological datasets has profoundly transformed our understanding and interpretation of biological phenomena. Innovative platforms have emerged, providing automated analysis to unravel essential insights about proteins and the complexities of their interactions. These computational advancements align with traditional studies, which employ experimental techniques to discern and quantify physical and functional protein-protein interactions (PPIs). Among these techniques, tandem mass spectrometry is notably recognized for its precision and sensitivity in identifying PPIs. These approaches might serve as important information enabling the identification of PPIs with potential pharmacological significance. This review aims to convey our experience using computational tools for detecting PPI networks and offer an analysis of platforms that facilitate predictions derived from experimental data.
采用计算工具分析大量生物数据集,深刻地改变了我们对生物现象的理解和解释。创新平台不断涌现,它们提供自动分析功能,帮助我们深入了解蛋白质及其相互作用的复杂性。这些计算技术的进步与传统研究相吻合,后者采用实验技术来辨别和量化蛋白质与蛋白质之间的物理和功能性相互作用(PPIs)。在这些技术中,串联质谱法因其识别 PPI 的精确性和灵敏度而备受认可。这些方法可作为鉴定具有潜在药理意义的 PPI 的重要信息。本综述旨在介绍我们使用计算工具检测 PPI 网络的经验,并对有助于从实验数据中得出预测结果的平台进行分析。
{"title":"The power of computational proteomics platforms to decipher protein-protein interactions","authors":"Mariela González-Avendaño , Joaquín López , Ariela Vergara-Jaque , Oscar Cerda","doi":"10.1016/j.sbi.2024.102882","DOIUrl":"https://doi.org/10.1016/j.sbi.2024.102882","url":null,"abstract":"<div><p>Adopting computational tools for analyzing extensive biological datasets has profoundly transformed our understanding and interpretation of biological phenomena. Innovative platforms have emerged, providing automated analysis to unravel essential insights about proteins and the complexities of their interactions. These computational advancements align with traditional studies, which employ experimental techniques to discern and quantify physical and functional protein-protein interactions (PPIs). Among these techniques, tandem mass spectrometry is notably recognized for its precision and sensitivity in identifying PPIs. These approaches might serve as important information enabling the identification of PPIs with potential pharmacological significance. This review aims to convey our experience using computational tools for detecting PPI networks and offer an analysis of platforms that facilitate predictions derived from experimental data.</p></div>","PeriodicalId":10887,"journal":{"name":"Current opinion in structural biology","volume":"88 ","pages":"Article 102882"},"PeriodicalIF":6.1,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141606931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}