Pub Date : 2015-08-20Epub Date: 2015-07-23DOI: 10.1016/j.chembiol.2015.06.021
Agnieszka Szwajda, Prson Gautam, Leena Karhinen, Sawan Kumar Jha, Jani Saarela, Sushil Shakyawar, Laura Turunen, Bhagwan Yadav, Jing Tang, Krister Wennerberg, Tero Aittokallio
Chemical perturbation screens offer the possibility to identify actionable sets of cancer-specific vulnerabilities. However, most inhibitors of kinases or other cancer targets result in polypharmacological effects, which complicate the identification of target dependencies directly from the drug-response phenotypes. In this study, we developed a chemical systems biology approach that integrates comprehensive drug sensitivity and selectivity profiling to provide functional insights into both single and multi-target oncogenic signal addictions. When applied to 21 breast cancer cell lines, perturbed with 40 kinase inhibitors, the subtype-specific addiction patterns clustered in agreement with patient-derived subtypes, while showing considerable variability between the heterogeneous breast cancers. Experimental validation of the top predictions revealed a number of co-dependencies between kinase targets that led to unexpected synergistic combinations between their inhibitors, such as dasatinib and axitinib in the triple-negative basal-like HCC1937 cell line.
{"title":"Systematic Mapping of Kinase Addiction Combinations in Breast Cancer Cells by Integrating Drug Sensitivity and Selectivity Profiles.","authors":"Agnieszka Szwajda, Prson Gautam, Leena Karhinen, Sawan Kumar Jha, Jani Saarela, Sushil Shakyawar, Laura Turunen, Bhagwan Yadav, Jing Tang, Krister Wennerberg, Tero Aittokallio","doi":"10.1016/j.chembiol.2015.06.021","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.06.021","url":null,"abstract":"<p><p>Chemical perturbation screens offer the possibility to identify actionable sets of cancer-specific vulnerabilities. However, most inhibitors of kinases or other cancer targets result in polypharmacological effects, which complicate the identification of target dependencies directly from the drug-response phenotypes. In this study, we developed a chemical systems biology approach that integrates comprehensive drug sensitivity and selectivity profiling to provide functional insights into both single and multi-target oncogenic signal addictions. When applied to 21 breast cancer cell lines, perturbed with 40 kinase inhibitors, the subtype-specific addiction patterns clustered in agreement with patient-derived subtypes, while showing considerable variability between the heterogeneous breast cancers. Experimental validation of the top predictions revealed a number of co-dependencies between kinase targets that led to unexpected synergistic combinations between their inhibitors, such as dasatinib and axitinib in the triple-negative basal-like HCC1937 cell line. </p>","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.06.021","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33867881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-08-20Epub Date: 2015-07-23DOI: 10.1016/j.chembiol.2015.06.018
Christopher B Marotta, Henry A Lester, Dennis A Dougherty
Nicotinic acetylcholine receptors (nAChRs) are vital to neuronal signaling, are implicated in important processes such as learning and memory, and are therapeutic targets for neural diseases. The α7 nAChR has been implicated in Alzheimer's disease and schizophrenia, and allosteric modulators have become one focus of drug development efforts. We investigate the mode of action of the α7-selective positive allosteric modulator, PNU-120596, and show that the higher potency of acetylcholine in the presence of PNU-120596 is not due to an altered agonist binding site. In addition, we propose several residues in the gating interface and transmembrane region that are functionally important to transduction of allosteric properties, and link PNU-120596, the acetylcholine binding region, and the receptor gate. These results suggest global protein stabilization from a communication network through several key residues that alter the gating equilibrium of the receptor while leaving the agonist binding properties unperturbed.
{"title":"An Unaltered Orthosteric Site and a Network of Long-Range Allosteric Interactions for PNU-120596 in α7 Nicotinic Acetylcholine Receptors.","authors":"Christopher B Marotta, Henry A Lester, Dennis A Dougherty","doi":"10.1016/j.chembiol.2015.06.018","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.06.018","url":null,"abstract":"<p><p>Nicotinic acetylcholine receptors (nAChRs) are vital to neuronal signaling, are implicated in important processes such as learning and memory, and are therapeutic targets for neural diseases. The α7 nAChR has been implicated in Alzheimer's disease and schizophrenia, and allosteric modulators have become one focus of drug development efforts. We investigate the mode of action of the α7-selective positive allosteric modulator, PNU-120596, and show that the higher potency of acetylcholine in the presence of PNU-120596 is not due to an altered agonist binding site. In addition, we propose several residues in the gating interface and transmembrane region that are functionally important to transduction of allosteric properties, and link PNU-120596, the acetylcholine binding region, and the receptor gate. These results suggest global protein stabilization from a communication network through several key residues that alter the gating equilibrium of the receptor while leaving the agonist binding properties unperturbed. </p>","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.06.018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33867887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-08-20Epub Date: 2015-07-30DOI: 10.1016/j.chembiol.2015.06.022
Jesus F Barajas, Ryan M Phelan, Andrew J Schaub, Jaclyn T Kliewer, Peter J Kelly, David R Jackson, Ray Luo, Jay D Keasling, Shiou-Chuan Tsai
The terminal reductase (R) domain from the non-ribosomal peptide synthetase (NRPS) module MxaA in Stigmatella aurantiaca Sga15 catalyzes a non-processive four-electron reduction to produce the myxalamide family of secondary metabolites. Despite widespread use in nature, a lack of structural and mechanistic information concerning reductive release from polyketide synthase (PKS) and NRPS assembly lines principally limits our ability to redesign R domains with altered or improved activity. Here we report crystal structures for MxaA R, both in the absence and, for the first time, in the presence of the NADPH cofactor. Molecular dynamics simulations were employed to provide a deeper understanding of this domain and further identify residues critical for structural integrity, substrate binding, and catalysis. Aggregate computational and structural findings provided a basis for mechanistic investigations and, in the process, delivered a rationally altered variant with improved activity toward highly reduced substrates.
{"title":"Comprehensive Structural and Biochemical Analysis of the Terminal Myxalamid Reductase Domain for the Engineered Production of Primary Alcohols.","authors":"Jesus F Barajas, Ryan M Phelan, Andrew J Schaub, Jaclyn T Kliewer, Peter J Kelly, David R Jackson, Ray Luo, Jay D Keasling, Shiou-Chuan Tsai","doi":"10.1016/j.chembiol.2015.06.022","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.06.022","url":null,"abstract":"<p><p>The terminal reductase (R) domain from the non-ribosomal peptide synthetase (NRPS) module MxaA in Stigmatella aurantiaca Sga15 catalyzes a non-processive four-electron reduction to produce the myxalamide family of secondary metabolites. Despite widespread use in nature, a lack of structural and mechanistic information concerning reductive release from polyketide synthase (PKS) and NRPS assembly lines principally limits our ability to redesign R domains with altered or improved activity. Here we report crystal structures for MxaA R, both in the absence and, for the first time, in the presence of the NADPH cofactor. Molecular dynamics simulations were employed to provide a deeper understanding of this domain and further identify residues critical for structural integrity, substrate binding, and catalysis. Aggregate computational and structural findings provided a basis for mechanistic investigations and, in the process, delivered a rationally altered variant with improved activity toward highly reduced substrates. </p>","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.06.022","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33888273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-08-20Epub Date: 2015-08-06DOI: 10.1016/j.chembiol.2015.07.010
Wouter A van der Linden, Ehud Segal, Matthew A Child, Anna Byzia, Marcin Drąg, Matthew Bogyo
Bleomycin hydrolase (BLMH) is a neutral cysteine aminopeptidase that has been ascribed roles in many physiological and pathological processes, yet its primary biological function remains enigmatic. In this work, we describe the results of screening of a library of fluorogenic substrates to identify non-natural amino acids that are optimally recognized by BLMH. This screen identified several substrates with kcat/KM values that are substantially improved over the previously reported fluorogenic substrates for this enzyme. The substrate sequences were used to design activity-based probes that showed potent labeling of recombinant BLMH as well as endogenously expressed BLMH in cell extracts, and in intact cells. Importantly, we identify potent BLMH inhibitors that are able to fully inhibit endogenous BLMH activity in intact cells. These probes and inhibitors will be valuable new reagents to study BLMH function in cellular and animal models of human diseases where BLMH is likely to be involved.
{"title":"Design and Synthesis of Activity-Based Probes and Inhibitors for Bleomycin Hydrolase.","authors":"Wouter A van der Linden, Ehud Segal, Matthew A Child, Anna Byzia, Marcin Drąg, Matthew Bogyo","doi":"10.1016/j.chembiol.2015.07.010","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.07.010","url":null,"abstract":"<p><p>Bleomycin hydrolase (BLMH) is a neutral cysteine aminopeptidase that has been ascribed roles in many physiological and pathological processes, yet its primary biological function remains enigmatic. In this work, we describe the results of screening of a library of fluorogenic substrates to identify non-natural amino acids that are optimally recognized by BLMH. This screen identified several substrates with kcat/KM values that are substantially improved over the previously reported fluorogenic substrates for this enzyme. The substrate sequences were used to design activity-based probes that showed potent labeling of recombinant BLMH as well as endogenously expressed BLMH in cell extracts, and in intact cells. Importantly, we identify potent BLMH inhibitors that are able to fully inhibit endogenous BLMH activity in intact cells. These probes and inhibitors will be valuable new reagents to study BLMH function in cellular and animal models of human diseases where BLMH is likely to be involved. </p>","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.07.010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33905812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-08-20DOI: 10.1016/j.chembiol.2015.08.001
Eva Asp, Ming Proschitsky, Rajaraman Krishnan
Proteopathies are a large and diverse group of human diseases that are caused by protein misfolding. Well-known examples of proteopathies are Alzheimer's and Parkinson's disease, which are both linked to amyloid fibril formation. In this issue of Chemistry & Biology, Castellano et al. (2015) describe the way to harness the power of a protein from baker's yeast, Hsp104, to disaggregate the fibrils.
{"title":"Remodeling Amyloid Fibers: Baker's Yeast Shows Us the Way.","authors":"Eva Asp, Ming Proschitsky, Rajaraman Krishnan","doi":"10.1016/j.chembiol.2015.08.001","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.08.001","url":null,"abstract":"<p><p>Proteopathies are a large and diverse group of human diseases that are caused by protein misfolding. Well-known examples of proteopathies are Alzheimer's and Parkinson's disease, which are both linked to amyloid fibril formation. In this issue of Chemistry & Biology, Castellano et al. (2015) describe the way to harness the power of a protein from baker's yeast, Hsp104, to disaggregate the fibrils. </p>","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.08.001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34110641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-08-20DOI: 10.1016/j.chembiol.2015.08.002
Ulrike Holzgrabe
Griselimycin (GM), a natural product isolated a half century ago, is having a bit of a renaissance. After being known for more than 50 years, it is now being pursued as a treatment for tuberculosis. With the new mechanism of action, excellent in vitro and in vivo activity against sensitive and drug-resistant Mycobacterium tuberculosis, and the improved pharmacokinetic properties, the cyclohexyl derivative of GM demonstrates a high translational potential.
{"title":"New Griselimycins for Treatment of Tuberculosis.","authors":"Ulrike Holzgrabe","doi":"10.1016/j.chembiol.2015.08.002","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.08.002","url":null,"abstract":"<p><p>Griselimycin (GM), a natural product isolated a half century ago, is having a bit of a renaissance. After being known for more than 50 years, it is now being pursued as a treatment for tuberculosis. With the new mechanism of action, excellent in vitro and in vivo activity against sensitive and drug-resistant Mycobacterium tuberculosis, and the improved pharmacokinetic properties, the cyclohexyl derivative of GM demonstrates a high translational potential. </p>","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.08.002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34110642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-08-20Epub Date: 2015-07-16DOI: 10.1016/j.chembiol.2015.06.015
David C Montgomery, Alexander W Sorum, Laura Guasch, Marc C Nicklaus, Jordan L Meier
The finding that chromatin modifications are sensitive to changes in cellular cofactor levels potentially links altered tumor cell metabolism and gene expression. However, the specific enzymes and metabolites that connect these two processes remain obscure. Characterizing these metabolic-epigenetic axes is critical to understanding how metabolism supports signaling in cancer, and developing therapeutic strategies to disrupt this process. Here, we describe a chemical approach to define the metabolic regulation of lysine acetyltransferase (KAT) enzymes. Using a novel chemoproteomic probe, we identify a previously unreported interaction between palmitoyl coenzyme A (palmitoyl-CoA) and KAT enzymes. Further analysis reveals that palmitoyl-CoA is a potent inhibitor of KAT activity and that fatty acyl-CoA precursors reduce cellular histone acetylation levels. These studies implicate fatty acyl-CoAs as endogenous regulators of histone acetylation, and suggest novel strategies for the investigation and metabolic modulation of epigenetic signaling.
{"title":"Metabolic Regulation of Histone Acetyltransferases by Endogenous Acyl-CoA Cofactors.","authors":"David C Montgomery, Alexander W Sorum, Laura Guasch, Marc C Nicklaus, Jordan L Meier","doi":"10.1016/j.chembiol.2015.06.015","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.06.015","url":null,"abstract":"<p><p>The finding that chromatin modifications are sensitive to changes in cellular cofactor levels potentially links altered tumor cell metabolism and gene expression. However, the specific enzymes and metabolites that connect these two processes remain obscure. Characterizing these metabolic-epigenetic axes is critical to understanding how metabolism supports signaling in cancer, and developing therapeutic strategies to disrupt this process. Here, we describe a chemical approach to define the metabolic regulation of lysine acetyltransferase (KAT) enzymes. Using a novel chemoproteomic probe, we identify a previously unreported interaction between palmitoyl coenzyme A (palmitoyl-CoA) and KAT enzymes. Further analysis reveals that palmitoyl-CoA is a potent inhibitor of KAT activity and that fatty acyl-CoA precursors reduce cellular histone acetylation levels. These studies implicate fatty acyl-CoAs as endogenous regulators of histone acetylation, and suggest novel strategies for the investigation and metabolic modulation of epigenetic signaling. </p>","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.06.015","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34299772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Thiostrepton (TSR) is an archetypal thiopeptide antibiotic possessing a quinaldic acid (QA) moiety in the side ring system. According to the mechanism of TSR previously known to target bacterial ribosome, we recently designed and biosynthesized several TSR derivatives that varied in QA substitution. Utilizing these thiopeptide antibiotics to treat the intracellular pathogen Mycobacterium marinum, we herein report a novel mode of action of TSRs, which induce ER stress-mediated autophagy to enhance host cell defense. This intracellular response, which is sensitive to the modification of the QA group, serves as an indirect but unignorable mechanism for eliminating intracellular pathogens. TSRs are thus the only type of antibiotics, to our knowledge, with the dual action on both the parasitic bacteria and the infected host cells. The newly observed mechanism of TSRs may inspire the future change in the treatment of intracellular pathogens, by taking host response into account.
{"title":"Thiopeptide Antibiotics Exhibit a Dual Mode of Action against Intracellular Pathogens by Affecting Both Host and Microbe.","authors":"Qingfei Zheng, Qinglan Wang, Shoufeng Wang, Jiequn Wu, Qian Gao, Wen Liu","doi":"10.1016/j.chembiol.2015.06.019","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.06.019","url":null,"abstract":"<p><p>Thiostrepton (TSR) is an archetypal thiopeptide antibiotic possessing a quinaldic acid (QA) moiety in the side ring system. According to the mechanism of TSR previously known to target bacterial ribosome, we recently designed and biosynthesized several TSR derivatives that varied in QA substitution. Utilizing these thiopeptide antibiotics to treat the intracellular pathogen Mycobacterium marinum, we herein report a novel mode of action of TSRs, which induce ER stress-mediated autophagy to enhance host cell defense. This intracellular response, which is sensitive to the modification of the QA group, serves as an indirect but unignorable mechanism for eliminating intracellular pathogens. TSRs are thus the only type of antibiotics, to our knowledge, with the dual action on both the parasitic bacteria and the infected host cells. The newly observed mechanism of TSRs may inspire the future change in the treatment of intracellular pathogens, by taking host response into account. </p>","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.06.019","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33868852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-08-20Epub Date: 2015-08-06DOI: 10.1016/j.chembiol.2015.07.009
Brian Belardi, Carolyn R Bertozzi
The importance and complexity associated with the totality of glycan structures, i.e. the glycome, has garnered significant attention from chemists and biologists alike. However, what is lacking from this biochemical picture is how cells, tissues, and organisms interpret glycan patterns and translate this information into appropriate responses. Lectins, glycan-binding proteins, are thought to bridge this gap by decoding the glycome and dictating cell fate based on the underlying chemical identities and properties of the glycome. Yet, our understanding of the in vivo ligands and function for most lectins is still incomplete. This review focuses on recent advances in chemical tools to study the specificity and dynamics of mammalian lectins in live cells. A picture emerges of lectin function that is highly sensitive to its organization, which in turn drastically shapes immunity and cancer progression. We hope this review will inspire biologists to make use of these new techniques and stimulate chemists to continue developing innovative approaches to probe lectin biology in vivo.
{"title":"Chemical Lectinology: Tools for Probing the Ligands and Dynamics of Mammalian Lectins In Vivo.","authors":"Brian Belardi, Carolyn R Bertozzi","doi":"10.1016/j.chembiol.2015.07.009","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.07.009","url":null,"abstract":"<p><p>The importance and complexity associated with the totality of glycan structures, i.e. the glycome, has garnered significant attention from chemists and biologists alike. However, what is lacking from this biochemical picture is how cells, tissues, and organisms interpret glycan patterns and translate this information into appropriate responses. Lectins, glycan-binding proteins, are thought to bridge this gap by decoding the glycome and dictating cell fate based on the underlying chemical identities and properties of the glycome. Yet, our understanding of the in vivo ligands and function for most lectins is still incomplete. This review focuses on recent advances in chemical tools to study the specificity and dynamics of mammalian lectins in live cells. A picture emerges of lectin function that is highly sensitive to its organization, which in turn drastically shapes immunity and cancer progression. We hope this review will inspire biologists to make use of these new techniques and stimulate chemists to continue developing innovative approaches to probe lectin biology in vivo. </p>","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.07.009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33905811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-08-20Epub Date: 2015-08-06DOI: 10.1016/j.chembiol.2015.06.024
Remigiusz A Serwa, Fernando Abaitua, Eberhard Krause, Edward W Tate, Peter O'Hare
Protein fatty acylation regulates diverse aspects of cellular function and organization and plays a key role in host immune responses to infection. Acylation also modulates the function and localization of virus-encoded proteins. Here, we employ chemical proteomics tools, bio-orthogonal probes, and capture reagents to study myristoylation and palmitoylation during infection with herpes simplex virus (HSV). Using in-gel fluorescence imaging and quantitative mass spectrometry, we demonstrate a generalized reduction in myristoylation of host proteins, whereas palmitoylation of host proteins, including regulators of interferon and tetraspanin family proteins, was selectively repressed. Furthermore, we found that a significant fraction of the viral proteome undergoes palmitoylation; we identified a number of virus membrane glycoproteins, structural proteins, and kinases. Taken together, our results provide broad oversight of protein acylation during HSV infection, a roadmap for similar analysis in other systems, and a resource with which to pursue specific analysis of systems and functions.
{"title":"Systems Analysis of Protein Fatty Acylation in Herpes Simplex Virus-Infected Cells Using Chemical Proteomics.","authors":"Remigiusz A Serwa, Fernando Abaitua, Eberhard Krause, Edward W Tate, Peter O'Hare","doi":"10.1016/j.chembiol.2015.06.024","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.06.024","url":null,"abstract":"<p><p>Protein fatty acylation regulates diverse aspects of cellular function and organization and plays a key role in host immune responses to infection. Acylation also modulates the function and localization of virus-encoded proteins. Here, we employ chemical proteomics tools, bio-orthogonal probes, and capture reagents to study myristoylation and palmitoylation during infection with herpes simplex virus (HSV). Using in-gel fluorescence imaging and quantitative mass spectrometry, we demonstrate a generalized reduction in myristoylation of host proteins, whereas palmitoylation of host proteins, including regulators of interferon and tetraspanin family proteins, was selectively repressed. Furthermore, we found that a significant fraction of the viral proteome undergoes palmitoylation; we identified a number of virus membrane glycoproteins, structural proteins, and kinases. Taken together, our results provide broad oversight of protein acylation during HSV infection, a roadmap for similar analysis in other systems, and a resource with which to pursue specific analysis of systems and functions. </p>","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.06.024","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33905809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}