Biochemical Journal最新文献_第4页

ATP-competitive inhibitors of PI3K enzymes demonstrate an isoform selective dual action by controlling membrane binding. PI3K 酶的 ATP 竞争性抑制剂通过控制膜结合，显示出同工酶选择性的双重作用。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-12-04 DOI: 10.1042/BCJ20240479

Grace Q Gong, Glenn R Masson, Woo-Jeong Lee, James M J Dickson, Jackie D Kendall, Manoj K Rathinaswamy, Christina M Buchanan, Martin Middleditch, Brady M Owen, Julie A Spicer, Gordon W Rewcastle, William A Denny, John E Burke, Peter R Shepherd, Roger L Williams, Jack U Flanagan

{"title":"ATP-competitive inhibitors of PI3K enzymes demonstrate an isoform selective dual action by controlling membrane binding.","authors":"Grace Q Gong, Glenn R Masson, Woo-Jeong Lee, James M J Dickson, Jackie D Kendall, Manoj K Rathinaswamy, Christina M Buchanan, Martin Middleditch, Brady M Owen, Julie A Spicer, Gordon W Rewcastle, William A Denny, John E Burke, Peter R Shepherd, Roger L Williams, Jack U Flanagan","doi":"10.1042/BCJ20240479","DOIUrl":"10.1042/BCJ20240479","url":null,"abstract":"PI3Kα, consisting of the p110α isoform of the catalytic subunit of PI 3-kinase (encoded by PIK3CA) and the p85α regulatory subunit (encoded by PI3KR1) is activated by growth factor receptors. The identification of common oncogenic mutations in PIK3CA has driven the development of many inhibitors that bind to the ATP-binding site in the p110α subunit. Upon activation, PI3Kα undergoes conformational changes that promote its membrane interaction and catalytic activity, yet the effects of ATP-site directed inhibitors on the PI3Kα membrane interaction are unknown. Using FRET and biolayer interferometry assays, we show that a class of ATP-site directed inhibitors represented by GSK2126458 block the growth factor activated PI3KαWT membrane interaction, an activity dependent on the ligand forming specific ATP-site interactions. The membrane interaction for hot spot oncogenic mutations that bypass normal p85α regulatory mechanisms was insensitive to GSK2126458, while GSK2126458 could regulate mutations found outside of these hot spot regions. Our data show that the effect of GSK126458 on the membrane interaction requires the enzyme to revert from its growth factor activated state to a basal state. We find that an ATP substrate analogue can increase the wild type PI3Kα membrane interaction, uncovering a substrate based regulatory event that can be mimicked by different inhibitor chemotypes. Our findings, together with the discovery of small molecule allosteric activators of PI3Kα illustrate that PI3Kα membrane interactions can be modulated by factors related to ligand binding both within the ATP site and at allosteric sites.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1787-1802"},"PeriodicalIF":4.4,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7617104/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A prescription for engineering PFAS biodegradation. 全氟辛烷磺酸生物降解工程的处方。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-12-04 DOI: 10.1042/BCJ20240283

Lawrence P Wackett, Serina L Robinson

引用次数: 0

Sequence variation in the active site of mobile colistin resistance proteins is evolutionarily accommodated through inter-domain interactions. 在进化过程中，MCR 蛋白活性位点的序列变异是通过结构域间的相互作用来实现的。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-12-04 DOI: 10.1042/BCJ20240373

Avani Joshi, Nishad Matange

{"title":"Sequence variation in the active site of mobile colistin resistance proteins is evolutionarily accommodated through inter-domain interactions.","authors":"Avani Joshi, Nishad Matange","doi":"10.1042/BCJ20240373","DOIUrl":"10.1042/BCJ20240373","url":null,"abstract":"Sequence variation among homologous proteins can shed light on their function and ancestry. In this study, we analyze variation at catalytic residues among MCR (mobile colistin resistance) proteins, which confer resistance to the last resort antibiotic, colistin, in gram-negative bacteria. We show that not all naturally occurring variants at a lipid A-binding residue, Ser284, are tolerated in MCR-1. In particular, the substitution of Ser284 with Asp, found naturally in MCR-5, resulted in diminished colistin resistance. Using phylogenetic analyses and structure predictions we trace back variation at this site among MCRs to their ancestors, i.e. EptA phosphoethanolamine transferases that are encoded by diverse bacterial genomes. Mutational studies and AlphaFold-based structural modeling revealed that the functional importance of position 284 varies between phylogenetically distant MCRs, i.e. MCR-1 and MCR-5. Despite a high degree of similarity among their catalytic domains, inter-domain interactions were not conserved between MCR-1 and MCR-5 due to their different ancestries, providing a mechanistic basis behind the different phenotypes of similar mutations at position 284. Our study thus uncovers subtle differences in the organization of domains among MCR proteins that can lead to substantial differences in their catalytic properties and mutational tolerances.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1741-1755"},"PeriodicalIF":4.4,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7617329/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The genetic and molecular basis of a connexin-linked skin disease. 连接蛋白相关皮肤病的遗传和分子基础。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-11-20 DOI: 10.1042/BCJ20240374

Sergiu A Lucaciu, Dale W Laird

引用次数: 0

Protein kinase A and local signaling in cancer. 癌症中的蛋白激酶 A 和局部信号传导。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-11-20 DOI: 10.1042/BCJ20230352

Kacey J Rosenthal, John D Gordan, John D Scott

引用次数: 0

Exploring the dynamics and interactions of the N-myc transactivation domain through solution nuclear magnetic resonance spectroscopy. 通过溶液核磁共振探索 N-myc 转录激活结构域的动力学和相互作用。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-11-06 DOI: 10.1042/BCJ20240248

Ewa Rejnowicz, Matthew Batchelor, Eoin Leen, Mohd Syed Ahangar, Selena G Burgess, Mark W Richards, Arnout P Kalverda, Richard Bayliss

{"title":"Exploring the dynamics and interactions of the N-myc transactivation domain through solution nuclear magnetic resonance spectroscopy.","authors":"Ewa Rejnowicz, Matthew Batchelor, Eoin Leen, Mohd Syed Ahangar, Selena G Burgess, Mark W Richards, Arnout P Kalverda, Richard Bayliss","doi":"10.1042/BCJ20240248","DOIUrl":"10.1042/BCJ20240248","url":null,"abstract":"Myc proteins are transcription factors crucial for cell proliferation. They have a C-terminal domain that mediates Max and DNA binding, and an N-terminal disordered region culminating in the transactivation domain (TAD). The TAD participates in many protein-protein interactions, notably with kinases that promote stability (Aurora-A) or degradation (ERK1, GSK3) via the ubiquitin-proteasome system. We probed the structure, dynamics and interactions of N-myc TAD using nuclear magnetic resonance (NMR) spectroscopy following its complete backbone assignment. Chemical shift analysis revealed that N-myc has two regions with clear helical propensity: Trp77-Glu86 and Ala122-Glu132. These regions also have more restricted ps-ns motions than the rest of the TAD, and, along with the phosphodegron, have comparatively high transverse (R2) 15N relaxation rates, indicative of slower timescale dynamics and/or chemical exchange. Collectively these features suggest differential propensities for structure and interaction, either internal or with binding partners, across the TAD. Solution studies on the interaction between N-myc and Aurora-A revealed a previously uncharacterised binding site. The specificity and kinetics of sequential phosphorylation of N-myc by ERK1 and GSK3 were characterised using NMR and resulted in no significant structural changes outside the phosphodegron. When the phosphodegron was doubly phosphorylated, N-myc formed a robust interaction with the Fbxw7-Skp1 complex, but mapping the interaction by NMR suggests a more extensive interface. Our study provides foundational insights into N-myc TAD dynamics and a backbone assignment that will underpin future work on the structure, dynamics, interactions and regulatory post-translational modifications of this key oncoprotein.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1535-1556"},"PeriodicalIF":4.4,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555651/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The impact of cell states on heterochromatin dynamics. 细胞状态对异染色质动态的影响

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-11-06 DOI: 10.1042/bcj20240139

Abby Trouth,Giovana M B Veronezi,Srinivas Ramachandran

引用次数: 0

Histone deacetylase 7 activates 6-phosphogluconate dehydrogenase via an enzyme-independent mechanism that involves the N-terminal protein-protein interaction domain. 组蛋白去乙酰化酶 7 通过一种与酶无关的机制激活 6-磷酸葡萄糖酸脱氢酶，该机制涉及 N 端蛋白-蛋白相互作用结构域。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-11-06 DOI: 10.1042/BCJ20240380

Yizhuo Wang, James E B Curson, Divya Ramnath, Kaustav Das Gupta, Robert C Reid, Denuja Karunakaran, David P Fairlie, Matthew J Sweet

{"title":"Histone deacetylase 7 activates 6-phosphogluconate dehydrogenase via an enzyme-independent mechanism that involves the N-terminal protein-protein interaction domain.","authors":"Yizhuo Wang, James E B Curson, Divya Ramnath, Kaustav Das Gupta, Robert C Reid, Denuja Karunakaran, David P Fairlie, Matthew J Sweet","doi":"10.1042/BCJ20240380","DOIUrl":"10.1042/BCJ20240380","url":null,"abstract":"Histone deacetylase 7 (HDAC7) is a member of the class IIa family of classical HDACs with important roles in cell development, differentiation, and activation, including in macrophages and other innate immune cells. HDAC7 and other class IIa HDACs act as transcriptional repressors in the nucleus but, in some cell types, they can also act in the cytoplasm to modify non-nuclear proteins and/or scaffold signalling complexes. In macrophages, HDAC7 is a cytoplasmic protein with both pro- and anti-inflammatory functions, with the latter activity involving activation of the pentose phosphate pathway (PPP) enzyme 6-phosphogluconate dehydrogenase (6PGD) and the generation of anti-inflammatory metabolite ribulose-5-phosphate. Here, we used ectopic expression systems and biochemical approaches to investigate the mechanism by which HDAC7 promotes 6PGD enzyme activity. We reveal that HDAC7 enzyme activity is not required for its activation of 6PGD and that the N-terminal protein-protein interaction domain of HDAC7 is sufficient to initiate this response. Mechanistically, the N-terminus of HDAC7 increases the affinity of 6PGD for NADP+, promotes the generation of a shorter form of 6PGD, and enhances the formation of higher order protein complexes, implicating its scaffolding function in engagement of the PPP. This contrasts with the pro-inflammatory function of HDAC7 in macrophages, in which it promotes deacetylation of the glycolytic enzyme pyruvate kinase M2 for inflammatory cytokine production.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1569-1584"},"PeriodicalIF":4.4,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Epigenetics and alternative splicing in cancer: old enemies, new perspectives. 癌症中的表观遗传学和替代剪接：老对手，新视角。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-11-06 DOI: 10.1042/bcj20240221

Madhura R Pandkar,Sanjeev Shukla

{"title":"Epigenetics and alternative splicing in cancer: old enemies, new perspectives.","authors":"Madhura R Pandkar,Sanjeev Shukla","doi":"10.1042/bcj20240221","DOIUrl":"https://doi.org/10.1042/bcj20240221","url":null,"abstract":"In recent years, significant strides in both conceptual understanding and technological capabilities have bolstered our comprehension of the factors underpinning cancer initiation and progression. While substantial insights have unraveled the molecular mechanisms driving carcinogenesis, there has been an overshadowing of the critical contribution made by epigenetic pathways, which works in concert with genetics. Mounting evidence demonstrates cancer as a complex interplay between genetics and epigenetics. Notably, epigenetic elements play a pivotal role in governing alternative pre-mRNA splicing, a primary contributor to protein diversity. In this review, we have provided detailed insights into the bidirectional communication between epigenetic modifiers and alternative splicing, providing examples of specific genes and isoforms affected. Notably, succinct discussion on targeting epigenetic regulators and the potential of the emerging field of epigenome editing to modulate splicing patterns is also presented. In summary, this review offers valuable insights into the intricate interplay between epigenetics and alternative splicing in cancer, paving the way for novel approaches to understanding and targeting this critical process.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"12 1","pages":"1497-1518"},"PeriodicalIF":4.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Exopolysaccharide is detrimental for the symbiotic performance of Sinorhizobium fredii HH103 mutants with a truncated lipopolysaccharide core. 外多糖不利于具有截短脂多糖核心的裂殖单胞菌 HH103 突变体的共生性能。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-10-25 DOI: 10.1042/bcj20240599

Francisco Fuentes-Romero,Marcello Mercogliano,Stefania De Chiara,Cynthia Alías-Villegas,Pilar Navarro-Gómez,Sebastián Acosta-Jurado,Alba Silipo,Carlos Medina,Miguel-Ángel Rodríguez-Carvajal,Marta S Dardanelli,José-Enrique Ruiz-Sainz,Francisco-Javier López-Baena,Antonio Molinaro,José-María Vinardell,Flaviana Di Lorenzo

{"title":"Exopolysaccharide is detrimental for the symbiotic performance of Sinorhizobium fredii HH103 mutants with a truncated lipopolysaccharide core.","authors":"Francisco Fuentes-Romero,Marcello Mercogliano,Stefania De Chiara,Cynthia Alías-Villegas,Pilar Navarro-Gómez,Sebastián Acosta-Jurado,Alba Silipo,Carlos Medina,Miguel-Ángel Rodríguez-Carvajal,Marta S Dardanelli,José-Enrique Ruiz-Sainz,Francisco-Javier López-Baena,Antonio Molinaro,José-María Vinardell,Flaviana Di Lorenzo","doi":"10.1042/bcj20240599","DOIUrl":"https://doi.org/10.1042/bcj20240599","url":null,"abstract":"The nitrogen-fixing rhizobia-legume symbiosis relies on a complex interchange of molecular signals between the two partners during the whole interaction. On the bacterial side, different surface polysaccharides, such as lipopolysaccharide (LPS) and exopolysaccharide (EPS), might play important roles for the success of the interaction. In a previous work we studied two Sinorhizobium fredii HH103 mutants affected in the rkpK and lpsL genes, which are responsible for the production of glucuronic acid and galacturonic acid, respectively. Both mutants produced an altered LPS, and the rkpK mutant, in addition, lacked EPS. These mutants were differently affected in symbiosis with Glycine max and Vigna unguiculata, with the lpsL mutant showing a stronger impairment than the rkpK mutant. In the present work we have further investigated the LPS structure and the symbiotic abilities of the HH103 lpsL and rkpK mutants. We demonstrate that both strains produce the same LPS, with a truncated core oligosaccharide devoid of uronic acids. We show that the symbiotic performance of the lpsL mutant with Macroptilium atropurpureum and Glycyrrhiza uralensis is worse than that of the rkpK mutant. Introduction of an exoA mutation (which avoids EPS production) in HH103 lpsL improved its symbiotic performance with G. max, M. atropurpureum, and G. uralensis to the level exhibited by HH103 rkpK, suggesting that the presence of EPS might hide the truncated LPS produced by the former mutant.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"5 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0