Biochemical Journal最新文献_第4页

Development of circadian rhythms in mammalian systems. 哺乳动物生理节律的发展。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-12-23 DOI: 10.1042/BCJ20210060

Junghyun Lee, Sevde Goker, Sookkyung Lim, Christian I Hong

引用次数: 0

Gα12 and Gα13 proteins are required for transforming growth factor-β-induced myofibroblast differentiation. TGF-β诱导的肌成纤维细胞分化需要Ga12和Ga13蛋白。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-12-18 DOI: 10.1042/BCJ20240317

Eleanor B Reed, Albert Sitikov, Kun Woo D Shin, Robert B Hamanaka, Rengül Cetin-Atalay, Gökhan M Mutlu, Alexander A Mongin, Nickolai O Dulin

{"title":"Gα12 and Gα13 proteins are required for transforming growth factor-β-induced myofibroblast differentiation.","authors":"Eleanor B Reed, Albert Sitikov, Kun Woo D Shin, Robert B Hamanaka, Rengül Cetin-Atalay, Gökhan M Mutlu, Alexander A Mongin, Nickolai O Dulin","doi":"10.1042/BCJ20240317","DOIUrl":"10.1042/BCJ20240317","url":null,"abstract":"Myofibroblast differentiation, characterized by accumulation of cytoskeletal and extracellular matrix proteins by fibroblasts, is a key process in wound healing and pathogenesis of tissue fibrosis. Transforming growth factor-β (TGF-β) is the most powerful known driver of myofibroblast differentiation. TGF-β signals through transmembrane receptor serine/threonine kinases that phosphorylate Smad transcription factors (Smad2/3) leading to activation of transcription of target genes. Heterotrimeric G proteins mediate distinct signaling from seven-transmembrane G protein coupled receptors, which are not known to be linked to Smad activation. We tested whether G protein signaling plays any role in TGF-β-induced myofibroblast differentiation, using primary cultured human lung fibroblasts. Activation of Gαs by cholera toxin blocked TGF-β-induced myofibroblast differentiation without affecting Smad2/3 phosphorylation. Neither inhibition of Gαi by pertussis toxin nor siRNA-mediated combined knockdown of Gαq and Gα11 had a significant effect on TGF-β-induced myofibroblast differentiation. In contrast, combined knockdown of Gα12 and Gα13 significantly inhibited TGF-β-stimulated expression of myofibroblast marker proteins (collagen-1, fibronectin, smooth-muscle α-actin), with siGα12 being significantly more potent than siGα13. Mechanistically, combined knockdown of Gα12 and Gα13 resulted in substantially reduced phosphorylation of Smad2 and Smad3 in response to TGF-β, which was accompanied by a significant decrease in the expression of TGF-β receptors (TGFBR1, TGFBR2) and of Smad3. Thus, our study uncovers a novel role of Gα12/13 proteins in the control of TGF-β signaling and myofibroblast differentiation.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1937-1948"},"PeriodicalIF":4.4,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11668492/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765758","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

On the function of TRAP substrate-binding proteins: the isethionate-specific binding protein IseP. 关于 TRAP 底物结合蛋白的功能：异蛋氨酸特异性结合蛋白 IseP。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-12-18 DOI: 10.1042/BCJ20240540

Michael C Newton-Vesty, Michael J Currie, James S Davies, Santosh Panjikar, Ashish Sethi, Andrew E Whitten, Zachary D Tillett, David M Wood, Joshua D Wright, Michael J Love, Timothy M Allison, Sam A Jamieson, Peter D Mace, Rachel A North, Renwick C J Dobson

{"title":"On the function of TRAP substrate-binding proteins: the isethionate-specific binding protein IseP.","authors":"Michael C Newton-Vesty, Michael J Currie, James S Davies, Santosh Panjikar, Ashish Sethi, Andrew E Whitten, Zachary D Tillett, David M Wood, Joshua D Wright, Michael J Love, Timothy M Allison, Sam A Jamieson, Peter D Mace, Rachel A North, Renwick C J Dobson","doi":"10.1042/BCJ20240540","DOIUrl":"10.1042/BCJ20240540","url":null,"abstract":"Bacteria evolve mechanisms to compete for limited resources and survive in new niches. Here we study the mechanism of isethionate import from the sulfate-reducing bacterium Oleidesulfovibrio alaskensis. The catabolism of isethionate by Desulfovibrio species has been implicated in human disease, due to hydrogen sulfide production, and has potential for industrial applications. O. alaskensis employs a tripartite ATP-independent periplasmic (TRAP) transporter (OaIsePQM) to import isethionate, which relies on the substrate-binding protein (OaIseP) to scavenge isethionate and deliver it to the membrane transporter component (OaIseQM) for import into the cell. We determined the binding affinity of isethionate to OaIseP by isothermal titration calorimetry, KD = 0.95 µM (68% CI = 0.6-1.4 µM), which is weaker compared with other TRAP substrate-binding proteins. The X-ray crystal structures of OaIseP in the ligand-free and isethionate-bound forms were obtained and showed that in the presence of isethionate, OaIseP adopts a closed conformation whereby two domains of the protein fold over the substrate. We serendipitously discovered two crystal forms with sulfonate-containing buffers (HEPES and MES) bound in the isethionate-binding site. However, these do not evoke domain closure, presumably because of the larger ligand size. Together, our data elucidate the molecular details of how a TRAP substrate-binding protein binds a sulfonate-containing substrate, rather than a typical carboxylate-containing substrate. These results may inform future antibiotic development to target TRAP transporters and provide insights into protein engineering of TRAP transporter substrate-binding proteins.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1901-1920"},"PeriodicalIF":4.4,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11668362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667211","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

Ubiquitin E3 ligases in the plant Arg/N-degron pathway. 植物Arg/N-degron通路中的泛素E3连接酶。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-12-18 DOI: 10.1042/BCJ20240132

Keely E A Oldham, Peter D Mabbitt

{"title":"Ubiquitin E3 ligases in the plant Arg/N-degron pathway.","authors":"Keely E A Oldham, Peter D Mabbitt","doi":"10.1042/BCJ20240132","DOIUrl":"10.1042/BCJ20240132","url":null,"abstract":"Regulation of protein longevity via the ubiquitin (Ub) - proteasome pathway is fundamental to eukaryotic biology. Ubiquitin E3 ligases (E3s) interact with substrate proteins and provide specificity to the pathway. A small subset of E3s bind to specific exposed N-termini (N-degrons) and promote the ubiquitination of the bound protein. Collectively these E3s, and other N-degron binding proteins, are known as N-recognins. There is considerable functional divergence between fungi, animal, and plant N-recognins. In plants, at least three proteins (PRT1, PRT6, and BIG) participate in the Arg/N-degron pathway. PRT1 has demonstrated E3 ligase activity, whereas PRT6 and BIG are candidate E3s. The Arg/N-degron pathway plays a central role in plant development, germination, and submersion tolerance. The pathway has been manipulated both to improve crop performance and for conditional protein degradation. A more detailed structural and biochemical understanding of the Arg/N-recognins and their substrates is required to fully realise the biotechnological potential of the pathway. This perspective focuses on the structural and molecular details of substrate recognition and ubiquitination in the plant Arg/N-degron pathway. While PRT1 appears to be plant specific, the PRT6 and BIG proteins are similar to UBR1 and UBR4, respectively. Analysis of the cryo-EM structures of Saccharomyces UBR1 suggests that the mode of ubiquitin conjugating enzyme (E2) and substrate recruitment is conserved in PRT6, but regulation of the two N-recognins may be significantly different. The structurally characterised domains from human UBR4 are also likely to be conserved in BIG, however, there are sizeable gaps in our understanding of both proteins.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"481 24","pages":"1949-1965"},"PeriodicalIF":4.4,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11668491/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817013","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 PRL2 Phosphatase Upregulates miR-21 through Activation of the JAK2/STAT3 Pathway to Downregulate the PTEN Tumor Suppressor. PRL2磷酸酶通过激活JAK2/STAT3通路上调miR-21，下调PTEN肿瘤抑制因子。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-12-12 DOI: 10.1042/BCJ20240626

Zhong-Yin Zhang, Qinglin Li, Yunpeng Bai, Sarah M Cavender, Yiming Miao, Frederick Nguele Meke, Emily L Lasse-Opsahl, Peipei Zhu, Gina M Doody, W Andy Tao

{"title":"The PRL2 Phosphatase Upregulates miR-21 through Activation of the JAK2/STAT3 Pathway to Downregulate the PTEN Tumor Suppressor.","authors":"Zhong-Yin Zhang, Qinglin Li, Yunpeng Bai, Sarah M Cavender, Yiming Miao, Frederick Nguele Meke, Emily L Lasse-Opsahl, Peipei Zhu, Gina M Doody, W Andy Tao","doi":"10.1042/BCJ20240626","DOIUrl":"https://doi.org/10.1042/BCJ20240626","url":null,"abstract":"The Phosphatases of Regenerating Liver (PRLs) are members of the protein tyrosine phosphatase (PTP) superfamily that play pro-oncogenic roles in cell proliferation, migration, and survival. We previously demonstrated that PRLs can post-translationally downregulate PTEN, a tumor suppressor frequently inactivated in human cancers, by dephosphorylating PTEN at Tyr336, which promotes the NEDD4-mediated PTEN ubiquitination and proteasomal degradation. Here we report that PRLs can also reduce PTEN expression by upregulating MicroRNA-21 (miR-21), which is one of the most frequently overexpressed miRNAs in solid tumors. We observe a broad correlation between PRL and miR-21 levels in multiple human cancers. Mechanistically, PRL2, the most abundant and ubiquitously expressed PRL family member, promotes the JAK2/STAT3 pathway-mediated miR-21 expression by directly dephosphorylating JAK2 at Tyr570. Finally, we confirm that the PRL2-mediated miR-21 expression contributes to its oncogenic potential in breast cancer cells. Our study defines a new functional role of PRL2 in PTEN regulation through a miR-21-dependent post-transcriptional mechanism, in addition to our previously reported NEDD4-dependent post-translational PTEN regulation. Together, these studies further establish the PRLs as negative regulators of PTEN.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812135","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

Biochemical basis and therapeutic potential of mitochondrial uncoupling in cardiometabolic syndrome. 线粒体解偶联在心脏代谢综合征中的生化基础和治疗潜力。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-12-04 DOI: 10.1042/BCJ20240005

Bernardo Gindri Dos Santos, Niki F Brisnovali, Leigh Goedeke

{"title":"Biochemical basis and therapeutic potential of mitochondrial uncoupling in cardiometabolic syndrome.","authors":"Bernardo Gindri Dos Santos, Niki F Brisnovali, Leigh Goedeke","doi":"10.1042/BCJ20240005","DOIUrl":"https://doi.org/10.1042/BCJ20240005","url":null,"abstract":"Mild uncoupling of oxidative phosphorylation is an intrinsic property of all mitochondria, allowing for adjustments in cellular energy metabolism to maintain metabolic homeostasis. Small molecule uncouplers have been extensively studied for their potential to increase metabolic rate, and recent research has focused on developing safe and effective mitochondrial uncoupling agents for the treatment of obesity and cardiometabolic syndrome (CMS). Here, we provide a brief overview of CMS and cover the recent mechanisms by which chemical uncouplers regulate CMS-associated risk-factors and comorbidities, including dyslipidemia, insulin resistance, steatotic liver disease, type 2 diabetes, and atherosclerosis. Additionally, we review the current landscape of uncoupling agents, focusing on repurposed FDA-approved drugs and compounds in advanced preclinical or early-stage clinical development. Lastly, we discuss recent molecular insights by which chemical uncouplers enhance cellular energy expenditure, highlighting their potential as a new addition to the current CMS drug landscape, and outline several limitations that need to be addressed before these agents can successfully be introduced into clinical practice.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"481 23","pages":"1831-1854"},"PeriodicalIF":4.4,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765735","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

Macromolecular crowding and bicarbonate enhance the hydrogen peroxide-induced inactivation of glyceraldehyde-3-phosphate dehydrogenase. 大分子拥挤和碳酸氢盐会增强过氧化氢诱导的甘油醛-3-磷酸脱氢酶失活。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-12-04 DOI: 10.1042/BCJ20240597

Rebecca H J Bloemen, Rafael Radi, Michael J Davies, Eduardo Fuentes-Lemus

{"title":"Macromolecular crowding and bicarbonate enhance the hydrogen peroxide-induced inactivation of glyceraldehyde-3-phosphate dehydrogenase.","authors":"Rebecca H J Bloemen, Rafael Radi, Michael J Davies, Eduardo Fuentes-Lemus","doi":"10.1042/BCJ20240597","DOIUrl":"10.1042/BCJ20240597","url":null,"abstract":"The active site Cys residue in glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is sensitive to oxidation by hydrogen peroxide (H2O2), with this resulting in enzyme inactivation. This re-routes the carbon flux from glycolysis to the pentose phosphate pathway favoring the formation of NADPH and synthetic intermediates required for antioxidant defense and repair systems. Consequently, GAPDH inactivation serves as a redox switch for metabolic adaptation under conditions of oxidative stress. However, there is a major knowledge gap as to how GAPDH is efficiently oxidized and inactivated, when the increase in intracellular H2O2 is modest, and there is a high concentration of alternative (non-signaling) thiols and efficient peroxide removing systems. We have therefore explored whether GAPDH inactivation is enhanced by two factors of in vivo relevance: macromolecular crowding, an inherent property of biological environments, and the presence of bicarbonate, an abundant biological buffer. Bicarbonate is already known to modulate H2O2 metabolism via formation of peroxymonocarbonate. GAPDH activity was assessed in experiments with low doses of H2O2 under both dilute and crowded conditions (induced by inert high molecular mass polymers and small molecules), in both the absence and presence of 25 mM sodium bicarbonate. H2O2-induced inactivation of GAPDH was observed to be significantly enhanced under macromolecular crowding conditions, with bicarbonate having an additional effect. These data strongly suggest that these two factors are of major importance in redox switch mechanisms involving GAPDH (and possibly other thiol-dependent systems) within the cellular environment.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1855-1866"},"PeriodicalIF":4.4,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11668361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646879","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

Editorial Note: Camelid single-domain antibodies raised by DNA immunization are potent inhibitors of EGFR signaling. 编辑注：DNA免疫引起的骆驼单域抗体是EGFR信号传导的有效抑制剂。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-12-04 DOI: 10.1042/BCJ20180795_EDN

引用次数: 0

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