Biochemical Journal最新文献_第9页

AMP-activated protein kinase can be allosterically activated by ADP but AMP remains the key activating ligand AMP 激活的蛋白激酶可被 ADP 异源激活，但 AMP 仍是关键的激活配体

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-04-24 DOI: 10.1042/bcj20240082

Hawley, Simon A., Russell, Fiona M., Hardie, D. Grahame

{"title":"AMP-activated protein kinase can be allosterically activated by ADP but AMP remains the key activating ligand","authors":"Hawley, Simon A., Russell, Fiona M., Hardie, D. Grahame","doi":"10.1042/bcj20240082","DOIUrl":"https://doi.org/10.1042/bcj20240082","url":null,"abstract":"The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status. When activated by increases in ADP:ATP and/or AMP:ATP ratios (signalling energy deficit), AMPK acts to restore energy balance. Binding of AMP to one or more of three CBS repeats (CBS1, CBS3, CBS4) on the AMPK-γ subunit activates the kinase complex by three complementary mechanisms: (i) promoting α-subunit Thr172 phosphorylation by the upstream kinase LKB1; (ii) protecting against Thr172 dephosphorylation; (iii) allosteric activation. Surprisingly, binding of ADP has been reported to mimic the first two effects, but not the third. We now show that at physiologically relevant concentrations of Mg.ATP2− (above those used in the standard assay) ADP binding does cause allosteric activation. However, ADP causes only a modest activation because (unlike AMP), at concentrations just above those where activation becomes evident, ADP starts to cause competitive inhibition at the catalytic site. Our results cast doubt on the physiological relevance of the effects of ADP and suggest that AMP is the primary activator in vivo. We have also made mutations to hydrophobic residues involved in binding adenine nucleotides at each of the three γ subunit CBS repeats of the human α2β2γ1 complex and examined their effects on regulation by AMP and ADP. Mutation of the CBS3 site has the largest effects on all three mechanisms of AMP activation, especially at lower ATP concentrations, while mutation of CBS4 reduces the sensitivity to AMP. All three sites appear to be required for allosteric activation by ADP.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"102 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140632188","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

Evidence that Xrn1 is in complex with Gcn1, and is required for full levels of eIF2α phosphorylation. 有证据表明，Xrn1 与 Gcn1 复合物，是全水平 eIF2α 磷酸化所必需的。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-04-10 DOI: 10.1042/BCJ20220531

Renuka Shanmugam, Reuben Anderson, Anja H Schiemann, Evelyn Sattlegger

{"title":"Evidence that Xrn1 is in complex with Gcn1, and is required for full levels of eIF2α phosphorylation.","authors":"Renuka Shanmugam, Reuben Anderson, Anja H Schiemann, Evelyn Sattlegger","doi":"10.1042/BCJ20220531","DOIUrl":"10.1042/BCJ20220531","url":null,"abstract":"The protein kinase Gcn2 and its effector protein Gcn1 are part of the general amino acid control signalling (GAAC) pathway best known in yeast for its function in maintaining amino acid homeostasis. Under amino acid limitation, Gcn2 becomes activated, subsequently increasing the levels of phosphorylated eIF2α (eIF2α-P). This leads to the increased translation of transcriptional regulators, such as Gcn4 in yeast and ATF4 in mammals, and subsequent re-programming of the cell's gene transcription profile, thereby allowing cells to cope with starvation. Xrn1 is involved in RNA decay, quality control and processing. We found that Xrn1 co-precipitates Gcn1 and Gcn2, suggesting that these three proteins are in the same complex. Growth under starvation conditions was dependent on Xrn1 but not on Xrn1-ribosome association, and this correlated with reduced eIF2α-P levels. Constitutively active Gcn2 leads to a growth defect due to eIF2α-hyperphosphorylation, and we found that this phenotype was independent of Xrn1, suggesting that xrn1 deletion does not enhance eIF2α de-phosphorylation. Our study provides evidence that Xrn1 is required for efficient Gcn2 activation, directly or indirectly. Thus, we have uncovered a potential new link between RNA metabolism and the GAAC.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"481-498"},"PeriodicalIF":4.1,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11088878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140027295","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

Correction: Proteasome and thiol involvement in quality control of glycosylphosphatidylinositol anchor addition 更正：蛋白酶体和硫醇参与糖基磷脂酰肌醇锚添加的质量控制

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-04-10 DOI: 10.1042/bj3320111_cor

Wilbourn, Barry, Nesbeth, Darren N., Wainwright, Linda J., Field, Mark C.

引用次数: 0

Long-range electron proton coupling in respiratory complex I — insights from molecular simulations of the quinone chamber and antiporter-like subunits 呼吸复合体 I 中的长程电子质子耦合--从醌室和类逆流器亚基的分子模拟中获得的启示

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-04-10 DOI: 10.1042/bcj20240009

Djurabekova, Amina, Lasham, Jonathan, Zdorevskyi, Oleksii, Zickermann, Volker, Sharma, Vivek

引用次数: 0

Expression of Concern: Protease-activated receptor-2 promotes kidney tubular epithelial inflammation by inhibiting autophagy via the PI3K/Akt/mTOR signalling pathway 关注表达：蛋白酶激活受体-2通过PI3K/Akt/mTOR信号通路抑制自噬，从而促进肾小管上皮细胞炎症

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-04-10 DOI: 10.1042/bcj20170272_eoc

Du, Chunyang, Zhang, Tao, Xiao, Xia, Shi, Yonghong, Duan, Huijun, Ren, Yunzhuo

引用次数: 0

Activin E is a transforming growth factor β ligand that signals specifically through activin receptor-like kinase 7. 激活素 E 是一种 TGFβ 配体，可通过激活素受体样激酶 7 发出特异性信号。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-04-10 DOI: 10.1042/BCJ20230404

Kylie A Vestal, Chandramohan Kattamuri, Muhasin Koyiloth, Luisina Ongaro, James A Howard, Aimee M Deaton, Simina Ticau, Aditi Dubey, Daniel J Bernard, Thomas B Thompson

{"title":"Activin E is a transforming growth factor β ligand that signals specifically through activin receptor-like kinase 7.","authors":"Kylie A Vestal, Chandramohan Kattamuri, Muhasin Koyiloth, Luisina Ongaro, James A Howard, Aimee M Deaton, Simina Ticau, Aditi Dubey, Daniel J Bernard, Thomas B Thompson","doi":"10.1042/BCJ20230404","DOIUrl":"10.1042/BCJ20230404","url":null,"abstract":"Activins are one of the three distinct subclasses within the greater Transforming growth factor β (TGFβ) superfamily. First discovered for their critical roles in reproductive biology, activins have since been shown to alter cellular differentiation and proliferation. At present, members of the activin subclass include activin A (ActA), ActB, ActC, ActE, and the more distant members myostatin and GDF11. While the biological roles and signaling mechanisms of most activins class members have been well-studied, the signaling potential of ActE has remained largely unknown. Here, we characterized the signaling capacity of homodimeric ActE. Molecular modeling of the ligand:receptor complexes showed that ActC and ActE shared high similarity in both the type I and type II receptor binding epitopes. ActE signaled specifically through ALK7, utilized the canonical activin type II receptors, ActRIIA and ActRIIB, and was resistant to the extracellular antagonists follistatin and WFIKKN. In mature murine adipocytes, ActE invoked a SMAD2/3 response via ALK7, like ActC. Collectively, our results establish ActE as a specific signaling ligand which activates the type I receptor, ALK7.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"547-564"},"PeriodicalIF":4.1,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11088876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140292629","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

DoUBLing up: ubiquitin and ubiquitin-like proteases in genome stability DoUBLing起来：泛素和泛素样蛋白酶在基因组稳定性中的作用

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-04-10 DOI: 10.1042/bcj20230284

Foster, Benjamin M., Wang, Zijuan, Schmidt, Christine K.

{"title":"DoUBLing up: ubiquitin and ubiquitin-like proteases in genome stability","authors":"Foster, Benjamin M., Wang, Zijuan, Schmidt, Christine K.","doi":"10.1042/bcj20230284","DOIUrl":"https://doi.org/10.1042/bcj20230284","url":null,"abstract":"Maintaining stability of the genome requires dedicated DNA repair and signalling processes that are essential for the faithful duplication and propagation of chromosomes. These DNA damage response (DDR) mechanisms counteract the potentially mutagenic impact of daily genotoxic stresses from both exogenous and endogenous sources. Inherent to these DNA repair pathways is the activity of protein factors that instigate repair processes in response to DNA lesions. The regulation, coordination, and orchestration of these DDR factors is carried out, in a large part, by post-translational modifications, such as phosphorylation, ubiquitylation, and modification with ubiquitin-like proteins (UBLs). The importance of ubiquitylation and UBLylation with SUMO in DNA repair is well established, with the modified targets and downstream signalling consequences relatively well characterised. However, the role of dedicated erasers for ubiquitin and UBLs, known as deubiquitylases (DUBs) and ubiquitin-like proteases (ULPs) respectively, in genome stability is less well established, particularly for emerging UBLs such as ISG15 and UFM1. In this review, we provide an overview of the known regulatory roles and mechanisms of DUBs and ULPs involved in genome stability pathways. Expanding our understanding of the molecular agents and mechanisms underlying the removal of ubiquitin and UBL modifications will be fundamental for progressing our knowledge of the DDR and likely provide new therapeutic avenues for relevant human diseases, such as cancer.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"13 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140346240","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

The deubiquitinase function of ataxin-3 and its role in the pathogenesis of Machado-Joseph disease and other diseases. 共济失调蛋白-3的去泛素化酶功能及其在马查多-约瑟夫病和其他疾病的发病机制中的作用。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-03-20 DOI: 10.1042/BCJ20240017

Anastasiya Potapenko, Jennilee M Davidson, Albert Lee, Angela S Laird

{"title":"The deubiquitinase function of ataxin-3 and its role in the pathogenesis of Machado-Joseph disease and other diseases.","authors":"Anastasiya Potapenko, Jennilee M Davidson, Albert Lee, Angela S Laird","doi":"10.1042/BCJ20240017","DOIUrl":"10.1042/BCJ20240017","url":null,"abstract":"Machado-Joseph disease (MJD) is a devastating and incurable neurodegenerative disease characterised by progressive ataxia, difficulty speaking and swallowing. Consequently, affected individuals ultimately become wheelchair dependent, require constant care, and face a shortened life expectancy. The monogenic cause of MJD is expansion of a trinucleotide (CAG) repeat region within the ATXN3 gene, which results in polyglutamine (polyQ) expansion within the resultant ataxin-3 protein. While it is well established that the ataxin-3 protein functions as a deubiquitinating (DUB) enzyme and is therefore critically involved in proteostasis, several unanswered questions remain regarding the impact of polyQ expansion in ataxin-3 on its DUB function. Here we review the current literature surrounding ataxin-3's DUB function, its DUB targets, and what is known regarding the impact of polyQ expansion on ataxin-3's DUB function. We also consider the potential neuroprotective effects of ataxin-3's DUB function, and the intersection of ataxin-3's role as a DUB enzyme and regulator of gene transcription. Ataxin-3 is the principal pathogenic protein in MJD and also appears to be involved in cancer. As aberrant deubiquitination has been linked to both neurodegeneration and cancer, a comprehensive understanding of ataxin-3's DUB function is important for elucidating potential therapeutic targets in these complex conditions. In this review, we aim to consolidate knowledge of ataxin-3 as a DUB and unveil areas for future research to aid therapeutic targeting of ataxin-3's DUB function for the treatment of MJD and other diseases.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"481 6","pages":"461-480"},"PeriodicalIF":4.1,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11088879/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140142709","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

Novel modifications of PARP inhibitor veliparib increase PARP1 binding to DNA breaks. PARP 抑制剂 veliparib 的新型修饰可增加 PARP1 与 DNA 断裂的结合。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-03-20 DOI: 10.1042/BCJ20230406

Uday Kiran Velagapudi, Élise Rouleau-Turcotte, Ramya Billur, Xuwei Shao, Manisha Patil, Ben E Black, John M Pascal, Tanaji T Talele

{"title":"Novel modifications of PARP inhibitor veliparib increase PARP1 binding to DNA breaks.","authors":"Uday Kiran Velagapudi, Élise Rouleau-Turcotte, Ramya Billur, Xuwei Shao, Manisha Patil, Ben E Black, John M Pascal, Tanaji T Talele","doi":"10.1042/BCJ20230406","DOIUrl":"10.1042/BCJ20230406","url":null,"abstract":"Catalytic poly(ADP-ribose) production by PARP1 is allosterically activated through interaction with DNA breaks, and PARP inhibitor compounds have the potential to influence PARP1 allostery in addition to preventing catalytic activity. Using the benzimidazole-4-carboxamide pharmacophore present in the first generation PARP1 inhibitor veliparib, a series of 11 derivatives was designed, synthesized, and evaluated as allosteric PARP1 inhibitors, with the premise that bulky substituents would engage the regulatory helical domain (HD) and thereby promote PARP1 retention on DNA breaks. We found that core scaffold modifications could indeed increase PARP1 affinity for DNA; however, the bulk of the modification alone was insufficient to trigger PARP1 allosteric retention on DNA breaks. Rather, compounds eliciting PARP1 retention on DNA breaks were found to be rigidly held in a position that interferes with a specific region of the HD domain, a region that is not targeted by current clinical PARP inhibitors. Collectively, these compounds highlight a unique way to trigger PARP1 retention on DNA breaks and open a path to unveil the pharmacological benefits of such inhibitors with novel properties.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"437-460"},"PeriodicalIF":4.1,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11070930/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139899305","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

Reporter cell lines to screen for inhibitors or regulators of the KRAS-RAF-MEK1/2-ERK1/2 pathway. 报告细胞系，以筛选 KRAS-RAF-MEK1/2-ERK1/2 通路的抑制剂或调节剂。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-03-20 DOI: 10.1042/BCJ20240015

Laura Weatherdon, Kate Stuart, Megan Cassidy, Alberto Moreno de la Gándara, Hanneke Okkenhaug, Markus Muellener, Grahame Mckenzie, Simon J Cook, Rebecca Gilley

{"title":"Reporter cell lines to screen for inhibitors or regulators of the KRAS-RAF-MEK1/2-ERK1/2 pathway.","authors":"Laura Weatherdon, Kate Stuart, Megan Cassidy, Alberto Moreno de la Gándara, Hanneke Okkenhaug, Markus Muellener, Grahame Mckenzie, Simon J Cook, Rebecca Gilley","doi":"10.1042/BCJ20240015","DOIUrl":"10.1042/BCJ20240015","url":null,"abstract":"The RAS-regulated RAF-MEK1/2-ERK1/2 signalling pathway is activated in cancer due to mutations in RAS proteins (especially KRAS), BRAF, CRAF, MEK1 and MEK2. Whilst inhibitors of KRASG12C (lung adenocarcinoma) and BRAF and MEK1/2 (melanoma and colorectal cancer) are clinically approved, acquired resistance remains a problem. Consequently, the search for new inhibitors (especially of RAS proteins), new inhibitor modalities and regulators of this pathway, which may be new drug targets, continues and increasingly involves cell-based screens with small molecules or genetic screens such as RNAi, CRISPR or protein interference. Here we describe cell lines that exhibit doxycycline-dependent expression KRASG12V or BRAFV600E and harbour a stably integrated EGR1:EmGFP reporter gene that can be detected by flow cytometry, high-content microscopy or immunoblotting. KRASG12V or BRAFV600E-driven EmGFP expression is inhibited by MEK1/2 or ERK1/2 inhibitors (MEKi and ERKi). BRAFi inhibit BRAFV600E-driven EmGFP expression but enhance the response to KRASG12V, recapitulating paradoxical activation of wild type RAF proteins. In addition to small molecules, expression of iDab6, encoding a RAS-specific antibody fragment inhibited KRASG12V- but not BRAFV600E-driven EmGFP expression. Finally, substitution of EmGFP for a bacterial nitroreductase gene allowed KRASG12V or BRAFV600E to drive cell death in the presence of a pro-drug, which may allow selection of pathway inhibitors that promote survival. These cell lines should prove useful for cell-based screens to identify new regulators of KRAS- or BRAF-dependent ERK1/2 signalling (drug target discovery) as well as screening or triaging 'hits' from drug discovery screens.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"405-422"},"PeriodicalIF":4.1,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11088904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139911924","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