Journal of Biological Chemistry最新文献_第9页

Mechanistic differences in eukaryotic initiation factor requirements for eIF4GI-driven cap-independent translation of structured mRNAs. 真核生物启动因子对 eIF4GI 驱动的不依赖帽子的结构化 mRNA 翻译的要求存在机制差异。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-10-09 DOI: 10.1016/j.jbc.2024.107866

Baishakhi Saha, Solomon A Haizel, Dixie J Goss

{"title":"Mechanistic differences in eukaryotic initiation factor requirements for eIF4GI-driven cap-independent translation of structured mRNAs.","authors":"Baishakhi Saha, Solomon A Haizel, Dixie J Goss","doi":"10.1016/j.jbc.2024.107866","DOIUrl":"10.1016/j.jbc.2024.107866","url":null,"abstract":"Protein translation is globally downregulated under stress conditions. Many proteins that are synthesized under stress conditions use a cap-independent translation initiation pathway. A subset of cellular mRNAs that encode for these proteins contain stable secondary structures within their 5'UTR, and initiate cap-independent translation using elements called cap-independent translation enhancers or internal ribosome entry sites within their 5'UTRs. The interaction among initiation factors such as eukaryotic initiation factor 4E (eIF4E), eIF4A, and eIF4GI, especially in regulating the eIF4F complex during noncanonical translation initiation of different 5'UTR mRNAs, is poorly understood. Here, equilibrium-binding assays, CD studies and in vitro translation assays were used to elucidate the recruitment of these initiation factors to the highly structured 5'UTRs of fibroblast-growth factor 9 (FGF-9) and hypoxia inducible factor 1 subunit alpha (HIF-1α) encoding mRNAs. We showed that eIF4A and eIF4E enhanced eIF4GI's binding affinity to the uncapped 5'UTR of HIF-1α mRNA, inducing conformational changes in the protein/RNA complex. In contrast, these factors have no effect on the binding of eIF4GI to the 5'UTR of FGF-9 mRNA. Recently, Izidoro et al. reported that the interaction of 42nt unstructured RNA to human eIF4F complex is dominated by eIF4E and ATP-bound state of eIF4A. Here, we show that structured 5'UTR mRNA binding mitigates this requirement. Based on these observations, we describe two possible cap-independent translation mechanisms for FGF-9 and HIF-1α encoding mRNAs used by cells to mitigate cellular stress conditions.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390805","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}

引用次数: 0

Cellular NS1-BP protein interacts with the mRNA export receptor NXF1 to mediate nuclear export of influenza virus M mRNAs. 细胞 NS1-BP 蛋白与 mRNA 导出受体 NXF1 相互作用，介导流感病毒 M mRNA 的核导出。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-10-09 DOI: 10.1016/j.jbc.2024.107871

Ke Zhang, Tolga Cagatay, Dongqi Xie, Alexia E Angelos, Serena Cornelius, Vasilisa Aksenova, Sadaf Aslam, Zhiyu He, Matthew Esparza, Ashley Vazhavilla, Mary Dasso, Adolfo García-Sastre, Yi Ren, Beatriz M A Fontoura

{"title":"Cellular NS1-BP protein interacts with the mRNA export receptor NXF1 to mediate nuclear export of influenza virus M mRNAs.","authors":"Ke Zhang, Tolga Cagatay, Dongqi Xie, Alexia E Angelos, Serena Cornelius, Vasilisa Aksenova, Sadaf Aslam, Zhiyu He, Matthew Esparza, Ashley Vazhavilla, Mary Dasso, Adolfo García-Sastre, Yi Ren, Beatriz M A Fontoura","doi":"10.1016/j.jbc.2024.107871","DOIUrl":"10.1016/j.jbc.2024.107871","url":null,"abstract":"Influenza A viruses have eight genomic RNAs that are transcribed in the host cell nucleus. Two of the viral mRNAs undergo alternative splicing. The M1 mRNA encodes the matrix protein 1 (M1) and is also spliced into M2 mRNA, which encodes the proton channel matrix protein 2 (M2). Our previous studies have shown that the cellular Non-Structural protein 1 (NS1)-binding protein (NS1-BP) interacts with the viral NS1 and M1 mRNA to promote M1 to M2 splicing. Another pool of NS1 protein binds the mRNA export receptor nuclear RNA export factor-1 (NXF1), leading to nuclear retention of cellular mRNAs. Here, we show a series of biochemical and cell biological findings that suggest a model for nuclear export of M1 and M2 mRNAs despite the mRNA nuclear export inhibition imposed by the viral NS1 protein. NS1-BP competes with NS1 for NXF1 binding, allowing the recruitment of NXF1 to the M mRNAs after splicing. NXF1 then binds germinal center-associated nuclear protein, a member of the transcription and export complex-2. Although both NS1 and NS1-BP remain in complex with germinal center-associated nuclear protein-NXF1, they dissociate once this complex docks at the nuclear pore complex, and the M mRNAs are translocated to the cytoplasm. Since this mRNA nuclear export pathway is key for expression of M1 and M2 proteins that function in viral intracellular trafficking and budding, these viral-host interactions are critical for influenza virus replication.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390803","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}

引用次数: 0

Engineered TIMP2 with narrow MMP-9 specificity is an effective inhibitor of invasion and proliferation of triple negative breast cancer cells. 经改造的 TIMP2 具有狭窄的 MMP-9 特异性，可有效抑制三阴性乳腺癌细胞的侵袭和增殖。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-10-09 DOI: 10.1016/j.jbc.2024.107867

Naama Rotenberg, Mark Feldman, Jason Shirian, Alexandra Hockla, Evette S Radisky, Julia M Shifman

{"title":"Engineered TIMP2 with narrow MMP-9 specificity is an effective inhibitor of invasion and proliferation of triple negative breast cancer cells.","authors":"Naama Rotenberg, Mark Feldman, Jason Shirian, Alexandra Hockla, Evette S Radisky, Julia M Shifman","doi":"10.1016/j.jbc.2024.107867","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.107867","url":null,"abstract":"Matrix metalloproteinases (MMPs) are a family of endopeptidases that degrade extracellular matrix (ECM) proteins, functioning in various physiological processes such as tissue remodeling, embryogenesis, and morphogenesis. Dysregulation of these enzymes is linked to multiple diseases. Specific inhibition of particular MMPs is crucial for anti-MMP drug development as some MMPs have shown anti-disease properties. In this study, we aimed to design a highly specific inhibitor of MMP-9, that plays a crucial role in cell invasion and metastasis, using tissue inhibitor of metalloproteinases 2 (TIMP2), an endogenous broad-family MMP inhibitor, as a prototype. In our earlier work, we were able to narrow down the specificity of the N-terminal domain of TIMP2 (N-TIMP2) toward MMP-9, yet at the expense of lowering its affinity to MMP-9. In this study, a library of N-TIMP2 mutants based on previous design with randomized additional positions was sorted for binding to MMP-9 using yeast surface display. Two selected N-TIMP2 mutants were expressed, purified and their inhibitory activity against a panel of MMPs was measured. The best engineered N-TIMP2 mutant (REY) exhibited a 2-fold higher affinity to MMP-9 compared to that of the WT N-TIMP2, and 6- to 1.1x104-fold increase in binding specificity toward MMP-9 compared to five alternative MMPs. Moreover, REY demonstrated a significant increase in inhibition of cell invasion and proliferation compared to the WT N-TIMP2 in MDA-MB-231 breast cancer cells. Therefore, our engineered N-TIMP2 mutant emerges as a promising candidate for future therapeutic development, offering precise targeting of MMP-9 in MMP-9-driven diseases.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142466206","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}

引用次数: 0

HSP70 inhibits CHIP E3 ligase activity to maintain germline function in Caenorhabditis elegans. HSP70 可抑制 CHIP E3 连接酶的活性，从而维持秀丽隐杆线虫的种系功能。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-10-09 DOI: 10.1016/j.jbc.2024.107864

Pankaj Thapa, Rupesh V Chikale, Natalia A Szulc, Maria-Teodora Pandrea, Agnieszka Sztyler, Khushboo Jaggi, Marta Niklewicz, Remigiusz A Serwa, Thorsten Hoppe, Wojciech Pokrzywa

{"title":"HSP70 inhibits CHIP E3 ligase activity to maintain germline function in Caenorhabditis elegans.","authors":"Pankaj Thapa, Rupesh V Chikale, Natalia A Szulc, Maria-Teodora Pandrea, Agnieszka Sztyler, Khushboo Jaggi, Marta Niklewicz, Remigiusz A Serwa, Thorsten Hoppe, Wojciech Pokrzywa","doi":"10.1016/j.jbc.2024.107864","DOIUrl":"10.1016/j.jbc.2024.107864","url":null,"abstract":"The ubiquitin-proteasome system is crucial for proteostasis, particularly during proteotoxic stress. The interaction between heat shock protein (HSP) 70 and the ubiquitin ligase CHIP plays a key role in this process. Our study investigates the Caenorhabditis elegans orthologs HSP-1 and CHN-1, demonstrating that HSP-1 binding decreases CHN-1 E3 ligase activity, aligning with the inhibitory effects observed in human HSP70-CHIP interactions. To explore the physiological significance of this inhibition, we utilized the HSP-1EEYD mutant, which binds CHN-1 without reducing its activity, expressed in C. elegans. Our results reveal that the HSP-1-CHN-1 interaction is critical for maintaining germline integrity under heat stress by preventing excessive turnover of essential reproductive proteins. In HSP-1EEYD nematodes, this protective mechanism is impaired, leading to disrupted stress-induced apoptosis, which is restored by CHN-1 depletion. Additionally, proteomic analysis identified DAF-18/PTEN as a potential CHN-1 substrate, which becomes destabilized when CHN-1 activity is not downregulated by HSP-1 during stress. Depleting DAF-18 significantly compromises the reproductive benefits observed from CHN-1 knockout in HSP-1EEYD mutants, suggesting that the maintenance of DAF-18 plays a role in the observed phenotypes. These findings highlight the importance of HSP-1 in regulating CHN-1 E3 ligase activity to preserve germline function under stress conditions.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390804","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}

引用次数: 0

A Non-natural Peptide Targeting the A-kinase Anchoring Function of PI3Kγ for Therapeutic cAMP Modulation in Pulmonary Cells. 一种靶向 PI3Kγ 的 A- 激酶锚定功能的非天然肽，用于治疗性调节肺细胞中的 cAMP。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-10-09 DOI: 10.1016/j.jbc.2024.107873

Angela Della Sala, Laura Tasca, Cosmin Butnarasu, Valentina Sala, Giulia Prono, Alessandra Murabito, Olga Valentina Garbero, Enrico Millo, Leonardo Terranova, Francesco Blasi, Andrea Gramegna, Stefano Aliberti, Alberto Massarotti, Sonja Visentin, Emilio Hirsch, Alessandra Ghigo

{"title":"A Non-natural Peptide Targeting the A-kinase Anchoring Function of PI3Kγ for Therapeutic cAMP Modulation in Pulmonary Cells.","authors":"Angela Della Sala, Laura Tasca, Cosmin Butnarasu, Valentina Sala, Giulia Prono, Alessandra Murabito, Olga Valentina Garbero, Enrico Millo, Leonardo Terranova, Francesco Blasi, Andrea Gramegna, Stefano Aliberti, Alberto Massarotti, Sonja Visentin, Emilio Hirsch, Alessandra Ghigo","doi":"10.1016/j.jbc.2024.107873","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.107873","url":null,"abstract":"A-kinase anchoring proteins (AKAPs) are key orchestrators of cyclic AMP (cAMP) signaling that act by recruiting protein kinase A (PKA) in proximity of its substrates and regulators to specific subcellular compartments. Modulation of AKAPs function offers the opportunity to achieve compartment-restricted modulation of the cAMP/PKA axis, paving the way to new targeted treatments. For instance, blocking the AKAP activity of PI3Kγ improves lung function by inducing cAMP-mediated bronchorelaxation, ion transport and anti-inflammatory responses. Here, we report the generation of a non-natural peptide, DRI-Pep #20, optimized to disrupt the AKAP function of PI3Kγ. DRI-Pep #20 mimicked the native interaction between the N-terminal domain of PI3Kγ and PKA, demonstrating nanomolar affinity for PKA, high resistance to protease degradation and high permeability to the pulmonary mucus barrier. DRI-Pep #20 triggered cAMP elevation both in vivo in the airway tract of mice upon intratracheal administration, and in vitro in bronchial epithelial cells of cystic fibrosis (CF) patients. In CF cells, DRI-Pep #20 rescued the defective function of the cAMP-operated channel cystic fibrosis conductance regulator (CFTR), by boosting the efficacy of approved CFTR modulators. Overall, this study unveils DRI-Pep #20 as a potent PI3Kγ/PKA disruptor for achieving therapeutic cAMP elevation in chronic respiratory disorders.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406422","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}

引用次数: 0

A human lectin array for characterizing host-pathogen interactions. 用于描述宿主与病原体相互作用特征的人类凝集素阵列。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-10-09 DOI: 10.1016/j.jbc.2024.107869

Stefi V Benjamin, Sabine A F Jégouzo, Chloe Lieng, Connor Daniels, Marine Coispeau, Rikin J Lau, Suyeon Kim, Yasmine Metaxa, James Philpott, Tiannuo Li, Chao Dai, Xin Wang, Maddy L Newby, Gerald B Pier, Max Crispin, Abigail Clements, Maureen E Taylor, Kurt Drickamer

{"title":"A human lectin array for characterizing host-pathogen interactions.","authors":"Stefi V Benjamin, Sabine A F Jégouzo, Chloe Lieng, Connor Daniels, Marine Coispeau, Rikin J Lau, Suyeon Kim, Yasmine Metaxa, James Philpott, Tiannuo Li, Chao Dai, Xin Wang, Maddy L Newby, Gerald B Pier, Max Crispin, Abigail Clements, Maureen E Taylor, Kurt Drickamer","doi":"10.1016/j.jbc.2024.107869","DOIUrl":"10.1016/j.jbc.2024.107869","url":null,"abstract":"A human lectin array has been developed to probe the interactions of innate immune receptors with pathogenic and commensal microorganisms. Following the successful introduction of a lectin array containing all of the cow C-type carbohydrate-recognition domains (CRDs), a human array described here contains the C-type CRDs as well as CRDs from other classes of sugar-binding receptors, including galectins, siglecs, R-type CRDs, ficolins, intelectins, and chitinase-like lectins. The array is constructed with CRDs modified with single-site biotin tags, ensuring that the sugar-binding sites in CRDs are displayed on a streptavidin-coated surface in a defined orientation and are accessible to the surfaces of microbes. A common approach used for expression and display of CRDs from all of the different structural categories of glycan-binding receptors allows comparisons across lectin families. In addition to previously documented protocols for binding of fluorescently labeled bacteria, methods have been developed for detecting unlabeled bacteria bound to the array by counter-staining with DNA-binding dye. Screening has also been undertaken with viral glycoproteins and bacterial and fungal polysaccharides. The array provides an unbiased screen for sugar ligands that interact with receptors and many show binding not anticipated from earlier studies. For example, some of the galectins bind with high affinity to bacterial glycans that lack lactose or N-acetyllactosamine. The results demonstrate the utility of the human lectin array for providing a unique overview of the interactions of multiple classes of glycan-binding proteins in the innate immune system with different types of microorganisms.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390802","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}

引用次数: 0

Redox control of the deubiquitinating enzyme Ubp2 regulates translation during stress. 去泛素化酶 Ubp2 的氧化还原控制调节应激过程中的翻译。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-10-09 DOI: 10.1016/j.jbc.2024.107870

Clara M Santos, Blanche K Cizubu, Dinachi A Okonkwo, Chia-Yu Chen, Natori Maske, Nathan A Snyder, Vanessa Simões, Erica J Washington, Gustavo M Silva

{"title":"Redox control of the deubiquitinating enzyme Ubp2 regulates translation during stress.","authors":"Clara M Santos, Blanche K Cizubu, Dinachi A Okonkwo, Chia-Yu Chen, Natori Maske, Nathan A Snyder, Vanessa Simões, Erica J Washington, Gustavo M Silva","doi":"10.1016/j.jbc.2024.107870","DOIUrl":"10.1016/j.jbc.2024.107870","url":null,"abstract":"Protein ubiquitination is essential to govern cells' ability to cope with harmful environments by regulating many aspects of protein dynamics from synthesis to degradation. As important as the ubiquitination process, the reversal of ubiquitin chains mediated by deubiquitinating enzymes (DUBs) is critical for proper recovery from stress and re-establishment of proteostasis. Although it is known that ribosomes are decorated with K63-linked polyubiquitin chains that control protein synthesis under stress, the mechanisms by which these ubiquitin chains are reversed and regulate proteostasis during stress recovery remain elusive. Here, we showed in budding yeast that the DUB Ubp2 is redox-regulated during oxidative stress in a reversible manner, which determines the levels of K63-linked polyubiquitin chains present on ribosomes. We also demonstrate that Ubp2 can cleave single ubiquitin moieties out of chains and its activity is modulated by a series of repeated domains and the formation of disulfide bonds. By combining cellular, biochemical, and proteomics analyses, we showed that Ubp2 is crucial for restoring translation after stress cessation, indicating an important role in determining the cellular response to oxidative stress. Our work demonstrates a novel role for Ubp2, revealing that a range of signaling pathways can be controlled by redox regulation of DUB activity in eukaryotes, which in turn will define cellular states of health and diseases.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390806","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}

引用次数: 0

How the double-ring ClpAP protease motor grips the substrate to unfold and degrade stable proteins. 双环 ClpAP 蛋白酶马达如何抓住底物，展开并降解稳定的蛋白质。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2024-10-05 DOI: 10.1016/j.jbc.2024.107861

Tsai-Ting Shih,Robert T Sauer,Tania A Baker

{"title":"How the double-ring ClpAP protease motor grips the substrate to unfold and degrade stable proteins.","authors":"Tsai-Ting Shih,Robert T Sauer,Tania A Baker","doi":"10.1016/j.jbc.2024.107861","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.107861","url":null,"abstract":"Loops in the axial channels of ClpAP and other AAA+ proteases bind a short peptide degron connected by a linker to the N- or C-terminal residue of a native protein to initiate degradation. ATP hydrolysis then powers pore-loop movements that translocate these segments through the channel until a native domain is pulled against the narrow channel entrance, creating an unfolding force. Substrate unfolding is thought to depend on strong contacts between pore loops and a subset of amino acids in the unstructured sequence directly preceding the folded domain. Here, we identify such contact sequences that promote grip for ClpAP and use ClpA structures to place these sequences within ClpA's two AAA+ rings. The positions and chemical nature of certain residues within an unstructured segment that are positioned to interact with the D2 ring have major positive effects on substrate unfolding, whereas segments located within the D1 ring have little consequence. Within the D2-bound segment, two short elements are critical for accelerating degradation; one is at the 'top' of D2 and consists of at least two properly positioned non-slippery residues. In contrast, the second D2 element, which can be as short as one residue, is positioned to contact pore loops near the 'bottom' of this ring. Comparison with similar studies for ClpXP reveals that positioning a well-gripped substrate sequence within the major unfoldase motor is more important than its proximity to the folded domain and that charged, polar, and hydrophobic residues all contribute favorable contacts to substrate grip.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385410","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}

引用次数: 0

Different charged biopolymers induce α-synuclein to form fibrils with distinct structures. 不同的带电生物聚合物会诱导α-突触核蛋白形成具有不同结构的纤维。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2024-10-05 DOI: 10.1016/j.jbc.2024.107862

Yuxuan Yao,Qinyue Zhao,Youqi Tao,Kaien Liu,Tianyi Cao,Zipeng Chen,Cong Liu,WeiDong Le,Jing Zhao,Dan Li,Wenyan Kang

{"title":"Different charged biopolymers induce α-synuclein to form fibrils with distinct structures.","authors":"Yuxuan Yao,Qinyue Zhao,Youqi Tao,Kaien Liu,Tianyi Cao,Zipeng Chen,Cong Liu,WeiDong Le,Jing Zhao,Dan Li,Wenyan Kang","doi":"10.1016/j.jbc.2024.107862","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.107862","url":null,"abstract":"The aggregation of α-synuclein (α-syn) into amyloid fibrils, a key process in the development of Parkinson's disease (PD) and other synucleinopathies, is influenced by a range of factors such as charged biopolymers, chaperones, and metabolites. However, the specific impacts of different biopolymers on α-syn fibril structure are not well understood. In our work, we found that different polyanions and polycations, such as polyphosphate (polyP), polyuridine (polyU), and polyamines (including putrescine, spermidine, and spermine), markedly altered the fibrillation kinetics of α-syn in vitro. Furthermore, seeding assay revealed distinct cross-seeding capacities across different biopolymer-induced α-syn fibrils, suggesting the formation of structurally distinct strains under different conditions. Utilizing cryo-electron microscopy (cryo-EM), we further examined the detailed structural configuration of α-syn fibrils formed in the presence of these biopolymers. Notably, we found that while polyamines do not change the atomic structure of α-syn fibrils, polyU and polyP induce the formation of distinct amyloid fibrils, exhibiting a range of structural polymorphs. Our work offers valuable insights into how various charged biopolymers affect the aggregation process and the resultant structures of α-syn fibrils, thereby enhancing our understanding of the structural variations in α-syn fibrils across different pathological conditions.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385419","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}

引用次数: 0

The Unique Pt(II)-Induced Nucleolar Stress Response and its Deviation from DNA Damage Response Pathways. 独特的铂(II)诱导的核极应激反应及其与 DNA 损伤反应途径的偏差

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-10-05 DOI: 10.1016/j.jbc.2024.107858

Hannah C Pigg, Katelyn R Alley, Christopher R Griffin, Caleb H Moon, Sarah J Kraske, Victoria J DeRose

{"title":"The Unique Pt(II)-Induced Nucleolar Stress Response and its Deviation from DNA Damage Response Pathways.","authors":"Hannah C Pigg, Katelyn R Alley, Christopher R Griffin, Caleb H Moon, Sarah J Kraske, Victoria J DeRose","doi":"10.1016/j.jbc.2024.107858","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.107858","url":null,"abstract":"The mechanisms of action for the platinum compounds cisplatin and oxaliplatin have yet to be fully elucidated, despite the worldwide use of these drugs. Recent studies suggest that the two compounds may be working through different mechanisms, with cisplatin inducing cell death via the DNA damage response (DDR) and oxaliplatin utilizing a nucleolar stress-based cell death pathway. While cisplatin-induced DDR has been subject to much research, the mechanisms for oxaliplatin's influence on the nucleolus are not well understood. Prior work has outlined structural parameters for Pt(II) derivatives capable of nucleolar stress induction. In this work, we gain insight into the nucleolar stress response induced by these Pt(II) derivatives by investigating potential correlations between this unique pathway and DDR. Key findings from this study indicate that Pt(II)-induced nucleolar stress occurs when DDR is inhibited and works independently of the ATM/ATR-dependent DDR pathway. We also determine that Pt(II)-induced stress may be linked to the G1 cell cycle phase, as cisplatin can induce nucleolar stress when cell cycle inhibition occurs at the G1/S checkpoint. Finally, we compare Pt(II)-induced nucleolar stress with other small-molecule nucleolar stress-inducing compounds Actinomycin D, BMH-21, and CX-5461, and find that only Pt(II) compounds cause irreversible nucleolar stress. Taken together, these findings contribute to a better understanding of Pt(II)-induced nucleolar stress, its deviation from ATM/ATR-dependent DDR, and the possible influence of cell cycle on the ability of Pt(II) compounds to cause nucleolar stress.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390807","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}

引用次数: 0