Biochemical Journal最新文献_第4页

Single-molecule observations of human small heat shock proteins in complex with aggregation-prone client proteins. 人小热休克蛋白与易聚集的客户蛋白复合物的单分子观察。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2025-05-06 DOI: 10.1042/BCJ20240473

Lauren Rice, Nicholas Marzano, Dezerae Cox, Bailey Skewes, Antoine M van Oijen, Heath Ecroyd

{"title":"Single-molecule observations of human small heat shock proteins in complex with aggregation-prone client proteins.","authors":"Lauren Rice, Nicholas Marzano, Dezerae Cox, Bailey Skewes, Antoine M van Oijen, Heath Ecroyd","doi":"10.1042/BCJ20240473","DOIUrl":"10.1042/BCJ20240473","url":null,"abstract":"Small heat shock proteins (sHsps) are molecular chaperones that act to prevent the aberrant aggregation of misfolded proteins. Whilst it is suggested that sHsps prevent aggregation by binding to misfolded client proteins, the dynamic and heterogeneous nature of sHsps has hindered attempts to establish the mechanistic details of how sHsp-client protein complexes form. Single-molecule approaches have emerged as a powerful tool to investigate dynamic and heterogeneous interactions such as those that can occur between sHsps and their client proteins. Here, we use total internal reflection fluorescence microscopy to observe and characterise the complexes formed between model aggregation-prone client proteins (firefly luciferase, rhodanese and chloride intracellular channel 1 protein), and the human sHsps αB-crystallin (αB-c; HSPB5) and Hsp27 (HSPB1). We show that small (monomeric or dimeric) forms of both αB-c and Hsp27 bind to misfolded or oligomeric forms of the client proteins at early stages of aggregation, resulting in the formation of soluble sHsp-client complexes. Stoichiometric analysis of these complexes revealed that additional αB-c subunits accumulate onto pre-existing sHsp-client complexes to form larger species - this does not occur to the same extent for Hsp27. Instead, Hsp27-client interactions tend to be more transient than those of αB-c. Elucidating these mechanisms of sHsp function is crucial to our understanding of how these molecular chaperones act to inhibit protein aggregation and maintain cellular proteostasis.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"482 9","pages":"413-432"},"PeriodicalIF":4.4,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203938/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961012","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

Metal-sensing properties of the disordered loop from the Arabidopsis metal transceptor IRT1. 拟南芥金属受体IRT1紊乱环的金属传感特性。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2025-05-06 DOI: 10.1042/BCJ20240685

Virginia Cointry, Reyes Ródenas, Nelly Morellet, Steven Fanara, Valérie Cotelle, Julie Neveu, Grégory Vert

{"title":"Metal-sensing properties of the disordered loop from the Arabidopsis metal transceptor IRT1.","authors":"Virginia Cointry, Reyes Ródenas, Nelly Morellet, Steven Fanara, Valérie Cotelle, Julie Neveu, Grégory Vert","doi":"10.1042/BCJ20240685","DOIUrl":"10.1042/BCJ20240685","url":null,"abstract":"The plant iron-regulated transporter 1 (IRT1) iron transporter is a plasma membrane protein that takes up iron in the root under iron-limited conditions. Besides its primary metal substrate iron, IRT1 transports other divalent metals that overaccumulate in plants when soil iron is low and IRT1 is highly expressed. We previously reported that the intracellular regulatory loop between transmembrane helices TM4 and TM5 is involved in the post-translational regulation of IRT1 by its non-iron metal substrates. Upon excess of zinc, IRT1 undergoes phosphorylation by CIPK23 followed by its ubiquitination by IDF1 to target IRT1 for vacuolar degradation. This zinc-dependent down-regulation of IRT1 requires the presence of four histidine (H) residues in the IRT1 loop, which directly bind zinc. However, how selective metal binding is achieved and how this allows downstream regulation to take place is largely not known. Here, we characterized the metal-binding properties and structure of the IRT1 loop to better understand the molecular basis of non-iron metal sensing and signaling. Using a combination of circular dichroism and NMR, we reveal that zinc and manganese bind to the IRT1 loop with nanomolar range affinity and that metal binding does not trigger structuration of the loop. We validate that zinc and manganese binding is mediated by four H residues and identify aspartic acid (D) residue D173 as helping in metal co-ordination and participating to metal sensing and metal-dependent degradation of IRT1 in plants. Altogether, our data provide further understanding of how IRT1 regulatory loop senses high cytosolic divalent metal concentrations to regulate metal uptake in plants.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"482 9","pages":"451-466"},"PeriodicalIF":4.4,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975710","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

EZH2 promotes chemoresistance in colorectal cancer by inhibiting autophagy through NRP1 suppression. EZH2通过抑制NRP1抑制自噬，促进结直肠癌的化疗耐药。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2025-05-02 DOI: 10.1042/bcj20240607

Hong Deng,Qin Xu,Qiang Zhang,Chunfeng Liu,Lei Ren

{"title":"EZH2 promotes chemoresistance in colorectal cancer by inhibiting autophagy through NRP1 suppression.","authors":"Hong Deng,Qin Xu,Qiang Zhang,Chunfeng Liu,Lei Ren","doi":"10.1042/bcj20240607","DOIUrl":"https://doi.org/10.1042/bcj20240607","url":null,"abstract":"Colorectal cancer (CRC) is characterized by aggressive tumor growth and chemoresistance, with Enhancer of zeste homolog 2 (EZH2) serving a pivotal role in these processes. However, the mechanisms by which it drives tumor proliferation and therapeutic resistance through autophagy regulation remain unclear. Here, we demonstrated that EZH2 expression is elevated in CRC tissues and cell lines, correlating with chemoresistance and diagnostic potential (Area Under the Curve, AUC = 0.968). EZH2 knockdown markedly reduced CRC cell proliferation, while its overexpression promoted tumor growth and increased resistance to irinotecan. Mechanistically, EZH2 suppressed autophagy in CRC cells, a process linked to chemosensitivity, by directly regulating LC3bI/II expression. Notably, EZH2 enhanced the Neuropilin-1 (NRP1) level by binding to the NRP1 promoter, thereby promoting tumor proliferation and irinotecan resistance through autophagy inhibition. NRP1 depletion partially reversed these effects, underscoring the crucial role of the EZH2-NRP1 axis in CRC. Our findings highlight that targeting the EZH2-NRP1 interaction could represent a novel therapeutic approach to overcoming chemoresistance in CRC.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"109 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143902895","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

Cytokines from parasites: manipulating host responses by molecular mimicry. 来自寄生虫的细胞因子：通过分子模仿操纵宿主反应。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2025-04-29 DOI: 10.1042/bcj20253061

Rick M Maizels,Henry J McSorley,Hermelijn H Smits,Peter Ten Dijke,Andrew P Hinck

{"title":"Cytokines from parasites: manipulating host responses by molecular mimicry.","authors":"Rick M Maizels,Henry J McSorley,Hermelijn H Smits,Peter Ten Dijke,Andrew P Hinck","doi":"10.1042/bcj20253061","DOIUrl":"https://doi.org/10.1042/bcj20253061","url":null,"abstract":"Helminth parasites have evolved sophisticated methods for manipulating the host immune response to ensure long-term survival in their chosen niche, for example, by secreting products that interfere with the host cytokine network. Studies on the secretions of Heligmosomoides polygyrus have identified a family of transforming growth factor-β (TGF-β) mimics (TGMs), which bear no primary amino acid sequence similarity to mammalian TGF-β, but functionally replicate or antagonise TGF-β effects in restricted cell types. The prototypic member, TGM1, induces in vitro differentiation of Foxp3+ T regulatory cells and attenuates airway allergic and intestinal inflammation in animal models. TGM1 is one of a family of ten TGM proteins expressed by H. polygyrus. It is a five-domain modular protein in which domains 1-2 bind TGFBR1, and domain 3 binds TGFBR2; domains 4-5 increase its potency by binding a co-receptor, CD44, highly expressed on immune cells. Domains 4-5 are more diverse in other TGMs, which bind co-receptors on cells such as fibroblasts. One variant, TGM6, lacks domains 1-2 and hence cannot transduce a signal but binds TGFBR2 through domain 3 and a co-receptor expressed on fibroblasts through domains 4-5 and blocks TGF-β signalling in fibroblasts and epithelial cells; T cells do not express the co-receptor and are not inhibited by TGM6. Hence, different family members have evolved to act as agonists or antagonists on various cell types. TGMs, which function by molecularly mimicking binding of the host cytokine to the host TGF-β receptors, are examples of highly evolved immunomodulators from parasites, including those that block interleukin (IL)-13 and IL-33 signalling, modulate macrophage and dendritic cell responses and modify host cell metabolism. The emerging panoply and potency of helminth evasion molecules illustrates the range of strategies in play to maintain long-term infections in the mammalian host.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"25 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893187","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

Structural characterisation of a cysteine-rich conotoxin, sigma(σ)S-GVIIIA, extracted from the defensive venom of the marine cone snail Conus geographus. 从海锥螺防御毒液中提取的一种富含半胱氨酸的螺毒素sigma(σ) s - gviii的结构特征。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2025-04-23 DOI: 10.1042/bcj20240753

Yoshimi Peck,David Wilson,Danica Lennox-Bulow,Julien Giribaldi,Jamie Seymour,Sebastien Dutertre,K Rosengren,Michael Liddell,Norelle Daly

{"title":"Structural characterisation of a cysteine-rich conotoxin, sigma(σ)S-GVIIIA, extracted from the defensive venom of the marine cone snail Conus geographus.","authors":"Yoshimi Peck,David Wilson,Danica Lennox-Bulow,Julien Giribaldi,Jamie Seymour,Sebastien Dutertre,K Rosengren,Michael Liddell,Norelle Daly","doi":"10.1042/bcj20240753","DOIUrl":"https://doi.org/10.1042/bcj20240753","url":null,"abstract":"The activity of the serotonin type 3 (5-HT3) receptor is associated with neurodegenerative, inflammatory and metabolic diseases, neuropsychiatric disorders, and cancer. Structural analysis of modulators of this receptor is likely to aid in future medicinal chemistry studies aimed at developing lead molecules targeting this receptor. Here we report the structure of a cone snail venom peptide that was purified from the crude venom of Conus geographus and shown to be an antagonist of the 5-HT3 receptor more than 25 years ago, sigma(σ)GVIIIA. This lag in structural characterisation studies is likely due to challenges in isolating the native peptide and difficulties in producing synthetic peptide due to the presence of ten cysteine residues involved in five disulfide bonds. Using NMR spectroscopy, we show that σS-GVIIIA adopts a growth factor cystine knot (GFCK) fold. This is the first example of a cone snail venom peptide experimentally determined to contain the GFCK structural motif, and the first example of a 5-HT3 receptor antagonist containing this motif. Our study also highlights complexities in the use of artificial intelligence-based structure prediction models. Peptide structure predictions using AlphaFold 3 were consistent with our NMR structure when the input sequence contained the well-conserved precursor sequence, but inconsistent when the precursor sequence was excluded. AI-based structure prediction of proteins is a rapidly advancing field, but this inconsistency emphasises the need for more experimental structural training data when novel structures are involved, as was the case here for a cysteine-rich peptide.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"34 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876477","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

Metal sensing properties of the disordered loop from the Arabidopsis metal transceptor IRT1. 拟南芥金属受体IRT1紊乱环的金属传感特性

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2025-04-17 DOI: 10.1042/BCJ-2024-0685

Virginia Cointry, Reyes Ródenas, Nelly Morellet, Steven Fanara, Valérie Cotelle, Julie Neveu, Grégory Vert

{"title":"Metal sensing properties of the disordered loop from the Arabidopsis metal transceptor IRT1.","authors":"Virginia Cointry, Reyes Ródenas, Nelly Morellet, Steven Fanara, Valérie Cotelle, Julie Neveu, Grégory Vert","doi":"10.1042/BCJ-2024-0685","DOIUrl":"https://doi.org/10.1042/BCJ-2024-0685","url":null,"abstract":"The plant IRT1 iron transporter is a plasma membrane protein that takes up iron in root upon iron-limited conditions. Besides its primary metal substrate iron, IRT1 transports other divalent metals that overaccumulate in plants when soil iron is low and IRT1 is highly expressed. We previously reported that the intracellular regulatory loop between transmembrane helices TM4 and TM5 is involved in the post-translational regulation of IRT1 by its non-iron metal substrates. Upon excess of zinc, IRT1 undergoes phosphorylation by CIPK23 followed by its ubiquitination by IDF1 to target IRT1 for vacuolar degradation. This zinc-dependent downregulation of IRT1 requires the presence of four histidine ( residues in the IRT1 loop, that directly bind zinc. However, how selective metal binding is achieved and how this allows downstream regulation to take place is largely unknown. Here, we characterized the metal binding properties and structure of the IRT1 loop to better understand the molecular basis of non-iron metal sensing and signaling. Using a combination of circular dichroism and NMR, we reveal that zinc and manganese bind to the IRT1 loop with nanomolar range affinity, and that metal binding does not trigger structuration of the loop. We validate that zinc and manganese binding is mediated by four residues and identify aspartic acid (D) residue D173 as helping in metal coordination and participating to metal sensing and metal-dependent degradation of IRT1 in plants. Altogether, our data provide further understanding about how IRT1 regulatory loop senses high cytosolic divalent metalconcentrations to regulate metal uptake in plants.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968078","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

Retraction: Lead induces the upregulation of protein arginine methyltransferase 5 possibly by its promoter demethylation. 撤回：铅可能通过启动子去甲基化诱导蛋白精氨酸甲基转移酶5的上调。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2025-04-10 DOI: 10.1042/bcj20180167_ret

引用次数: 0

Retraction: Insulin-induced Drosophila S6 kinase activation requires phosphoinositide 3-kinase and protein kinase B. 撤回：胰岛素诱导的果蝇S6激酶激活需要磷酸肌苷3激酶和蛋白激酶B。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2025-04-10 DOI: 10.1042/BJ20030577_RET

引用次数: 0

Retraction: Lead induces the upregulation of protein arginine methyltransferase 5 possibly by its promoter demethylation. 撤回：铅可能通过启动子去甲基化诱导蛋白精氨酸甲基转移酶5的上调。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2025-04-10 DOI: 10.1042/bcj20180009_ret