Biochimica et biophysica acta. General subjects最新文献

No structure, no problem: Protein stabilization by Hero proteins and other chaperone-like IDPs.

IF 2.8 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2025-03-02 DOI: 10.1016/j.bbagen.2025.130786

Andy Y W Lam, Yukihide Tomari, Kotaro Tsuboyama

In order for a protein to function, it must fold into its proper three-dimensional structure. Otherwise, improperly folded proteins are typically prone to aggregate through a process that is detrimental to cellular health. It is widely known that a diverse group of proteins, called molecular chaperones, function to promote proper folding of other proteins and prevent aggregation. In contrast, intrinsically disordered proteins (IDPs) lack substantial tertiary structures, but nonetheless serve important functional roles. In some cases, IDPs have been observed to display remarkably chaperone-like activities, where they stabilize the activities of client proteins and prevent their aggregation. While it was previously thought that chaperone-like IDPs were mainly utilized by extremophilic organisms in their survival of extreme stress, we recently showed that a group of chaperone-like IDPs, we named heat-resistant obscure (Hero) proteins, are also widespread in non-extremophile animals, including humans and flies. Thus, we should consider the possibility that IDPs serve significant chaperone-like functions in protein stabilization relevant to physiological conditions. However, as most of our understanding of how chaperones function is based on insights from their structured domains, it is unclear how chaperone-like IDPs elicit chaperone-like effects without these structures. Here we summarize our understanding of Hero proteins to date, and based on experimental evidence, outline the features that are likely important for their protein stabilizing activities. We draw on concepts from the studies of chaperones and chaperone-like IDPs, in order to draft potential models of how chaperone-like IDPs achieve chaperone-like effects in the absence of well-defined structures.

{"title":"No structure, no problem: Protein stabilization by Hero proteins and other chaperone-like IDPs.","authors":"Andy Y W Lam, Yukihide Tomari, Kotaro Tsuboyama","doi":"10.1016/j.bbagen.2025.130786","DOIUrl":"https://doi.org/10.1016/j.bbagen.2025.130786","url":null,"abstract":"<p><p>In order for a protein to function, it must fold into its proper three-dimensional structure. Otherwise, improperly folded proteins are typically prone to aggregate through a process that is detrimental to cellular health. It is widely known that a diverse group of proteins, called molecular chaperones, function to promote proper folding of other proteins and prevent aggregation. In contrast, intrinsically disordered proteins (IDPs) lack substantial tertiary structures, but nonetheless serve important functional roles. In some cases, IDPs have been observed to display remarkably chaperone-like activities, where they stabilize the activities of client proteins and prevent their aggregation. While it was previously thought that chaperone-like IDPs were mainly utilized by extremophilic organisms in their survival of extreme stress, we recently showed that a group of chaperone-like IDPs, we named heat-resistant obscure (Hero) proteins, are also widespread in non-extremophile animals, including humans and flies. Thus, we should consider the possibility that IDPs serve significant chaperone-like functions in protein stabilization relevant to physiological conditions. However, as most of our understanding of how chaperones function is based on insights from their structured domains, it is unclear how chaperone-like IDPs elicit chaperone-like effects without these structures. Here we summarize our understanding of Hero proteins to date, and based on experimental evidence, outline the features that are likely important for their protein stabilizing activities. We draw on concepts from the studies of chaperones and chaperone-like IDPs, in order to draft potential models of how chaperone-like IDPs achieve chaperone-like effects in the absence of well-defined structures.</p>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":" ","pages":"130786"},"PeriodicalIF":2.8,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555735","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

“Mannose glycans as key players in trained immunity: A novel anti-tumoral catalyst”

IF 2.8 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2025-02-21 DOI: 10.1016/j.bbagen.2025.130779

Pedro Almeida , Inês Alves , Ângela Fernandes , Cláudia Lima , Rui Freitas , Isaac Braga , Jorge Correia , Carmen Jerónimo , Salomé S. Pinho

Cell wall glycans isolated from microorganisms are long known to provoke strong immune responses piloted by innate immune cell populations, including monocytes, in the context of Trained Immunity (TI). However, the contribution of yeast-derived mannan in the reprogramming of monocytes remains ill-defined. Here, we demonstrated that TI is often accompanied by an altered gene expression profile of selected glycan-binding proteins expressed by monocytes, including DC-SIGN and Dectin-2. Additionally, we showed that mannan, a mannose rich glycan, can trigger an enhanced immune phenotype compatible with TI in healthy monocytes, with glycan-primed cells exhibiting enhanced pro-inflammatory cytokine secretion (TNFα and IL-6) and higher activation (CD86) levels. Furthermore, the glycan-mediated priming of monocytes also imposed alterations to the expression of certain Glycan-Binding Proteins, such as DC-SIGN. Importantly, we established that these mannan-trained immune cells displayed an improved capacity to kill tumor cells in vitro. Lastly, we confirmed that monocytes from non-muscle invasive bladder cancer patients treated with BCG instillations presented a TI phenotype, as was revealed by the higher cytokine production and activation. Altogether, this study lays the foundations for exploiting the immunological potential of glycan-derived pathogens in reprogramming innate immune cells towards an effective anti-tumor immune response.

{"title":"“Mannose glycans as key players in trained immunity: A novel anti-tumoral catalyst”","authors":"Pedro Almeida , Inês Alves , Ângela Fernandes , Cláudia Lima , Rui Freitas , Isaac Braga , Jorge Correia , Carmen Jerónimo , Salomé S. Pinho","doi":"10.1016/j.bbagen.2025.130779","DOIUrl":"10.1016/j.bbagen.2025.130779","url":null,"abstract":"<div><div>Cell wall glycans isolated from microorganisms are long known to provoke strong immune responses piloted by innate immune cell populations, including monocytes, in the context of Trained Immunity (TI). However, the contribution of yeast-derived mannan in the reprogramming of monocytes remains ill-defined. Here, we demonstrated that TI is often accompanied by an altered gene expression profile of selected glycan-binding proteins expressed by monocytes, including DC-SIGN and Dectin-2. Additionally, we showed that mannan, a mannose rich glycan, can trigger an enhanced immune phenotype compatible with TI in healthy monocytes, with glycan-primed cells exhibiting enhanced pro-inflammatory cytokine secretion (TNFα and IL-6) and higher activation (CD86) levels. Furthermore, the glycan-mediated priming of monocytes also imposed alterations to the expression of certain Glycan-Binding Proteins, such as DC-SIGN. Importantly, we established that these mannan-trained immune cells displayed an improved capacity to kill tumor cells <em>in vitro</em>. Lastly, we confirmed that monocytes from non-muscle invasive bladder cancer patients treated with BCG instillations presented a TI phenotype, as was revealed by the higher cytokine production and activation. Altogether, this study lays the foundations for exploiting the immunological potential of glycan-derived pathogens in reprogramming innate immune cells towards an effective anti-tumor immune response.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 5","pages":"Article 130779"},"PeriodicalIF":2.8,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482094","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

Inhibition of amyloid formation of prion fragment (106–128) by polyphenolic compounds

IF 2.8 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2025-02-21 DOI: 10.1016/j.bbagen.2025.130778

Deepika Regmi, Seymour Haque, Md Raza Ul Karim, Aleksander Stanic, Deguo Du

Prion diseases are characterized by the self-association and amyloid formation of misfolded prion proteins. Developing effective inhibitors of protein aggregation is critical for therapeutic intervention. In this study, we systematically evaluated a range of polyphenolic compounds as potential inhibitors of amyloid fibril formation of PrP(106–128), a prion fragment crucially involved in prion aggregation and propagation. Our findings demonstrate that the basic aromatic backbone structure of flavone alone is insufficient to inhibit PrP(106–128) amyloid formation. Remarkably, flavone molecules containing adjacent hydroxyl groups on the phenolic B or A ring efficiently inhibited PrP(106–128) fibrillization, whereas compounds lacking vicinal hydroxyl groups were less effective in inhibiting amyloid formation. Epigallocatechin-3-gallate (EGCG) was one of the most potent inhibitors found in this study, with the gallate moiety playing an active role in the inhibitory function. Our findings indicate a structure-dependent inhibition activity of the phenolic small molecules, where the number and positioning of hydroxyl groups on the phenyl ring play a pivotal role in inhibiting the aggregation of the peptide. The auto-oxidation of the catechol or pyrogallol moieties to form quinone structures, followed by their reaction with amino acid side chains of the peptide to form covalent adducts, likely account for the inhibitory activity of these phenolic compounds on PrP(106–128) amyloidogenesis. These results will help the design of novel polyphenolic molecules with optimized structural features as potent inhibitors of amyloid formation of both PrP(106–128) and the full-length prion proteins.

{"title":"Inhibition of amyloid formation of prion fragment (106–128) by polyphenolic compounds","authors":"Deepika Regmi, Seymour Haque, Md Raza Ul Karim, Aleksander Stanic, Deguo Du","doi":"10.1016/j.bbagen.2025.130778","DOIUrl":"10.1016/j.bbagen.2025.130778","url":null,"abstract":"<div><div>Prion diseases are characterized by the self-association and amyloid formation of misfolded prion proteins. Developing effective inhibitors of protein aggregation is critical for therapeutic intervention. In this study, we systematically evaluated a range of polyphenolic compounds as potential inhibitors of amyloid fibril formation of PrP(106–128), a prion fragment crucially involved in prion aggregation and propagation. Our findings demonstrate that the basic aromatic backbone structure of flavone alone is insufficient to inhibit PrP(106–128) amyloid formation. Remarkably, flavone molecules containing adjacent hydroxyl groups on the phenolic B or A ring efficiently inhibited PrP(106–128) fibrillization, whereas compounds lacking vicinal hydroxyl groups were less effective in inhibiting amyloid formation. Epigallocatechin-3-gallate (EGCG) was one of the most potent inhibitors found in this study, with the gallate moiety playing an active role in the inhibitory function. Our findings indicate a structure-dependent inhibition activity of the phenolic small molecules, where the number and positioning of hydroxyl groups on the phenyl ring play a pivotal role in inhibiting the aggregation of the peptide. The auto-oxidation of the catechol or pyrogallol moieties to form quinone structures, followed by their reaction with amino acid side chains of the peptide to form covalent adducts, likely account for the inhibitory activity of these phenolic compounds on PrP(106–128) amyloidogenesis. These results will help the design of novel polyphenolic molecules with optimized structural features as potent inhibitors of amyloid formation of both PrP(106–128) and the full-length prion proteins.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 5","pages":"Article 130778"},"PeriodicalIF":2.8,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482115","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

Rod and spherical selenium nanoparticles: Physicochemical properties and effects on red blood cells and neutrophils

IF 2.8 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2025-02-19 DOI: 10.1016/j.bbagen.2025.130777

Irina V. Gorudko , Daria V. Grigorieva , Grigory A. Gusakov , Lyudmila V. Baran , Veronika E. Reut , Ekaterina V. Sak , Ilya V. Baimler , Alexander V. Simakin , Alexey S. Dorokhov , Andrey Yu. Izmailov , Dmitriy A. Serov , Sergey V. Gudkov

The influence of selenium (Se) nanoparticles in the form of rods (SeNrs) and spheres (SeSps), synthesized by laser ablation, on the structural and functional properties of human blood erythrocytes and neutrophils was studied for anticancer activity in vitro. SeNrs and SeSps do not have cytotoxicity towards neutrophils and do not cause hemolysis. The elastic modulus and resistance of erythrocytes to HOCl-induced hemolysis increased after binding of Se nanoparticles to the plasma membrane. The interaction of Se nanoparticles with neutrophils is accompanied by their actin-dependent macropinocytosis, triggering intracellular signaling processes leading to the assembly and activation of NADPH oxidase. Comparative analysis of the effects of SeNrs and SeSps on cells showed that they have similar effects. This may be due to the fact that SeNrs interact with the cell surface with their end faces, and, therefore, have the same initial contact with the plasma membrane as SeSps. However, SeSps and SeNrs showed chronic cytotoxicity after 48 h incubation, indicating the need to find ways to reduce their toxicity further. Further use of Se nanoparticles in anisotropic form in biomedical research for the development of therapeutic agents seems promising.

{"title":"Rod and spherical selenium nanoparticles: Physicochemical properties and effects on red blood cells and neutrophils","authors":"Irina V. Gorudko , Daria V. Grigorieva , Grigory A. Gusakov , Lyudmila V. Baran , Veronika E. Reut , Ekaterina V. Sak , Ilya V. Baimler , Alexander V. Simakin , Alexey S. Dorokhov , Andrey Yu. Izmailov , Dmitriy A. Serov , Sergey V. Gudkov","doi":"10.1016/j.bbagen.2025.130777","DOIUrl":"10.1016/j.bbagen.2025.130777","url":null,"abstract":"<div><div>The influence of selenium (Se) nanoparticles in the form of rods (SeNrs) and spheres (SeSps), synthesized by laser ablation, on the structural and functional properties of human blood erythrocytes and neutrophils was studied for anticancer activity <em>in vitro</em>. SeNrs and SeSps do not have cytotoxicity towards neutrophils and do not cause hemolysis. The elastic modulus and resistance of erythrocytes to HOCl-induced hemolysis increased after binding of Se nanoparticles to the plasma membrane. The interaction of Se nanoparticles with neutrophils is accompanied by their actin-dependent macropinocytosis, triggering intracellular signaling processes leading to the assembly and activation of NADPH oxidase. Comparative analysis of the effects of SeNrs and SeSps on cells showed that they have similar effects. This may be due to the fact that SeNrs interact with the cell surface with their end faces, and, therefore, have the same initial contact with the plasma membrane as SeSps. However, SeSps and SeNrs showed chronic cytotoxicity after 48 h incubation, indicating the need to find ways to reduce their toxicity further. Further use of Se nanoparticles in anisotropic form in biomedical research for the development of therapeutic agents seems promising.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 5","pages":"Article 130777"},"PeriodicalIF":2.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463832","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

Study on the activity of targeted delivery of DOX against melanoma by exosome-like nanovesicles of Rhodiola rosea

IF 2.8 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2025-02-17 DOI: 10.1016/j.bbagen.2025.130776

Moxun Xu , Meitao Duan , Ming Chen , Ahmed Mahal , Lin Yang , Chen Meng , Zhiqiang Zhang , Jungang Ren , Ahmad J. Obaidullah , Shuxian Li , Chen Wang

Melanoma is the main cause of death from skin cancer. The current treatment methods have prominent toxic side effects. In order to more effectively inhibit melanoma and reduce the toxic side effects during treatment, this paper constructs an engineering system using DSPE-PEG2000-pYEEIE(pYEEIE) molecules to modify exosome-like nanovesicles vesicles of Rhodiola rosea (RELNs) and load Doxorubicin (DOX). As a drug system, the aim is to achieve better targeting activity of the system towards melanoma cell A375. The results showed that the morphology and particle size of the prepared RELNs met the defined criteria for evaluating extracellular vesicles. The pYEEIE-RELNs-DOX drug delivery system has a better inhibitory effect on cell proliferation compared to DOX and RELNs-DOX. At the same time, the pYEEIE-RELN-DOX drug delivery system also showed better targeting towards tumor cells. In summary, this study proposes for the first time RELNs as a new generation of drug delivery carriers and uses them for drug delivery and inhibition of melanoma cell toxicity. This lays the foundation for subsequent animal and clinical experiments, and provides new ideas for the treatment of skin cancer caused by melanoma.

{"title":"Study on the activity of targeted delivery of DOX against melanoma by exosome-like nanovesicles of Rhodiola rosea","authors":"Moxun Xu , Meitao Duan , Ming Chen , Ahmed Mahal , Lin Yang , Chen Meng , Zhiqiang Zhang , Jungang Ren , Ahmad J. Obaidullah , Shuxian Li , Chen Wang","doi":"10.1016/j.bbagen.2025.130776","DOIUrl":"10.1016/j.bbagen.2025.130776","url":null,"abstract":"<div><div>Melanoma is the main cause of death from skin cancer. The current treatment methods have prominent toxic side effects. In order to more effectively inhibit melanoma and reduce the toxic side effects during treatment, this paper constructs an engineering system using DSPE-PEG2000-pYEEIE(pYEEIE) molecules to modify exosome-like nanovesicles vesicles of <em>Rhodiola rosea</em> (RELNs) and load Doxorubicin (DOX). As a drug system, the aim is to achieve better targeting activity of the system towards melanoma cell A375. The results showed that the morphology and particle size of the prepared RELNs met the defined criteria for evaluating extracellular vesicles. The pYEEIE-RELNs-DOX drug delivery system has a better inhibitory effect on cell proliferation compared to DOX and RELNs-DOX. At the same time, the pYEEIE-RELN-DOX drug delivery system also showed better targeting towards tumor cells. In summary, this study proposes for the first time RELNs as a new generation of drug delivery carriers and uses them for drug delivery and inhibition of melanoma cell toxicity. This lays the foundation for subsequent animal and clinical experiments, and provides new ideas for the treatment of skin cancer caused by melanoma.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 5","pages":"Article 130776"},"PeriodicalIF":2.8,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456772","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

MicroRNA-6069 ASO inhibits the growth of hepatocellular carcinoma by PLEKHO1

IF 2.8 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2025-02-15 DOI: 10.1016/j.bbagen.2025.130774

Yan Jiang , Juan Tan , Shan Liao , Xinrong Liu , Wentao Yu , Zhen Zhang , Yang Liu

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. And due to the low early diagnostic rate of liver cancer, many patients miss the optimal time for surgical resection, so it is necessitate to identificate the novel therapeutic targets. This study investigates the role of microRNA-6069 (miR-6069) in HCC pathogenesis. We analyzed miR-6069 expression in the TCGA-LIHC cohort, revealing significant upregulation in tumor tissues compared to adjacent normal tissues, and verified it in human tissues. MiR-6069 antisense oligonucleotide(ASO) effectively inhibits HCC cell proliferation in vitro and suppresses subcutaneous HCC tumor growth in nude mice without affecting their weight. Through bioinformatics analysis and immunohistochemistry, we identified PLEKHO1 as a target of miR-6069, and its expression is negatively correlated with miR-6069 expression. Furthermore, using immunohistochemical staining, quantitative PCR (QT-PCR), and Western blot (WB) analysis, we observed that the expression of PLEKHO1 significantly increased in the tumors of nude mice following miR-6069 ASO intervention, and affecting the expression of downstream molecules in the AKT/PI3K signaling pathway. These findings suggest that miR-6069 may influence HCC proliferation by modulating the AKT/PI3K signaling pathway.These findings highlight miR-6069 as a promising therapeutic target in HCC management.

{"title":"MicroRNA-6069 ASO inhibits the growth of hepatocellular carcinoma by PLEKHO1","authors":"Yan Jiang , Juan Tan , Shan Liao , Xinrong Liu , Wentao Yu , Zhen Zhang , Yang Liu","doi":"10.1016/j.bbagen.2025.130774","DOIUrl":"10.1016/j.bbagen.2025.130774","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. And due to the low early diagnostic rate of liver cancer, many patients miss the optimal time for surgical resection, so it is necessitate to identificate the novel therapeutic targets. This study investigates the role of microRNA-6069 (miR-6069) in HCC pathogenesis. We analyzed miR-6069 expression in the TCGA-LIHC cohort, revealing significant upregulation in tumor tissues compared to adjacent normal tissues, and verified it in human tissues. MiR-6069 antisense oligonucleotide(ASO) effectively inhibits HCC cell proliferation in vitro and suppresses subcutaneous HCC tumor growth in nude mice without affecting their weight. Through bioinformatics analysis and immunohistochemistry, we identified PLEKHO1 as a target of miR-6069, and its expression is negatively correlated with miR-6069 expression. Furthermore, using immunohistochemical staining, quantitative PCR (QT-PCR), and Western blot (WB) analysis, we observed that the expression of PLEKHO1 significantly increased in the tumors of nude mice following miR-6069 ASO intervention, and affecting the expression of downstream molecules in the AKT/PI3K signaling pathway. These findings suggest that miR-6069 may influence HCC proliferation by modulating the AKT/PI3K signaling pathway.These findings highlight miR-6069 as a promising therapeutic target in HCC management.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 4","pages":"Article 130774"},"PeriodicalIF":2.8,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143428009","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

Change in selectivity of estrogen receptor alpha ligand-binding domain by mutations at residues H524/L525

IF 2.8 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2025-02-14 DOI: 10.1016/j.bbagen.2025.130775

Emma L. Arévalo-Salina , Takuya Nishigaki , Leticia Olvera , Martin González-Andrade , Wendy Xolalpa-Villanueva , Edith O. López-Romero , Xavier Soberón , Gloria Saab-Rincón

The estrogen receptor alpha (ERα) features a large ligand-binding pocket capable of accommodating a variety of conformationally diverse molecules, each eliciting unique cellular responses. This structural plasticity facilitates various conformational changes, exposing different interaction surfaces for cellular proteins, triggering a myriad of biological outcomes. Alterations in the ligand-binding domain, particularly through amino acid substitutions, can modify the recognition and selectivity of ERα for agonists versus antagonists. In our study, we engineered a small library of ERα variants by modifying residues 524 and 525. These modifications resulted in variants with up to seventy-fold increased selectivity for the antagonist endoxifen and up to fifty-fold increased selectivity for the antagonist 4-hydroxytamoxifen (4-OHT) over the natural ligand estradiol. Analyzing these variants elucidates the critical roles of residues 524 and 525 in determining agonist specificity for estradiol. This advancement holds significant potential for developing selective recognition molecules, a crucial step towards creating a biosensor for endoxifen, the active metabolite used in breast cancer treatment.

{"title":"Change in selectivity of estrogen receptor alpha ligand-binding domain by mutations at residues H524/L525","authors":"Emma L. Arévalo-Salina , Takuya Nishigaki , Leticia Olvera , Martin González-Andrade , Wendy Xolalpa-Villanueva , Edith O. López-Romero , Xavier Soberón , Gloria Saab-Rincón","doi":"10.1016/j.bbagen.2025.130775","DOIUrl":"10.1016/j.bbagen.2025.130775","url":null,"abstract":"<div><div>The estrogen receptor alpha (ERα) features a large ligand-binding pocket capable of accommodating a variety of conformationally diverse molecules, each eliciting unique cellular responses. This structural plasticity facilitates various conformational changes, exposing different interaction surfaces for cellular proteins, triggering a myriad of biological outcomes. Alterations in the ligand-binding domain, particularly through amino acid substitutions, can modify the recognition and selectivity of ERα for agonists versus antagonists. In our study, we engineered a small library of ERα variants by modifying residues 524 and 525. These modifications resulted in variants with up to seventy-fold increased selectivity for the antagonist endoxifen and up to fifty-fold increased selectivity for the antagonist 4-hydroxytamoxifen (4-OHT) over the natural ligand estradiol. Analyzing these variants elucidates the critical roles of residues 524 and 525 in determining agonist specificity for estradiol. This advancement holds significant potential for developing selective recognition molecules, a crucial step towards creating a biosensor for endoxifen, the active metabolite used in breast cancer treatment.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 4","pages":"Article 130775"},"PeriodicalIF":2.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143428008","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 roles of intrinsically disordered proteins in neurodegeneration

IF 2.8 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2025-02-13 DOI: 10.1016/j.bbagen.2025.130772

Kagistia Hana Utami , Satoru Morimoto , Yasue Mitsukura , Hideyuki Okano

Neurodegenerative diseases such as Amyotrophic Lateral Sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease share a common pathological hallmark: the accumulation of misfolded proteins, particularly involving intrinsically disordered proteins (IDPs) like TDP-43, FUS, Tau, α-synuclein, and Huntingtin. These proteins undergo pathological aggregation, forming toxic inclusions that disrupt cellular function. The dysregulation of proteostasis mechanisms, including the ubiquitin-proteasome system (UPS), ubiquitin-independent proteasome system (UIPS), autophagy, and molecular chaperones, exacerbates these proteinopathies by failing to clear misfolded proteins effectively. Emerging therapeutic strategies aim to restore proteostasis through proteasome activators, autophagy enhancers, and chaperone-based interventions to prevent the toxic accumulation of IDPs. Additionally, understanding liquid-liquid phase separation (LLPS) and its role in stress granule dynamics offers novel insights into how aberrant phase transitions contribute to neurodegeneration. By targeting the molecular pathways involved in IDP aggregation and proteostasis regulation, and better understanding the specificity of each component, research in this area will pave the way for innovative therapeutic approaches to combat these neurodegenerative diseases. This review discusses the molecular mechanisms underpinning IDP pathology, highlights recent advancements in drug discovery, and explores the potential of targeting proteostasis machinery to develop effective therapies.

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引用次数: 0

Entanglement of vimentin shapes the microrheological response of suspended-like melanoma WM35 cells to oscillatory strains induced by different AFM probe geometries

IF 2.8 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2025-02-13 DOI: 10.1016/j.bbagen.2025.130773

Joanna Zemła , Joanna Pabijan , Florian Kumpfe , Marcin Luty , Renata Szydlak , Ingrid H. Øvreeide , Victorien E. Prot , Bjørn T. Stokke , Małgorzata Lekka

Normal and pathological states of cells can be distinguished by their mechanical properties, which are thought to be determined by the organization of the actin network. In the body, cells exist in both adherent and non-adherent (suspended) states, and studies of the rheological properties of spread and suspended cells are needed to gain more insight into their response to strain. Herein, we show that WM35 melanoma cells in adherent and non-adherent states respond differently to oscillatory strain. We used an atomic force microscopy (AFM)-based microrheological approach to study the elasticity and fluidity of the cells, quantified by the storage (G') and loss (G") moduli and the transition frequency f_T (G' = G”). Our results show that spread cells are stiffer than the suspended-like cells (plateau shear modulus of 3.51 ± 0.43 kPa vs 2.67 ± 0.34 kPa). We also found, from measurements made with a conical probe, that suspended-like cells are more tolerant to imposed strains. Combining AFM results and fluorescence microscopy of the cytoskeleton, we conclude that the organization and distribution of actin and vimentin within the cell body strongly influence the rheological properties of spread and suspended-like WM35 cells. The data also suggest that phosphorylated vimentin is predominant in suspended-like cells, whereas in spread cells, vimentin intermittent filaments (VIFs) form an assembled network that contributes to higher G'. The entanglement of the disassembled VIFs in suspended-like WM35 cell influences the rheological properties of such cells.

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引用次数: 0

Analysis of lipids by Raman spectroscopy and mass spectrometry provides a detection tool and mechanistic insight into imatinib resistance in CML-BC

IF 2.8 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2025-02-10 DOI: 10.1016/j.bbagen.2025.130771

Manish Bhat , Panchali Saha , Mythreyi Narasimhan , Ashutosh Shelar , Arti Hole , C. Murali Krishna , Rukmini Govekar

Resistance to tyrosine kinase inhibitors (TKIs) is a major challenge in the treatment of chronic myeloid leukemia (CML). Established tests based on the known mechanisms of resistance in the initial chronic phase (CP) confirm resistance, reveal the underlying reason and thereby direct treatment modifications. In the terminal phase of blast crisis (BC), however, additional partially identified mechanisms of resistance exist which necessitates developing modalities to detect resistance regardless of the underlying mechanism and concurrent exploration of the resistance mechanism to assist in identification of appropriate drug targets. In this study both the clinical objectives were achieved by analysing lipids in BC cells, sensitive and resistant to TKIs, using the complementary strengths of distinct analytical technologies.

Raman spectroscopy, through the spectral signatures with lipids as a significant differentiating component could segregate resistant from sensitive cells in the Principal Component Analysis (PCA) and Principal Component based Linear Discriminant Analysis (PC-LDA). This provided a tool to rapidly detect resistance in CML-BC despite unclear mechanism of TKI resistance. The depth of coverage achievable by mass spectrometry allowed the generation of quantitative differential profile of individual lipids in resistant cells. The alterations were in diverse classes of lipids which are involved in cell signalling and inhibition studies could link these alterations to modulation of phospholipase A₂ (PLA₂) levels mediated by p38 mitogen activated protein kinase (p38MAPK), which is causally associated with TKI resistance in CML-BC. Together, lipid analysis using the two platforms, contributed to the detection and mechanistic understanding of imatinib resistance in CML-BC.

{"title":"Analysis of lipids by Raman spectroscopy and mass spectrometry provides a detection tool and mechanistic insight into imatinib resistance in CML-BC","authors":"Manish Bhat , Panchali Saha , Mythreyi Narasimhan , Ashutosh Shelar , Arti Hole , C. Murali Krishna , Rukmini Govekar","doi":"10.1016/j.bbagen.2025.130771","DOIUrl":"10.1016/j.bbagen.2025.130771","url":null,"abstract":"<div><div>Resistance to tyrosine kinase inhibitors (TKIs) is a major challenge in the treatment of chronic myeloid leukemia (CML). Established tests based on the known mechanisms of resistance in the initial chronic phase (CP) confirm resistance, reveal the underlying reason and thereby direct treatment modifications. In the terminal phase of blast crisis (BC), however, additional partially identified mechanisms of resistance exist which necessitates developing modalities to detect resistance regardless of the underlying mechanism and concurrent exploration of the resistance mechanism to assist in identification of appropriate drug targets. In this study both the clinical objectives were achieved by analysing lipids in BC cells, sensitive and resistant to TKIs, using the complementary strengths of distinct analytical technologies.</div><div>Raman spectroscopy, through the spectral signatures with lipids as a significant differentiating component could segregate resistant from sensitive cells in the Principal Component Analysis (PCA) and Principal Component based Linear Discriminant Analysis (PC-LDA). This provided a tool to rapidly detect resistance in CML-BC despite unclear mechanism of TKI resistance. The depth of coverage achievable by mass spectrometry allowed the generation of quantitative differential profile of individual lipids in resistant cells. The alterations were in diverse classes of lipids which are involved in cell signalling and inhibition studies could link these alterations to modulation of phospholipase A<sub>2</sub> (PLA<sub>2</sub>) levels mediated by p38 mitogen activated protein kinase (p38MAPK), which is causally associated with TKI resistance in CML-BC. Together, lipid analysis using the two platforms, contributed to the detection and mechanistic understanding of imatinib resistance in CML-BC.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 4","pages":"Article 130771"},"PeriodicalIF":2.8,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405613","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