Biochimica et biophysica acta. Proteins and proteomics最新文献

{"title":"Unravelling the phosphoregulatory network of protein kinase C-delta (PKC-δ)","authors":"Darshan Hebbal Raghu ,&nbsp;Leona Dcunha ,&nbsp;Mukhtar Ahmed ,&nbsp;Amal Fahma ,&nbsp;Althaf Mahin ,&nbsp;Athira Perunelly Gopalakrishnan ,&nbsp;Levin John ,&nbsp;Suhail Subair ,&nbsp;Prathik Basthikoppa Shivamurthy ,&nbsp;Susmi Varghese ,&nbsp;Samseera Ummar ,&nbsp;Mahammad Nisar ,&nbsp;Poornima Ramesh ,&nbsp;Inamul Hasan Madar ,&nbsp;Rajesh Raju","doi":"10.1016/j.bbapap.2025.141080","DOIUrl":"10.1016/j.bbapap.2025.141080","url":null,"abstract":"<div><div>Protein kinase C Delta (PRKCD) is a serine/threonine kinase involved in transcription regulation, cytoskeleton organization, DNA damage response, DNA repair and carcinogenesis. Several PRKCD phosphopeptides are frequently detected to be differentially regulated through mass spectrometry-based phosphoproteomics analysis. Here, we utilize publicly available phosphoproteomics data to decipher phosphoregulatory networks associated with PRKCD. Among 315 phosphoproteomics datasets demonstrating the differential regulation of phosphopeptides of PRKCD, the phosphosites S304, Y313, S645, S299, S302, S664, Y334, Y374, T295 and T507 predominantly represent PRKCD hyperphosphorylation in over 83 % of cases. Further, through co-differential regulation analysis of the predominant sites and associated phosphosites on other proteins, we propose that the autophosphorylation sites S302 and S304 are critically associated with the kinase activity of PRKCD and play a crucial role in modulating its downstream signaling pathways. Compared to known activation sites of PRKCD including Y313, Y334 and Y374, the sites S302 and S304 coregulated the most with the experimentally validated and predicted substrates. Besides that, phosphosites Y313, Y334 and Y374 are associated with stress signaling and cancer progression. Current study focuses on critical kinase-activation associated with phosphosites in kinases. This study highlights the sites S302 and S304 as activation sites and as key players in various cellular processes including cell cycle regulation, motility, adhesion and migration. Our approach and the stringent criteria adopted sets a robust platform to analyze differentially regulated phosphoproteome data in diverse biological contexts to interpret the predominant phosphosites, their co-regulation and the overall biological relevance of such regulation in pathophysiological processes.</div></div>","PeriodicalId":8760,"journal":{"name":"Biochimica et biophysica acta. Proteins and proteomics","volume":"1873 5","pages":"Article 141080"},"PeriodicalIF":2.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144212244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elucidation of multifunctionality and substrate specificity of human aspartate aminotransferases.","authors":"Tetsuya Miyamoto, Haruna Kito, Karen Sato, Toshihiko Sugiki, Kumiko Sakai-Kato","doi":"10.1016/j.bbapap.2025.141081","DOIUrl":"https://doi.org/10.1016/j.bbapap.2025.141081","url":null,"abstract":"<p><p>d-Serine and d-aspartate play crucial physiological roles in mammals. d-Serine is produced by serine racemase, but the biosynthetic pathway of d-aspartate remains unclear. In this study, we investigated the substrate specificity and multifunctionality of human aspartate aminotransferases (hGOT1 and hGOT2) to reveal whether they possess D-amino acid metabolic activity. Neither enzyme displayed racemase activity toward various amino acids including aspartate, although slight alanine racemase activity was detected. Likewise, neither exhibited lyase, dehydratase, or aspartate decarboxylase activities. Regarding aminotransferase activity, both displayed high activity toward l-aspartate and L-glutamate as amino donors, and they acted on some L-amino acids, but not D-amino acids. Intriguingly, we found that aminotransferase activity for oxaloacetate followed sigmoidal kinetics rather than typical Michaelis-Menten kinetics. Thermal shift assay experiments suggested that pyridoxal-5'-phosphate and oxaloacetate are involved in protein stability and the ability to bind oxaloacetate is different from hGOT1 and hGOT2. In summary, hGOTs accept some amino donors and acceptors and unique capacity to bind oxaloacetate.</p>","PeriodicalId":8760,"journal":{"name":"Biochimica et biophysica acta. Proteins and proteomics","volume":" ","pages":"141081"},"PeriodicalIF":2.5,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computing pathogenicity of mutations in human cytochrome P450 superfamily","authors":"Somnath Mondal ,&nbsp;Pranchal Shrivastava ,&nbsp;Rukmankesh Mehra","doi":"10.1016/j.bbapap.2025.141078","DOIUrl":"10.1016/j.bbapap.2025.141078","url":null,"abstract":"<div><div>Cytochrome P450 (CYPs) are crucial heme-containing enzymes that metabolize drugs and endogenous compounds. In humans, 57 CYP isoforms have been identified, with over 200 mutations linked to severe disorders. Our comprehensive computational study assessed the reason for the pathogenicity of mutations by comparing pathogenic and non-pathogenic variants. We analyzed 25,94,151 mutations across 26 CYP structures using structure- and sequence-based methods, revealing a meaningful stability pattern: non-pathogenic &gt; all &gt; pathogenic mutation datasets. Notably, pathogenic mutations were predominantly buried within CYP structures, indicating a higher potential for pathogenesis. We identified three key amino acid properties affected by mutations: Gibbs free energy, isoelectric point, and volume. Furthermore, diseased mutations significantly reduced positive residue content, particularly due to arginine mutations, which directly influenced the isoelectric point. Our findings indicate a greater likelihood of pathogenic mutations occurring at conserved sites, disrupting CYP function. A higher frequency of pathogenic mutations was observed in heme sites, primarily involving arginine, which may interfere with arginine-heme interactions. Molecular docking revealed a differential binding of heme in wild-type and pathogenic CYPs. This study provides a foundational analysis of mutation effects across multiple CYPs. It models the chemical basis of CYP-related pathogenicity, facilitating the development of a semi-quantitative disease prediction model.</div></div>","PeriodicalId":8760,"journal":{"name":"Biochimica et biophysica acta. Proteins and proteomics","volume":"1873 4","pages":"Article 141078"},"PeriodicalIF":2.5,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143941555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Parishin C modulates the amyloid transformation of alpha-synuclein protein by apparently interacting with the NAC domain","authors":"Almas Akhtar,&nbsp;Payal Singh,&nbsp;Nikita Admane,&nbsp;Abhinav Grover","doi":"10.1016/j.bbapap.2025.141076","DOIUrl":"10.1016/j.bbapap.2025.141076","url":null,"abstract":"<div><div>Parkinson's disease (PD) is a neurodegenerative disorder marked by the gradual deterioration of dopaminergic neurons in the brain and the presence of Lewy bodies (LB) within the remaining affected neurons, comprised of α-synuclein protein aggregates. Herein, we report a novel amyloid inhibitory potential of Parishin C on the amyloid transformation of the α-synuclein protein. Our studies involving computational screening and REMD simulation analysis revealed a strong interaction between Parishin C and the non-amyloid component (NAC domain), a known aggregation-prone region of the α-synuclein protein. Thioflavin T fluorescence assay demonstrated the inhibitory effect of Parishin C on amyloid transformation kinetics of α-synuclein, where even at the lowest concentration of Parishin C there was a 72 % reduction in the ThT maxima. ANS binding assay further revealed its ability to alter the surface hydrophobicity of the protein. An extensive evaluation using biophysical techniques indicated that Parishin C effectively prevented the formation of mature fibrillar species and promoted the formation of lower order aggregates with reduced cross-β-sheet signatures compared to the native α-synuclein aggregates. Collectively, our research highlights Parishin C's potential as a structural blueprint for developing new therapeutic compounds aimed at preventing the amyloidogenic transition in Parkinson's disease and related disorders.</div></div>","PeriodicalId":8760,"journal":{"name":"Biochimica et biophysica acta. Proteins and proteomics","volume":"1873 4","pages":"Article 141076"},"PeriodicalIF":2.5,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143932045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evolution of Chlorella sp. RCC288 proteome and transcriptome during its adaptation to oil mill wastewater","authors":"Bouthaina Menaa ,&nbsp;Rihab Hachicha ,&nbsp;Pascal Dubessay ,&nbsp;Slim Abdelkafi ,&nbsp;Imen Fendri ,&nbsp;Philippe Michaud","doi":"10.1016/j.bbapap.2025.141077","DOIUrl":"10.1016/j.bbapap.2025.141077","url":null,"abstract":"<div><div>Some species of microalgae, including <em>Chlorella</em>, can utilize a variety of dissolved organic carbon sources, such as sugars and organic acids, for growth. In the presence of both light and these organic substrates, they exhibit mixotrophic metabolism, combining heterotrophic assimilation of organic carbon with photosynthetic carbon fixation. In this study, we analyzed using proteomic and transcriptomic approaches the ability of <em>Chlorella</em> sp. to shift its metabolism when it was grown in photoautotrophy in BG-11 medium and mixotrophy in 30 % diluted olive mill wastewaters (OMWWs) pretreated with laccases. Using UniProt, InterPro, KEGG Pathway, and Gene Ontology databasesproteomic and transcriptomic data have been analyzed. In mixotrophy, over-expression of cell cycle, signaling, and transport proteins, as well as chaperone proteins, were identified and associated with an overall decrease in photosynthesis and carbohydrate/lipid metabolic pathways. In addition, the expression of light-independent protochlorophyllide reductase, malate synthase, acetyl-CoA carboxylase and pyruvate kinase were modulated. Surprisingly an upregulation of the ammonium transporter protein, which could play a role in OMWWs detoxification was detected. Homology modeling investigation of the three-dimensional structure of ammonium transporter protein revealed that it holds a functional trimeric structure with a lengthy C-terminal region that may be involved in the regulation and activation of ammonium transport.</div></div>","PeriodicalId":8760,"journal":{"name":"Biochimica et biophysica acta. Proteins and proteomics","volume":"1873 4","pages":"Article 141077"},"PeriodicalIF":2.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143941554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biophysical analysis of SECIS binding protein 2 (SBP2) from Naegleria gruberi","authors":"Jéssica Fernandes Scortecci ,&nbsp;Adriano de Freitas Fernandes ,&nbsp;Vitor Hugo Balasco Serrão ,&nbsp;Marinônio Lopes Cornélio ,&nbsp;Mario de Oliveira Neto ,&nbsp;Otavio Henrique Thiemann","doi":"10.1016/j.bbapap.2025.141075","DOIUrl":"10.1016/j.bbapap.2025.141075","url":null,"abstract":"<div><div>The Selenocysteine (Sec - U) biosynthesis pathway is present in eukaryotes and prokaryotes, in which its incorporation is directed by the stop codon UGA and the structural mRNA element named Sec Insertion Sequence (SECIS) that contain an essential kink-turn motif recognized by specific RNA-binding proteins. SBP2 is the key player in the interaction with the SECIS element in eukaryotes, and it is essential for the biosynthesis pathway. Free-living amoebas are part of the Heterolobosea phylum, and several species, including <em>Naegleria fowleri</em>, are known human pathogens. In 2013 it was reported that <em>Naegleria gruberi</em> (<em>Ng</em>SBP2), which is non-pathogenic, had a divergent SBP2 sequence and all the genes essential for Sec synthesis. The identity of <em>Ng</em>SBP2 is confirmed experimentally and its binding affinity to the SECIS element is demonstrated. The N-terminal and the C-terminal domains (<em>Ng</em>SBP2-NT and <em>Ng</em>SBP2-CT, respectively) of <em>Ng</em>SBP2 contain disordered regions, particularly in the N-terminal domain. The SECIS element is bonded to NgSBP2-CT, which results in a decrease in the disordered sequence of the domain, and the NgSBP2-NT domain interacts with NgSBP2-CT.SECIS complex, as we present here. The findings reveal the molecular interaction patterns underlying the selenocysteine incorporation pathway in an early-branching eukaryote, which is influenced by multiple protein-RNA interactions.</div></div>","PeriodicalId":8760,"journal":{"name":"Biochimica et biophysica acta. Proteins and proteomics","volume":"1873 4","pages":"Article 141075"},"PeriodicalIF":2.5,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143898770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural-functional relevance of DNAJBs in protein aggregation and associated neurodegenerative diseases","authors":"Siraj Fatima ,&nbsp;Priyanka Pandey ,&nbsp;Sandeep K. Sharma ,&nbsp;Smriti Priya","doi":"10.1016/j.bbapap.2025.141074","DOIUrl":"10.1016/j.bbapap.2025.141074","url":null,"abstract":"<div><div>DNAJ proteins, also known as HSP40s, are co-chaperones that regulate the multifunctionality of HSP70s in maintaining cellular protein homeostasis. The heterogeneous family of DNAJ co-chaperones is classified into three classes (A, B and C), where structural diversity within the class defines their specific functions. Among three classes, the DNAJB class of co-chaperones are associated with cellular compartment-specific protein folding, disaggregation and degradation of proteins and enables effective targeting of a broad spectrum of aggregation-prone substrate proteins. The structural divergence of DNAJBs is critical for regulating disaggregation and degradation functions through specific interactions with HSP70 and substrate proteins. While the role of DNAJBs in maintaining protein homeostasis is valuable in addressing protein aggregation in neurodegenerative diseases, a limited understanding of their mechanisms and cellular functions beyond co-chaperones restricts their therapeutic applications. In this review, the mechanism of DNAJBs regulating aggregation of pathogenic proteins such as α-synuclein, tau, amyloid-β, and huntingtin are discussed. Emphasis on the selectivity of DNAJBs towards folding, disaggregation and degradation functions of HSP70, substrate selection and involvement of different structural regions are explained to provide a structural and functional understanding of DNAJB proteins. Mutations in different DNAJBs linked with several proteins aggregation-related neuronal and neuromuscular diseases are discussed. The fundamental understanding of DNAJB diversity and functionality can assist future interventions for regulating protein homeostasis and managing associated diseases.</div></div>","PeriodicalId":8760,"journal":{"name":"Biochimica et biophysica acta. Proteins and proteomics","volume":"1873 4","pages":"Article 141074"},"PeriodicalIF":2.5,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143868449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of electrostatics in cold adaptation: A comparative study of eury- and stenopsychrophilic triose phosphate isomerase","authors":"Jan S. Nowak ,&nbsp;Sune Olesen ,&nbsp;Pengfei Tian ,&nbsp;René L. Bærentsen ,&nbsp;Ditlev E. Brodersen ,&nbsp;Daniel E. Otzen","doi":"10.1016/j.bbapap.2025.141072","DOIUrl":"10.1016/j.bbapap.2025.141072","url":null,"abstract":"<div><div>Psychrophilic (cold-active) organisms have developed enzymes that facilitate sufficient metabolic activity at low temperatures to sustain life. This occurs through molecular adaptations that tend to increase protein flexibility at the expense of stability. However, psychrophiles also vary in their growth conditions. Eurypsychrophiles thrive over a wide temperature range and often prefer temperatures above 20 °C, while stenopsychrophiles grow optimally below 15 °C and are more narrowly adapted to cold temperatures. To elucidate differences between these two classes of enzymes, we here compare the stability and unfolding kinetics of two orthologues of the basal household enzyme triose phosphate isomerase, one from the stenopsychrophilic Antarctic permafrost bacterium <em>Rhodonellum psychrophilum</em> (sTPI) and the other from the eurypsychrophilic Greenland ikaite column bacterium <em>Rhodococcus</em> sp. <em>JG-3</em> (eTPI). Remarkably, sTPI proved significantly more thermostable and resistant to chemical denaturation than its eurypsychrophilic counterpart, eTPI, in the absence of ionic components in solution, whereas inclusion of electrostatic screening agents in the form of sodium chloride or the charged denaturant guanidinium chloride largely cancelled out this difference. Thus, electrostatics play a prominent role in stabilizing the stenopsychrophilic sTPI, and a mandatory low-temperature growth environment does not preclude the development of considerable thermotolerance for individual enzymes. We were able to increase the thermostability of sTPI using an evolutionary machine learning model, which transferred several sTPI residues into the eTPI active site. While the stabilizing effect was modest, the combination of individual mutations was additive, underscoring the potential of combining multiple beneficial mutations to achieve enhanced enzyme properties.</div></div>","PeriodicalId":8760,"journal":{"name":"Biochimica et biophysica acta. Proteins and proteomics","volume":"1873 4","pages":"Article 141072"},"PeriodicalIF":2.5,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143829366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring human carboxylesterases 1 and 2 selectivity of two families of substrates at an atomistic level","authors":"Sergio R. Ribone ,&nbsp;Dario A. Estrin ,&nbsp;Mario A. Quevedo","doi":"10.1016/j.bbapap.2025.141069","DOIUrl":"10.1016/j.bbapap.2025.141069","url":null,"abstract":"<div><div>Human carboxylesterases (CES) are enzymes that play an important role in the metabolism and biotransformation of diverse substances. The two more relevant isoforms, CES1A1 and CES2A1, catalyze the hydrolysis of numerous approved drugs and prodrugs. The elucidation of CES isoform substrates specificity constitutes a very relevant medicinal chemistry issue. The general role pointed that the selectivity towards CES1A1 or CES2A1 depends on the size of the acyl and alkyl moieties present in the structure of the substrate, but several exceptions regarding substrate promiscuity towards both CES have been reported. In this work, a combination of classical molecular dynamics (MD) and hybrid quantum mechanics/molecular mechanics (QM/MM) simulations were applied with the purpose of studying the substrate selectivity of CES1A1 and CES2A1 on two sets of selected ligands: <em>p</em>-nitrophenyl ester derivatives (NPE) and pyrethroid stereoisomers (Pyr). The classical molecular modeling studies showed that the van der Waals (VDW) component of interaction, with the hydrophobic residues present on CES1A1 and CES2A1 subpocket 1 and subpocket 2, showed a significant contribution to the substrates-CES affinity properties. The hybrid QM/MM simulations exhibited that the rate-limiting step for the studied substrates reactions were related to the transition state (TS) with the higher steric hindrance molecular structure. In conclusion, it was possible to observe that the studied substrates generate the best possible interaction pattern with the residues from subpocket 1 and 2 in order to produce the corresponding affinity constant with the enzyme. Then, this interaction pattern drives the catalytic turn-over reaction through the presence or absence of a high steric hindrance center in the molecular structure of the rate-limiting reaction.</div></div>","PeriodicalId":8760,"journal":{"name":"Biochimica et biophysica acta. Proteins and proteomics","volume":"1873 4","pages":"Article 141069"},"PeriodicalIF":2.5,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143821517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Green tea polyphenol EGCG acts differentially on end-stage amyloid polymorphs of α-synuclein formed in different polyol osmolytes","authors":"Santosh Devi ,&nbsp;Dushyant K. Garg ,&nbsp;Rajiv Bhat","doi":"10.1016/j.bbapap.2025.141073","DOIUrl":"10.1016/j.bbapap.2025.141073","url":null,"abstract":"<div><div>Synucleinopathies are heterogenous group of disorders characterized by α-synuclein amyloid aggregates in the nervous system. Different synucleinopathy clinical subtypes are encoded by structurally diverse α-synuclein amyloid polymorphs referred to as ‘strains’. The underlying structural differences between polymorphs can potentially hamper the drug design against synucleinopathies. Polyphenolic compounds like EGCG have shown promise in inhibiting and remodeling of α-synuclein amyloid aggregates, but their effects on different polymorphs are not well-studied. The cellular environment is one factor contributing to the heterogeneity in the amyloid landscape. Herein, we generated diverse polymorphs of α-synuclein by fine-tuning its aggregation using different polyol osmolytes, varying in their physicochemical properties. These osmolytes act as globular protein stabilizers and conformational modulators of intrinsically disordered proteins. While the buffer control α-synuclein aggregates were evenly dispersed, the polyol-induced aggregate solutions contained a heterogeneous mixture of <em>co</em>-existing polymorphs, as evidenced by AFM and TEM measurements. The polyol-induced aggregated solutions consisted of a mixture of both fibrillar and nonfibrillar cross-β-rich species. Using various spectroscopic tools, we observed differences in the structures of osmolyte-induced polymorphic aggregates. We incubated these aggregates with EGCG and observed its disparate action over polymorphs wherein the treated species were either disintegrated or structurally altered. Contrary to previous reports, all EGCG-treated polymorphs were β-sheet-rich and seeding-competent. Our findings are relevant in assessing the efficacy of polyphenolic compounds on diverse aggregate strains encoding different proteinopathy variants. The formation of β-sheet-rich species in our study also engenders a more critical examination of EGCG's mode of action on diverse classes of amyloids.</div></div>","PeriodicalId":8760,"journal":{"name":"Biochimica et biophysica acta. Proteins and proteomics","volume":"1873 4","pages":"Article 141073"},"PeriodicalIF":2.5,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}