Biochimica et biophysica acta. Proteins and proteomics最新文献

{"title":"Crystal structure and molecular dynamics simulation of Mycobacterium tuberculosis MaoC-like dehydratase HtdX provide insights into substrate binding and membrane interactions","authors":"Rupam Biswas ,&nbsp;Gourab Bhattacharje ,&nbsp;Bina Kumari Singh ,&nbsp;Debajyoti Dutta ,&nbsp;Amit Basak ,&nbsp;Amit Kumar Das","doi":"10.1016/j.bbapap.2025.141082","DOIUrl":"10.1016/j.bbapap.2025.141082","url":null,"abstract":"<div><div>The growing challenge of drug resistance has intensified the search for new therapeutic targets against the virulent pathogen <em>Mycobacterium tuberculosis</em> (Mtb). The complex cell envelope of Mtb contains unique lipids, such as mycolic acids, which contribute to its survival under hostile conditions. While modern drugs like isoniazid inhibit mycolic acid biosynthesis through the fatty acid synthase II (FAS II) complex, alternative bypass pathways may facilitate the emergence of drug resistance. <em>HtdX</em>, a putative β-hydroxyacyl dehydratase gene conserved in the mycobacterial species, is hypothesized to play a role in these alternative fatty acid metabolism pathways. Although HtdX is expressed under nutrient-deficient conditions, its structural and functional characterization remains largely unexplored. This study presents the crystal structures of HtdX, revealing a MaoC-like dehydratase with a double hot-dog fold. Site-directed mutagenesis, enzyme kinetics, and fluorescence spectroscopy highlight the critical roles of the α2-β2 loop and the proline rich PP-loop in substrate specificity. The α2-β2 loop determines fatty acyl chain length specificity, while the PP-loop regulates the interaction between HtdX and the acyl carrier protein (AcpM). Computational predictions, complemented by molecular dynamics simulations and principal component analyses, establish that the N-terminal region of HtdX is essential for membrane binding. Overall, these findings offer insights into HtdX substrate specificity and provide theoretical understanding of its interaction with the membrane.</div></div>","PeriodicalId":8760,"journal":{"name":"Biochimica et biophysica acta. Proteins and proteomics","volume":"1873 5","pages":"Article 141082"},"PeriodicalIF":2.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144223353","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":"Glycoproteomic characterization of Neuropilin-1 reveals critical glycosylation sites for SARS-CoV-2 entry","authors":"Tuhin Das ,&nbsp;Shuhong Luo ,&nbsp;Panning Wang ,&nbsp;Jianmin Fang ,&nbsp;Asif Shajahan ,&nbsp;Lauren Peppi ,&nbsp;Sabyasachi Dash ,&nbsp;Kino Maravillas ,&nbsp;Rochelle N. Wickramasekara ,&nbsp;Parastoo Azadi ,&nbsp;Ruo-Pan Huang","doi":"10.1016/j.bbapap.2025.141089","DOIUrl":"10.1016/j.bbapap.2025.141089","url":null,"abstract":"<div><div>The binding of the SARS-CoV-2 spike (S) glycoprotein to human host receptors, including ACE2, NRP1, and AXL, is essential for viral entry. Glycosylation of both the spike protein and its host receptors can significantly influence these interactions. While NRP1 is recognized as a key host receptor, the role of its glycosylation in spike binding and viral infectivity has not been fully elucidated. In this study, we developed a spike-NRP1 binding assay using recombinant proteins in HEK293 cells and performed LC-MS-based glycoproteomic analysis to characterize NRP1 glycosylation. We identified three N-linked glycosylation sites (N150, N261, N522) and four O-linked glycosylation sites (S612, S637, T638, S641) on NRP1. Mutational analysis revealed that glycosylation at these specific sites is critical for spike binding, as single-site mutants showed significantly reduced interaction. Further characterization of terminal sialic acid linkages, bisecting GlcNAc, and fucosylation patterns provided insight into the complexity of NRP1 glycosylation. Functional assays demonstrated that loss of glycosylation impaired SARS-CoV-2 pseudovirus entry and altered IL-6 secretion, indicating a broader role in host immune modulation. These findings demonstrate that site-specific NRP1 glycosylation modulates spike binding and viral entry in a cell-based model, providing a foundation for future studies to explore the potential of targeting glycosylation-dependent mechanisms in SARS-CoV-2 infection.</div></div>","PeriodicalId":8760,"journal":{"name":"Biochimica et biophysica acta. Proteins and proteomics","volume":"1873 5","pages":"Article 141089"},"PeriodicalIF":2.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648361","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":"HDAC7 influences ER-⍺ transcription via NCoR-HDAC3 dissociation","authors":"Ishadi K.M. Kodikara,&nbsp;Valentine O. Nwanelo,&nbsp;Angela K. Belanger,&nbsp;Mary Kay H. Pflum","doi":"10.1016/j.bbapap.2025.141083","DOIUrl":"10.1016/j.bbapap.2025.141083","url":null,"abstract":"<div><div>HDAC7 (histone deacetylase 7) is involved in many diseases, including breast cancer. HDAC7 regulates gene expression epigenetically by assisting in the deacetylation of nucleosomal histones to remodel chromatin. However, HDAC7 is a pseudodeacetylase that displays weak enzymatic activity and cannot directly deacetylate histones. Instead, HDAC7 scaffolds histones to active HDAC3 (histone deacetylase 3) via NCoR (nuclear receptor corepressor) to regulate transcription. Recent evidence documented that the inactive pseudo-active site of HDAC7 binds an acetyllysine on the AR (androgen receptor) transcription factor to disrupt HDAC3-NCoR scaffolding and activate transcription. To expand on the acetylation-dependent reversible scaffolding observed with AR, here HDAC7 binding was tested with additional nuclear receptors, including GR (glucocorticoid receptor), PR (progesterone receptor), TR (thyroid receptor), and RXR (retinoid x receptor), with particular focus on ER-⍺ (estrogen receptor alpha). Acetyllysine-dependent HDAC7-NCoR-HDAC3 binding and gene expression was established with ER-⍺ in a physiologically relevant breast cancer cell line, which substantiates acetyllysine-mediated reversible scaffolding by HDAC7 in the epigenetic regulation of nuclear receptor transcriptional activation.</div></div>","PeriodicalId":8760,"journal":{"name":"Biochimica et biophysica acta. Proteins and proteomics","volume":"1873 5","pages":"Article 141083"},"PeriodicalIF":2.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293184","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":"2025-07-01","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":"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":"2025-07-01","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}

{"title":"Crystal structure of thymidine kinase from the multi-drug resistant col strain of Staphylococcus aureus","authors":"Anam Ashraf ,&nbsp;Ravi Kant Pal ,&nbsp;Md. Imtaiyaz Hassan","doi":"10.1016/j.bbapap.2025.141071","DOIUrl":"10.1016/j.bbapap.2025.141071","url":null,"abstract":"<div><div>Thymidine kinase (TK) is a key enzyme in the salvage pathway of thymidine that produces thymidine monophosphate. TK enzyme activity is tightly coupled to the cell cycle, exhibiting marked fluctuations in expression and activity. We report the crystal structure of TK from the <em>Staphylococcus aureus col</em> strain (Sa-TK), which has emerged as a promising therapeutic target. The overall structure of Sa-TK closely resembles that of human TK. The lasso region in the structure shows an open conformation due to the absence of a natural substrate. The phosphate donor site is bound with sulfate ions from the crystallization conditions. The P-loop is visible, but the complete P-β hairpin cannot be traced due to the flexibility of this region. Sa-TK assembles as a tetramer with unique inter-subunit interactions involving salt bridges between charged residues. Glu136 and Arg184, as well as Arg154 and Glu102 from each of the subunits, have β-sheet interactions that form salt bridges. The catalytically active site residue Glu89 is conserved, which is essential for enzyme activity. Sa-TK lacks a longer C-terminal sequence involved in mitotic regulation through proteolytic degradation, a feature that is likely absent in Sa-TK. The crystal structure of Sa-TK offers detailed insights into its structural and functional properties, highlighting its conserved nature and emphasizing the challenge of developing selective inhibitors that do not affect host TK. This detailed structural information presents a valuable opportunity for the rational design of novel antibacterial agents specifically targeting Sa-TK, offering a promising avenue for combating <em>S. aureus</em> infections.</div></div>","PeriodicalId":8760,"journal":{"name":"Biochimica et biophysica acta. Proteins and proteomics","volume":"1873 4","pages":"Article 141071"},"PeriodicalIF":2.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143785301","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":"2025-07-01","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":"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":"2025-07-01","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":"Efficient production of a novel recombinant fusion protein of EIEC effector IpaD and EGFP: Biophysical characterization and functional studies","authors":"Sudeshna Halder,&nbsp;Namita Jaiswal,&nbsp;Salari Charan Balajee,&nbsp;Nibedita Mahata","doi":"10.1016/j.bbapap.2025.141066","DOIUrl":"10.1016/j.bbapap.2025.141066","url":null,"abstract":"<div><div>The conserved invasion plasmid antigen D (IpaD) protein demonstrates broad protective capabilities against bacillary dysentery caused by Enteroinvasive <em>Escherichia coli</em> (EIEC) and <em>Shigella</em>. However, the instability of the IpaD protein at room temperature limits its therapeutic potential. The stabilization and efficient production of functional recombinant proteins remain critical challenges in therapeutic and vaccine development. This study presents a novel fluorescence fusion strategy for producing a stable IpaD-EGFP recombinant protein using a flexible linker (GGGGS)₃. The fusion technique enhances the expression level (∼53 %), solubility (∼77 %), and stability of the IpaD-EGFP fusion protein. Biophysical characterization studies suggest that the IpaD-EGFP fusion protein is stable at refrigerated temperatures for extended periods and up to 1 month at 25 °C. The IpaD-EGFP protein triggers apoptosis in Raw 267.4 cells through activation of caspases 3/7. The protein also induces antibody response in BALB/c mice indicating its immunogenicity. Together, these findings indicate that IpaD-EGFP generated in this study is a potential approach for the design and production of stable IpaD-based protein therapeutics, breaking the expensive “cold chain” of continuous refrigeration. Fusion approach significantly enhanced the solubility, yield, and stability of IpaD, while enabling efficient purification.</div></div>","PeriodicalId":8760,"journal":{"name":"Biochimica et biophysica acta. Proteins and proteomics","volume":"1873 4","pages":"Article 141066"},"PeriodicalIF":2.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630132","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":"2025-07-01","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}