Protein Science最新文献

Unambiguous assignment of kinked-β sheets leads to insights into molecular grammar of reversibility in biomolecular condensates. 结β片的明确分配导致洞察生物分子凝聚物可逆性的分子语法。

IF 5.2 3区生物学

Protein Science Pub Date : 2025-09-01 DOI: 10.1002/pro.70266

Irawati Roy, Rajeswari Appadurai, Anand Srivastava

{"title":"Unambiguous assignment of kinked-β sheets leads to insights into molecular grammar of reversibility in biomolecular condensates.","authors":"Irawati Roy, Rajeswari Appadurai, Anand Srivastava","doi":"10.1002/pro.70266","DOIUrl":"10.1002/pro.70266","url":null,"abstract":"Kinked- <math> <semantics><mrow><mi>β</mi></mrow> <annotation>$$ beta $$</annotation></semantics> </math> sheets are short peptide motifs that appear as distortions in <math> <semantics><mrow><mi>β</mi></mrow> <annotation>$$ beta $$</annotation></semantics> </math> strands and often mediate formation of reversible amyloid fibrils in prion-like proteins. Standard methods for assigning secondary structures cannot distinguish these esoteric motifs. Here, we provide a supervised machine learning-based structural quantification map to unambiguously characterize kinked- <math> <semantics><mrow><mi>β</mi></mrow> <annotation>$$ beta $$</annotation></semantics> </math> sheets from coordinate data. We find that these motifs, although deviating from standard <math> <semantics><mrow><mi>β</mi></mrow> <annotation>$$ beta $$</annotation></semantics> </math> strand region of the Ramachandran plot, scatter around the allowed regions. We also demonstrate the applicability of our technique in wresting out LARKS, which are kinked- <math> <semantics><mrow><mi>β</mi></mrow> <annotation>$$ beta $$</annotation></semantics> </math> strands with designated sequence. Additionally, from our exhaustive simulation generated conformations, we create a repository of potential kinked peptide-segments that can be used as a screening-library for assigning <math> <semantics><mrow><mi>β</mi></mrow> <annotation>$$ beta $$</annotation></semantics> </math> kinks in unresolved coordinate dataset. Overall, our map for kinked- <math> <semantics><mrow><mi>β</mi></mrow> <annotation>$$ beta $$</annotation></semantics> </math> provides a robust framework for detailed structural and kinetics investigation of these important motifs in prion-like proteins that lead to formation of amyloid fibrils.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"34 9","pages":"e70266"},"PeriodicalIF":5.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12355972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144856191","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

Comparative analysis of the extent of protein-protein interactions in icosahedral viral capsids. 二十面体病毒衣壳中蛋白-蛋白相互作用程度的比较分析。

IF 5.2 3区生物学

Protein Science Pub Date : 2025-09-01 DOI: 10.1002/pro.70257

Noah J Zimmerman, Oscar Rojas Labra, Vijay S Reddy

{"title":"Comparative analysis of the extent of protein-protein interactions in icosahedral viral capsids.","authors":"Noah J Zimmerman, Oscar Rojas Labra, Vijay S Reddy","doi":"10.1002/pro.70257","DOIUrl":"https://doi.org/10.1002/pro.70257","url":null,"abstract":"Nonenveloped viruses package, carry, and deliver their genomes to the targeted cells using protein shells known as capsids. The viral capsids come in different shapes and sizes, most exhibiting helical or icosahedral symmetries. Here, we analyzed 634 icosahedral capsids at high resolution (<4 Å) from 39 virus families with T-numbers ranging from 1 to 9 and evaluated the aggregated buried surface areas (BSAs) at the unique interfaces as a measure of capsid strength and protein-protein interactions (PPIs). The BSAs were further analyzed relative to their capsid diameters and the calculated molecular weight (MW) of coat protein subunits (CPs) occupying the icosahedral asymmetric unit (IAU). Our results show that naturally occurring viral capsids exhibit stronger PPIs relative to non-native and/or engineered capsids. Interestingly, the \"T = 2\" capsids cluster distinctly, exhibiting weaker PPIs relative to their capsid size and subunit MWs. Furthermore, the normalized BSAs by the MW of the CPs present in the IAU are fairly constant across different capsids, suggesting that the extent of the PPIs is proportional to the CP size with a few exceptions (e.g., \"T = 2\" capsids). We also identified the range of capsid diameters and MWs of CPs forming different T = number capsids, which suggest a CP of 30-50 kDa can be used to build any quasi-equivalent capsid with T-numbers 1-9. Furthermore, we identified the strongest capsids available at various diameters at 25 Å intervals. Taken together, in addition to the targeting specificities, the results from this study are useful for choosing viral capsids for biomedical applications.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"34 9","pages":"e70257"},"PeriodicalIF":5.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12375967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144966447","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

A multi-pore model of the blood-brain barrier tight junction strands recapitulates the permeability features of wild-type and mutant claudin-5. 血脑屏障紧密连接链的多孔模型概括了野生型和突变型claudin-5的渗透性特征。

IF 5.2 3区生物学

Protein Science Pub Date : 2025-09-01 DOI: 10.1002/pro.70271

Alessandro Berselli, Giulio Alberini, Linda Cerioni, Fabio Benfenati, Luca Maragliano

{"title":"A multi-pore model of the blood-brain barrier tight junction strands recapitulates the permeability features of wild-type and mutant claudin-5.","authors":"Alessandro Berselli, Giulio Alberini, Linda Cerioni, Fabio Benfenati, Luca Maragliano","doi":"10.1002/pro.70271","DOIUrl":"https://doi.org/10.1002/pro.70271","url":null,"abstract":"In the blood-brain barrier (BBB), endothelial cells are joined by tight junctions (TJs), multi-protein assemblies that seal the paracellular space and restrict molecular transport. Among the BBB TJ proteins, Claudin-5 (Cldn15) is the most abundant one. Structural models for claudin complexes, first introduced for channel-forming, selectively permeable claudins, comprise protomers arranged to form paracellular pores that regulate transport by electrostatic and/or steric effects arising from pore-lining residues. With limited exceptions, computational studies explored oligomers of only a few subunits, while TJs are formed by extended polymeric strands. Here, we employ multi-microsecond all-atom molecular dynamics and free-energy (FE) calculations to study two distinct models of TJ-forming Cldn15 complexes, called multi-Pore I and multi-Pore II, each comprising 16 protomers arranged around three adjacent pores. FE calculations of water and ions permeation reveal that, in both models, ion transport is hindered by FE barriers higher than in single pores. Moreover, only the multi-Pore I model captures the Cldn15 G60R variant's effect, making it anion-permeable. The results provide insights into Cldn15 structure and function and validate a structural model of BBB TJs useful for studying barrier impairment in brain diseases and for developing therapeutic approaches.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"34 9","pages":"e70271"},"PeriodicalIF":5.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12381782/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144966476","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

Re-engineering a transferase scaffold for indole C3 methylation in diketopiperazines. 重组二酮哌嗪中吲哚C3甲基化转移酶支架。

IF 5.2 3区生物学

Protein Science Pub Date : 2025-09-01 DOI: 10.1002/pro.70254

Mona Haase, Oliver H Weiergräber, Jörg Pietruszka

{"title":"Re-engineering a transferase scaffold for indole C3 methylation in diketopiperazines.","authors":"Mona Haase, Oliver H Weiergräber, Jörg Pietruszka","doi":"10.1002/pro.70254","DOIUrl":"https://doi.org/10.1002/pro.70254","url":null,"abstract":"The pyrroloindole (hexahydropyrrolo[2,3-b]indole, HPI) structural motif is present in a wide range of natural products with various biological activities, yet its chemical synthesis poses a challenge, particularly regarding methylation at the indole C3 position. In nature, S-adenosyl methionine (SAM)-dependent methyltransferases efficiently catalyze this reaction with high stereoselectivity. This study presents the investigation and rational re-design of a potential methyltransferase, termed SeMT, from the actinomycete Saccharopolyspora erythraea. While its three-dimensional structure elucidated via X-ray crystallography confirmed extensive structural similarity to cyclic dipeptide-processing methyltransferases such as SgMT, its putative catalytic center is clearly divergent. Accordingly, wild-type SeMT displayed minimal activity with diketopiperazine (DKP) substrates, triggering an extensive mutagenesis effort aimed at iteratively enhancing this methyltransferase function. This work yielded a variant with appreciable activity, which was comprehensively characterized. Notably, a specific mutation within the catalytic triad of SeMT proved critical not only for its own function but also for the temperature-activity profile of its homolog protein SgMT. Beyond the specific properties of SeMT, these findings hence provide important insights into the active center architecture of indole C3-methyltransferases, supporting further development of these enzymes into refined biocatalysts for synthetic applications.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"34 9","pages":"e70254"},"PeriodicalIF":5.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12394179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144966486","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

Taxonomic quasi-primes: peptides charting lineage-specific adaptations and disease-relevant loci. 分类准引物：绘制谱系特异性适应和疾病相关位点的肽。

IF 5.2 3区生物学

Protein Science Pub Date : 2025-09-01 DOI: 10.1002/pro.70241

Eleftherios Bochalis, Michail Patsakis, Nikol Chantzi, Ioannis Mouratidis, Dionysios V Chartoumpekis, Ilias Georgakopoulos-Soares

{"title":"Taxonomic quasi-primes: peptides charting lineage-specific adaptations and disease-relevant loci.","authors":"Eleftherios Bochalis, Michail Patsakis, Nikol Chantzi, Ioannis Mouratidis, Dionysios V Chartoumpekis, Ilias Georgakopoulos-Soares","doi":"10.1002/pro.70241","DOIUrl":"https://doi.org/10.1002/pro.70241","url":null,"abstract":"The identification of succinct, universal fingerprints that enable the characterization of individual taxonomies can reveal insights into trait development. Here, we introduce taxonomic quasi-primes, peptide k-mer sequences that are exclusively present in a specific taxonomy and absent from all others. By analyzing 24,073 reference proteomes, we identified these unique peptides at the superkingdom, kingdom, and phylum ranks. These sequences exhibit remarkable uniqueness at six- and seven-amino-acid lengths. For instance, the seven-mer SAPNYCY is found in 98.11% of eukaryotic species, while being completely absent from archaeal, bacterial, and viral reference proteomes. Functional analysis demonstrated that taxonomic quasi-prime containing proteins are enriched for processes defining a lineage, such as synaptic signaling in Chordata. Structural analysis revealed that these peptides are preferentially located within proteins, participating directly in enzymatic active sites, mediating protein-protein interactions, and stabilizing ligand binding. Moreover, we show that in human proteins, highly conserved Chordata quasi-prime loci are 2.08-fold more likely to harbor pathogenic variants than surrounding regions, directly linking these evolutionary signatures to disease. This study establishes taxonomic quasi-primes as markers that illuminate evolutionary pathways and provide a powerful method for identifying functionally indispensable and disease-relevant loci, which warrant further therapeutic and diagnostic investigation.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"34 9","pages":"e70241"},"PeriodicalIF":5.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12375989/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144966417","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

Detergent-free isolation and characterization of amyloid precursor protein C99 in E. coli native lipid-nanodiscs using non-ionic polymer. 用非离子聚合物分离大肠杆菌天然脂质纳米圆盘中的淀粉样前体蛋白C99。

IF 5.2 3区生物学

Protein Science Pub Date : 2025-09-01 DOI: 10.1002/pro.70276

Gaurav Sharma, Bankala Krishnarjuna, Volodymyr M Hiiuk, Magdalena I Ivanova, Pavel Nagorny, Ayyalusamy Ramamoorthy

{"title":"Detergent-free isolation and characterization of amyloid precursor protein C99 in E. coli native lipid-nanodiscs using non-ionic polymer.","authors":"Gaurav Sharma, Bankala Krishnarjuna, Volodymyr M Hiiuk, Magdalena I Ivanova, Pavel Nagorny, Ayyalusamy Ramamoorthy","doi":"10.1002/pro.70276","DOIUrl":"10.1002/pro.70276","url":null,"abstract":"Alzheimer's disease (AD), a progressive neurodegenerative disorder, is characterized by cognitive decline resulting from neuronal cell death. A key contributor to AD pathology is C99, a membrane-bound β-secretase-cleaved fragment of amyloid precursor protein (APP). C99 plays a central role in generating amyloid-beta (Aβ) isomers, which are directly implicated in disease progression. Understanding its structure and lipid interactions is essential for elucidating its mechanistic role in AD and guiding therapeutic development. C99 has been studied in membrane mimetics such as micelles, bicelles, and reconstituted nanodiscs. Although reconstituted nanodiscs provide a native-like lipid-bilayer environment, the use of detergents prior to reconstitution has been reported to disrupt native folding and lipid-protein interactions. In this study, we successfully isolated and purified C99 along with its associated lipids directly from E. coli cell membranes using a non-ionic pentyl-inulin polymer, avoiding the need for detergents. The purified C99-containing pentyl-inulin nanodiscs were characterized using SDS-PAGE, Western blotting, dynamic light scattering (DLS), 1H NMR spectroscopy, matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, and liquid chromatography-mass spectrometry (LC-MS). Notably, we observed SDS-stable oligomers of C99. DLS and 1H NMR confirmed the presence of large particles composed of pentyl-inulin and E. coli lipids. MALDI-TOF and LC-MS verified the molecular mass and amino acid sequence of C99, respectively. We propose that this detergent-free method for the direct isolation of C99 and native lipids using non-ionic pentyl-inulin may serve as a valuable tool for investigating the C99-secretase complex and for developing compounds aimed at inhibiting the production of amyloid-beta isomers.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"34 9","pages":"e70276"},"PeriodicalIF":5.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12363408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874899","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

N-terminal acetylation of superoxide dismutase 1 accelerates amyloid formation without general destabilization of the apo state. 超氧化物歧化酶1的n端乙酰化加速淀粉样蛋白的形成，而不会破坏载脂蛋白状态的稳定。

IF 5.2 3区生物学

Protein Science Pub Date : 2025-09-01 DOI: 10.1002/pro.70267

Kristine Steen Jensen

{"title":"N-terminal acetylation of superoxide dismutase 1 accelerates amyloid formation without general destabilization of the apo state.","authors":"Kristine Steen Jensen","doi":"10.1002/pro.70267","DOIUrl":"10.1002/pro.70267","url":null,"abstract":"Co- and post-translational modifications can significantly impact the structure, dynamics, and function of proteins. In this study, we investigate how N-terminal acetylation affects misfolding and self-assembly of the enzyme superoxide dismutase 1 (SOD1), implicated in amyotrophic lateral sclerosis (ALS). Studies of protein inclusions in patient samples and animal models have shown that wild-type SOD1 can form amyloid fibrils even when no mutations are found in the sod1 gene. This has identified SOD1 amyloid formation as a possible common denominator of ALS and may suggest that co- and post-translational modifications, like N-terminal acetylation found in human SOD1, can be a factor in disease development. In this work, the impact of N-terminal acetylation of SOD1 on stability and aggregation is characterized. Results show that the structure and thermal stability of the apo state are unaffected by the modification while the amyloid formation rate is significantly enhanced. This is caused by a shortening of the nucleation phase together with an increase of fibril elongation by more than 10-fold upon N-terminal acetylation of SOD1. Collectively, the findings demonstrate how regulation by co- and post-translational modifications can influence protein misfolding and self-assembly.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"34 9","pages":"e70267"},"PeriodicalIF":5.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12355962/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144856118","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

Thermotolerant class A acid phosphatase active across broad pH range and diverse substrates. 耐高温的A类酸性磷酸酶，在广泛的pH范围和不同的底物中都有活性。

IF 5.2 3区生物学

Protein Science Pub Date : 2025-09-01 DOI: 10.1002/pro.70244

Maria-Isabel Recio, José A Gavira, Jesús de La Torre, Mario Cano-Muñoz, Sergio Martínez-Rodriguez, Abdelali Daddaoua, Estrella Duque, Juan L Ramos

{"title":"Thermotolerant class A acid phosphatase active across broad pH range and diverse substrates.","authors":"Maria-Isabel Recio, José A Gavira, Jesús de La Torre, Mario Cano-Muñoz, Sergio Martínez-Rodriguez, Abdelali Daddaoua, Estrella Duque, Juan L Ramos","doi":"10.1002/pro.70244","DOIUrl":"10.1002/pro.70244","url":null,"abstract":"M2-32 is a non-specific acid phosphatase with a rare ability to function across a broad pH range (3.5-8.5). Analysis using SWISS-PROT Prf Profiles classifies it as a class A acid phosphatase (Z-score: 78.97), sharing 50%-60% sequence similarity with enzymes such as PhoC and PhoN. For detailed characterization, the gene encoding M2-32 was cloned into the pET28(b) vector, overexpressed in Escherichia coli BL21 (DE3), and subsequently purified. Although the monomeric form of M2-32 has a molecular weight of ~28 kDa, size exclusion chromatography, dynamic light scattering, and sedimentation studies revealed a dimeric form in solution. Enzymatic assays using p-nitrophenyl phosphate, 4-methylumbelliferyl phosphate, 3'-and 5'-adenosine monophosphate demonstrated robust activity over a pH range of 4.0-8.0 at both 30 and 50°C. Differential scanning fluorimetry indicated an unfolding temperature close to 47°C; however, the enzyme refolded after heat denaturation at 80°C. We have determined the x-ray crystal structure of M2-32 by molecular replacement using an AlphaFold2-guided truncated model, achieving a resolution of 2.2 Å. The protein crystallized as a dimer-of-dimers. Each monomer (residues 38-274) adopts an all-alpha-helical fold composed of 14 helices and two disulfide bonds. Docking studies with adenosine monophosphates, combined with site-directed mutagenesis, identified His174, Arg207, His213, Asp217 as critical catalytic residues, and Tyr136 and Ser172 probably involved in substrate recognition. Mutations at these positions resulted in over 90% loss of enzymatic activity, highlighting their functional significance.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"34 9","pages":"e70244"},"PeriodicalIF":5.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12356135/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144856190","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

Second-order allosteric control as a mechanism for compensatory mutations in B-cell translocation gene 2. b细胞易位基因2代偿性突变的二阶变构控制机制

IF 5.2 3区生物学

Protein Science Pub Date : 2025-09-01 DOI: 10.1002/pro.70270

Nicholas J Ose, Paul Campitelli, Tushar Modi, S Banu Ozkan

{"title":"Second-order allosteric control as a mechanism for compensatory mutations in B-cell translocation gene 2.","authors":"Nicholas J Ose, Paul Campitelli, Tushar Modi, S Banu Ozkan","doi":"10.1002/pro.70270","DOIUrl":"https://doi.org/10.1002/pro.70270","url":null,"abstract":"The mechanism underlying the pathogenic impact of mutations within intrinsically disordered regions of proteins remains enigmatic, and the mechanisms behind compensatory responses to these perturbations lie within an even deeper veil of obscurity. This study focuses on the compensatory mechanisms of single nucleotide variants within the disordered C-terminal tail of the BTG2 protein, a crucial regulator in cell cycle control. Here, we develop a novel approach by combining molecular dynamics simulations with time-dependent linear response theory to accurately compute the long-distance coupling dynamics between the tail and the structured domain. Using this approach, we reveal how specific mutations can counteract the functional disruptions caused by a known disease-associated mutation, V141M. Our findings demonstrate that the disordered tail regulates critical binding sites allosterically, and a weakening of this modulation may contribute to disease manifestation. However, compensatory mutations restore lost interactions between the disordered region and binding sites, exerting long-distance dynamic control over both critical binding sites and the mutation site 141M. This secondhand allosteric control could be a general mechanism for compensatory mutations to rescue function. These insights not only illuminate the pathogenic mechanisms at play but also offer a framework for identifying potential therapeutic targets in diseases associated with disordered protein regions.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"34 9","pages":"e70270"},"PeriodicalIF":5.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12375984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144966394","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

Structural and functional insights into the selective inhibition of mutant tau aggregation by purpurin and oleocanthal in frontotemporal dementia. 在额颞叶痴呆中，紫癜蛋白和油棕素选择性抑制突变型tau聚集的结构和功能。

IF 5.2 3区生物学

Protein Science Pub Date : 2025-09-01 DOI: 10.1002/pro.70240

Alladi Charanraj Goud, Ihor Kozlov, Patricie Skoupilová, Lukáš Malina, Sudeep Roy, Viswanath Das

{"title":"Structural and functional insights into the selective inhibition of mutant tau aggregation by purpurin and oleocanthal in frontotemporal dementia.","authors":"Alladi Charanraj Goud, Ihor Kozlov, Patricie Skoupilová, Lukáš Malina, Sudeep Roy, Viswanath Das","doi":"10.1002/pro.70240","DOIUrl":"https://doi.org/10.1002/pro.70240","url":null,"abstract":"Tau aggregation driven by microtubule-associated protein tau (MAPT) mutations is central to frontotemporal dementia pathology, yet no disease-modifying therapies effectively target mutant tau. Here, we identify purpurin (PUR) and oleocanthal (OLC) as selective inhibitors of mutant tau aggregation using peptide models spanning the R2R3 interface. Biophysical and cellular assays demonstrated that both compounds more effectively inhibit the aggregation of mutant tau peptides compared to wild-type, with PUR preferentially targeting V287I and N279K variants, and OLC showing broader inhibitory activity. Surface plasmon resonance and docking analyses revealed more stable interactions and lower binding free energies with mutant tau, consistent with their enhanced inhibitory effects. Computational studies using monomeric and fibrillar tau structures supported the mutation-specific binding profiles of PUR and OLC. Atomic force microscopy and confocal imaging confirmed reduced fibril formation, while post-transduction treatment assays showed that both compounds significantly suppressed intracellular tau propagation. Additionally, OLC reduced tau phosphorylation and oligomerization in SY5Y-TauP301L-EGFP cells expressing mutant tau. These findings highlight the potential of PUR and OLC as structurally distinct, mutation-targeted inhibitors of tau aggregation and propagation, providing a rationale for their further development as candidate therapeutics for frontotemporal dementia.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"34 9","pages":"e70240"},"PeriodicalIF":5.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12381781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144966411","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