The FEBS journal最新文献_第4页

In conversation with Małgorzata Kosla. 在与Małgorzata Kosla的对话中。

IF 4.2

The FEBS journal Pub Date : 2025-08-22 DOI: 10.1111/febs.70227

Małgorzata Kosla, Hajrah Khawaja

引用次数: 0

Structural and functional insights into a novel aldehyde deformylating oxygenase with enhanced efficiency for biofuel applications. 一种新型乙醛脱甲酰基加氧酶的结构和功能研究，提高了生物燃料应用的效率。

IF 4.2

The FEBS journal Pub Date : 2025-08-22 DOI: 10.1111/febs.70234

Nidar Treesukkasem, Surawit Visitsatthawong, Supacha Buttranon, Pattarawan Intasian, Juthamas Jaroensuk, Somchart Maenpuen, Jeerus Sucharitakul, Harshwardhan Poddar, Derren J Heyes, Nigel S Scrutton, Pimchai Chaiyen, Thanyaporn Wongnate

{"title":"Structural and functional insights into a novel aldehyde deformylating oxygenase with enhanced efficiency for biofuel applications.","authors":"Nidar Treesukkasem, Surawit Visitsatthawong, Supacha Buttranon, Pattarawan Intasian, Juthamas Jaroensuk, Somchart Maenpuen, Jeerus Sucharitakul, Harshwardhan Poddar, Derren J Heyes, Nigel S Scrutton, Pimchai Chaiyen, Thanyaporn Wongnate","doi":"10.1111/febs.70234","DOIUrl":"https://doi.org/10.1111/febs.70234","url":null,"abstract":"Aldehyde deformylating oxygenase (ADO) plays a crucial role in hydrocarbon biosynthesis by converting Cn fatty aldehydes into Cn-1 alkanes, key components of biofuels. However, ADO's low catalytic efficiency and thermostability hinder its industrial application. In this study, we identified a novel ADO from Pseudomonas plecoglossicida (PsADO) using the Enzyme Function Initiative-Enzyme Similarity Tool (EFI-EST). PsADO contains a novel loop motif with a disulfide bond that forms a new substrate tunnel, enhancing both thermostability and catalytic efficiency. PsADO exhibited a melting temperature (Tm) of over 61 °C, significantly higher than that of Prochlorococcus marinus ADO (PmADO, Tm = 41 °C), indicating superior stability. PsADO achieved its highest alkane yield at 10% oxygen, with a kcat of 1.38 min-1, 106 times higher than that of PmADO for tridecane formation. A hybrid reducing system, combining ferredoxin from Synechocystis sp. PCC6803 and ferredoxin-NADP+ reductase from Escherichia coli, further enhanced PsADO's activity compared with traditional chemical systems (PMS/NADH). AlphaFold 3 and CaverDock studies revealed that deleting PsADO's extended loop reduced alkane production by up to 9.4-fold, while the N47A variant reduced tridecane formation by 1.25-fold, confirming the importance of these structural features for substrate access and stability. These findings highlight PsADO's potential for biofuel applications, particularly in the production of long-chain alkanes for jet fuel. PsADO's improved stability and efficiency make it a promising candidate for industrial biotechnology and biofuel production, with further optimization potential through genetic and metabolic engineering.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144984609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Residual flexibility in the topologically constrained multivalent complex between the GKAP scaffold and LC8 hub proteins. GKAP支架和LC8枢纽蛋白之间的拓扑约束多价复合物的剩余灵活性。

IF 4.2

The FEBS journal Pub Date : 2025-08-22 DOI: 10.1111/febs.70219

Eszter Nagy-Kanta, Zsófia E Kálmán, Helena Tossavainen, Tünde Juhász, Fanni Farkas, József Hegedüs, Melinda Keresztes, Tamás Beke-Somfai, Zoltán Gáspári, Perttu Permi, Bálint Péterfia

{"title":"Residual flexibility in the topologically constrained multivalent complex between the GKAP scaffold and LC8 hub proteins.","authors":"Eszter Nagy-Kanta, Zsófia E Kálmán, Helena Tossavainen, Tünde Juhász, Fanni Farkas, József Hegedüs, Melinda Keresztes, Tamás Beke-Somfai, Zoltán Gáspári, Perttu Permi, Bálint Péterfia","doi":"10.1111/febs.70219","DOIUrl":"https://doi.org/10.1111/febs.70219","url":null,"abstract":"Guanylate kinase-associated protein (GKAP) is a large postsynaptic scaffold protein bearing two closely spaced noncanonical binding sites for the bivalent dynein light chain LC8 hub protein. This might allow the formation of heterogeneous complexes with different sizes and topologies. Here, we show that a well-defined hexameric complex is formed, composed of two GKAP molecules and two LC8 dimers. Using nuclear magnetic resonance (NMR) spectroscopy, we demonstrate that the LC8-binding segment of GKAP is intrinsically disordered and the flexibility of the linker region is largely retained even in the complex form. Molecular dynamics calculations suggest that, besides the tightly bound residues, the hexamer also exhibits several dynamically interchanging interactions, and that the two LC8 dimers might interact with each other. The flanking regions of the two binding sites on GKAP exhibit different interaction patterns, hinting at additional contacts that might explain the fixed stoichiometry of the assembly. Our results demonstrate that constrained stoichiometry can coexist with substantial flexibility in a multivalent system.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144984618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Nanoscale engagement of programmed death ligand 1 (PD-L1) in membrane lipid raft domains of cancer cells. 程序性死亡配体1 （PD-L1）在癌细胞膜脂筏结构域的纳米级参与。

IF 4.2

The FEBS journal Pub Date : 2025-08-22 DOI: 10.1111/febs.70238

Simone Civita, Martina Ruglioni, Matteo Mariangeli, Serena Barachini, Tiziano Salvadori, Sofia Cristiani, Vittoria Carnicelli, Iacopo Petrini, Irene Nepita, Marco Castello, Alberto Diaspro, Stefano Fogli, Paolo Bianchini, Barbara Storti, Ranieri Bizzarri, Romano Danesi

{"title":"Nanoscale engagement of programmed death ligand 1 (PD-L1) in membrane lipid raft domains of cancer cells.","authors":"Simone Civita, Martina Ruglioni, Matteo Mariangeli, Serena Barachini, Tiziano Salvadori, Sofia Cristiani, Vittoria Carnicelli, Iacopo Petrini, Irene Nepita, Marco Castello, Alberto Diaspro, Stefano Fogli, Paolo Bianchini, Barbara Storti, Ranieri Bizzarri, Romano Danesi","doi":"10.1111/febs.70238","DOIUrl":"https://doi.org/10.1111/febs.70238","url":null,"abstract":"Several tumors have evolved the ability to evade the immune system by expressing programmed death ligand 1 (PD-L1; also known as programmed cell death 1 ligand 1) on the membrane of neoplastic cells. PD-L1 binds the receptor programmed cell death protein 1 (PD-1) on T cells, deactivating the immune response. Accordingly, PD-L1 has recently become a crucial target for cancer therapy. Yet, the molecular organization of PD-L1 on the membrane is still rather obscure. Here, we investigated the plasma membrane organization of PD-L1 by a multiscale fluorescence imaging toolbox reaching the nanoscale by super-resolution microscopy. Our results indicate that a major fraction of PD-L1 is largely engaged in membrane nanodomains of 25 nm mean radius, which in turn organize in an irregular mesoscopic lattice with mean interdomain distance of about 180 nm. The significant colocalization of PD-L1 with lipid raft markers, which we assessed from 200 to 250 nm down to < 10 nm, supports a raft-driven organization of PD-L1, which may follow its extended palmitoylation upon expression. This pattern was also demonstrated in living cells by visualizing PD-L1 diffusion at different spatial scales. The raft-orchestrated multiscale PD-L1 organization on the cell membrane may afford novel targets for improved immuno-oncology strategies.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144984594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evolutionary divergence and functional insights into the heteromeric cis-prenyltransferase of Paramecium tetraurelia. 四甲草履虫异聚体顺戊烯基转移酶的进化分化及其功能研究。

IF 4.2

The FEBS journal Pub Date : 2025-08-22 DOI: 10.1111/febs.70237

Agnieszka Onysk, Kamil Steczkiewicz, Mariusz Radkiewicz, Paweł Link-Lenczowski, Przemysław Surowiecki, Karolina Sztompka, Kariona A Grabińska, Jacek K Nowak, Liliana Surmacz

{"title":"Evolutionary divergence and functional insights into the heteromeric cis-prenyltransferase of Paramecium tetraurelia.","authors":"Agnieszka Onysk, Kamil Steczkiewicz, Mariusz Radkiewicz, Paweł Link-Lenczowski, Przemysław Surowiecki, Karolina Sztompka, Kariona A Grabińska, Jacek K Nowak, Liliana Surmacz","doi":"10.1111/febs.70237","DOIUrl":"https://doi.org/10.1111/febs.70237","url":null,"abstract":"The biosynthesis of polyprenyl/dolichyl phosphate, an essential lipid carrier in protein glycosylation, occurs across all domains of life. Eukaryotic heteromeric enzymes involved in polyprenyl chain elongation consist of a highly conserved catalytic cis-prenyltransferase subunit (CPT-CS) and a less conserved CPT-accessory subunit (CPT-AS). Here, we present the first experimental evidence that dolichol biosynthesis in Paramecium tetraurelia is mediated by a heteromeric CPT complex. Using a multidisciplinary experimental approach, we identified two highly homologous catalytic CPT subunits, CPT1a and CPT1b, which exhibit high sequence similarity to other eukaryotic CPTs, along with a unique CPT-AS, named POC1 (partner of CPT1), which is a structural and functional relative of the human dehydrodolichyl diphosphate synthase complex subunit NUS1 (also known as NgBR) and yeast Nus1 CPT-AS. Despite low sequence similarity to other CPT-ASs, it retained a well-preserved C-terminal substrate-binding domain characteristic of its eukaryotic and prokaryotic counterparts. The loss of POC1 or CPT1a, but not CPT1b, results in a deficit in dolichol production, leading to a significant reduction in glycoprotein content and, ultimately, to the P. tetraurelia cell death. In a heterologous yeast system, both CPTs in complex with POC1 synthesized polyprenyl chains. The identification of a POC1 protein so distinct from other CPT-ASs may spark further efforts to uncover CPT-AS proteins in pathogenic protozoa, which have so far eluded detection despite phylogenetic evidences that CPT of Apicomplexa and Trichomonas sp. are heteromeric enzymes. Given their substantial sequence divergence from human NgBR and its animal orthologues, these protozoan CPT-ASs could represent highly specific targets for antiparasitic therapies.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144984506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Collagen XV preserves heart function and protects from pathological remodelling after myocardial infarction. 胶原XV保留心脏功能，防止心肌梗死后的病理重构。

IF 4.2

The FEBS journal Pub Date : 2025-08-20 DOI: 10.1111/febs.70212

Sanna-Maria Karppinen, Miki Aho, Zoltan Szabo, Johanna Magga, Laura Vainio, Erhe Gao, Paul Janmey, Lauri Eklund, Karolina Rasi, Ilkka Miinalainen, Lynn Y Sakai, Lasse Pakanen, Heikki Huikuri, Juhani Junttila, Risto Kerkelä, Taina Pihlajaniemi

{"title":"Collagen XV preserves heart function and protects from pathological remodelling after myocardial infarction.","authors":"Sanna-Maria Karppinen, Miki Aho, Zoltan Szabo, Johanna Magga, Laura Vainio, Erhe Gao, Paul Janmey, Lauri Eklund, Karolina Rasi, Ilkka Miinalainen, Lynn Y Sakai, Lasse Pakanen, Heikki Huikuri, Juhani Junttila, Risto Kerkelä, Taina Pihlajaniemi","doi":"10.1111/febs.70212","DOIUrl":"10.1111/febs.70212","url":null,"abstract":"Increasing knowledge of the components involved in left ventricle (LV) remodelling and fibrotic processes after a myocardial infarction is crucial to understanding heart pathology. We have here analysed collagen XV (ColXV) expression in human myocardial infarct samples and assessed how its deficiency affects cardiac responses, such as fibrogenesis and tissue stiffness, after acute myocardial infarction (AMI) in mice. We first observed high ColXV expression in human infarction scars. After ligating the left anterior descending artery in mice, cardiac function and remodelling were monitored by echocardiography, elasticity assessment, immunohistochemical analysis and ultrastructural assessments. After AMI, Col15a1-/- mice showed significantly increased tissue stiffness and upregulation of fibrosis-related genes in the remote myocardium. Striking differences were observed between the genotypes in the scar ultrastructure, protein compositions, cardiomyocyte morphology and intracellular architecture. Furthermore, the proportion of immature collagen fibres in the infarct border zone increased in Col15a1-/- mice, suggesting fragility and poor scar resistance to mechanical stress. Structural parameters indicated more substantial LV remodelling in the knockout mice, leading to a more dilated ventricle. Functionally, the ejection fraction and fractional shortening decreased significantly in Col15a1-/- mice, indicating impaired heart contractile capacity. The results show that in the event of an AMI, ColXV plays an essential role in sustaining cardiac structure and function. In the absence of ColXV, dysregulated remodelling results in disrupted scar and infarct border zone, and stiffer left ventricle. These changes lead to a more severe cardiac phenotype and may affect long-term survival after AMI.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144884711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural insights for enhanced ROS detoxification of eKatE, a recently identified catalase in atypical E. coli. 最近在非典型大肠杆菌中发现的过氧化氢酶eKatE增强ROS解毒的结构见解。

IF 4.2

The FEBS journal Pub Date : 2025-08-20 DOI: 10.1111/febs.70233

Eunhee Koh, Youngki Yoo, Mi Young Yoon, Myung Kyung Choi, Uijin Kim, Jun Bae Park, Sang Sun Yoon, Hyun-Soo Cho

{"title":"Structural insights for enhanced ROS detoxification of eKatE, a recently identified catalase in atypical E. coli.","authors":"Eunhee Koh, Youngki Yoo, Mi Young Yoon, Myung Kyung Choi, Uijin Kim, Jun Bae Park, Sang Sun Yoon, Hyun-Soo Cho","doi":"10.1111/febs.70233","DOIUrl":"https://doi.org/10.1111/febs.70233","url":null,"abstract":"Catalase is a crucial enzyme that protects organisms from reactive oxygen species (ROS)-induced oxidative stress. eKatE, a recently identified catalase variant in commensal Escherichia coli (E. coli), significantly contributes to infectious diseases and inflammatory bowel disease (IBD). Here, we enhanced the ROS detoxification capacity of eKatE, distinguishing it from the typical E. coli catalase KatE. eKatE forms a tetramer with a well-folded N-terminal arm and a dual conformation of the long R173eKatE, in contrast to the disordered N terminus and A173KatE of KatE. Additionally, a V256-induced bottleneck in the major channel enhances the sensitivity of eKatE to H2O2, differing from A256KatE. Furthermore, K294eKatE flipped inside to shield the major and lateral channels more effectively than K294KatE. Covalent bonding of C392eKatE to the essential Y415 increased the catalytic activity compared with that of H392KatE. Finally, the electrostatic potential surface of the eKatE tetramers differed from those of KatE, particularly near the substrate-inlet and product-outlet regions. These findings on the improved catalytic capacity of eKatE highlight its potential application in mitigating ROS-related diseases and treating IBD.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144984602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CMCS: classifying and analyzing clustered somatic mutations to elucidate the potential contributions in tumorigenesis. CMCS：分类和分析聚集性体细胞突变以阐明肿瘤发生的潜在贡献。

IF 4.2

The FEBS journal Pub Date : 2025-08-18 DOI: 10.1111/febs.70231

Jiaming Jin, Xinmiao Zhao, Shizheng Xiong, Linjie Zhao, Zhiheng He, Yuting Zhang, Haochuan Guo, Chengjun Gong, Li Guo, Tingming Liang

{"title":"CMCS: classifying and analyzing clustered somatic mutations to elucidate the potential contributions in tumorigenesis.","authors":"Jiaming Jin, Xinmiao Zhao, Shizheng Xiong, Linjie Zhao, Zhiheng He, Yuting Zhang, Haochuan Guo, Chengjun Gong, Li Guo, Tingming Liang","doi":"10.1111/febs.70231","DOIUrl":"10.1111/febs.70231","url":null,"abstract":"Clustered somatic mutations, which are common in cancer genomes and play critical roles in both pathological and physiological processes, are frequently accumulated in specific genomic regions. To enable efficient identification of these clustered mutations and gain insights into the potential functions of the associated genes in cancer, we developed the Cluster Mutation Classification System (CMCS; https://www.tmliang.cn/cluster/), a user-friendly web-based platform. CMCS aimed to screen genes harboring multiple clustered mutations based on the density-based spatial clustering of applications with noise (DBSCAN) algorithm and simultaneously estimate the potential molecular features and biological roles in tumorigenesis. The platform allows users to screen and analyze clustered somatic mutations to characterize mutation types, related genes, mutation ranges, and annotations. Furthermore, it facilitates downstream analyses of these genes, uncovering molecular alterations and potential clinical implications across various molecular levels. CMCS provides insights into the molecular characteristics of genes harboring clustered mutations by leveraging a multiomics approach, enriching our understanding of their relationships to cancer development and progression.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144877705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Molecular basis of domain-specific angiotensin I-converting enzyme inhibition by the antihypertensive drugs enalaprilat, ramiprilat, trandolaprilat, quinaprilat and perindoprilat. 降压药依那普利特、雷米普利特、曲多拉普利特、奎那普利特和培哚普利特抑制区域特异性血管紧张素i转换酶的分子基础

IF 4.2

The FEBS journal Pub Date : 2025-08-18 DOI: 10.1111/febs.70232

Kyle S Gregory, Vinasha Ramasamy, Edward D Sturrock, K Ravi Acharya

{"title":"Molecular basis of domain-specific angiotensin I-converting enzyme inhibition by the antihypertensive drugs enalaprilat, ramiprilat, trandolaprilat, quinaprilat and perindoprilat.","authors":"Kyle S Gregory, Vinasha Ramasamy, Edward D Sturrock, K Ravi Acharya","doi":"10.1111/febs.70232","DOIUrl":"10.1111/febs.70232","url":null,"abstract":"Angiotensin I-converting enzyme (ACE) is a dipeptidyl carboxypeptidase with two homologous catalytic domains [N- and C-domains (nACE and cACE)] that can cleave a range of substrates. cACE primarily cleaves the inactive decapeptide angiotensin I into the potent vasopressor angiotensin II, whereas nACE preferentially cleaves the antifibrotic tetrapeptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP). Several ACE inhibitors, which bind to both cACE and nACE active sites, are used clinically for the treatment of hypertension; however, serious side effects are seen in ~ 20-25% of patients due to nonselective inhibition. To improve ACE inhibitor side effect profiles, the design and development of selective inhibitors of cACE or nACE is desirable for the treatment of hypertension or fibrosis. The detailed molecular basis through which the clinically available ACE inhibitors bind and inhibit cACE and nACE was unknown. Thus, in this study, we have characterised the structural and kinetic basis for the interaction between cACE and nACE with enalaprilat, ramiprilat, trandolaprilat, quinaprilat and perindoprilat. The inhibitors display nanomolar inhibition of both domains, with moderate-to-low cACE-selectivity. Trandolaprilat possesses the highest affinity for both nACE and cACE, whereas quinaprilat displayed the largest cACE-selectivity. None of the binding modes of the inhibitors extend beyond the S1-S2' subsites to make use of the unique nACE/cACE residues that have been shown to influence domain selectivity. These findings supplement our understanding of ACE inhibition by the clinically used ACE inhibitors, and this information should be useful in the future design of more domain-selective inhibitors for the treatment of hypertension and cardiovascular diseases.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144877706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hydrophobic residues in the α-synuclein NAC domain drive seed-competent fibril formation and are targeted by peptide inhibitors. α-突触核蛋白NAC结构域的疏水残基驱动种子活性纤维的形成，并被肽抑制剂靶向。

IF 4.2

The FEBS journal Pub Date : 2025-08-17 DOI: 10.1111/febs.70222

Viswanath Das, Sayed Mostafa Modarres Mousavi, Narendran Annadurai, Sunčica Sukur, Faramarz Mehrnejad, Sajad Moradi, Lukáš Malina, Markéta Kolaříková, Vaclav Ranc, Ivo Frydrych, Roman Kouřil, Saman Hosseinkhani, Marián Hajdúch, Maryam Nikkhah

{"title":"Hydrophobic residues in the α-synuclein NAC domain drive seed-competent fibril formation and are targeted by peptide inhibitors.","authors":"Viswanath Das, Sayed Mostafa Modarres Mousavi, Narendran Annadurai, Sunčica Sukur, Faramarz Mehrnejad, Sajad Moradi, Lukáš Malina, Markéta Kolaříková, Vaclav Ranc, Ivo Frydrych, Roman Kouřil, Saman Hosseinkhani, Marián Hajdúch, Maryam Nikkhah","doi":"10.1111/febs.70222","DOIUrl":"https://doi.org/10.1111/febs.70222","url":null,"abstract":"Alpha-synuclein (αSyn) is a 14-kDa intrinsically disordered protein that aggregates into insoluble fibrils in synucleinopathies, including Lewy bodies, multiple system atrophy, and Parkinson's disease, contributing to neurotoxicity and disease progression. The ability of these fibrils to seed further aggregation of native protein is central to αSyn pathology. Here, we examined the broader non-amyloid component (NAC) domain, focusing on how residues flanking the hydrophobic 68-71 (GAVV) motif of αSyn (residues 8-11 in NAC35) modulate nucleation, stability, and pathological seeding. Using full-length NAC peptide and truncated variants, we show that the 68-71 (GAVV) stretch is critical for nucleation and aggregation into prion-like fibrils. Peptide inhibitors targeting this hydrophobic region block the formation of seed-competent fibrils. Molecular dynamics simulations showed that these inhibitors alter peptide-peptide interactions and contact key hydrophobic residues within the NAC domain. Further analysis indicates that residues beyond the 68-71 (GAVV) motif, such as 79-95, are critical for stabilizing fibrils and promoting seeding competency. Peptide B interactions with key hydrophobic motifs within the NAC domain were visualized in silico, offering mechanistic insights into how it disrupts aggregation.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0