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Bacterial Regulatory Circuits are Linked and Extended by Small RNAs 细菌调控回路是由小rna连接和扩展的。
IF 4.7 2区 生物学
Journal of Molecular Biology Pub Date : 2025-03-03 DOI: 10.1016/j.jmb.2025.169059
Susan Gottesman
{"title":"Bacterial Regulatory Circuits are Linked and Extended by Small RNAs","authors":"Susan Gottesman","doi":"10.1016/j.jmb.2025.169059","DOIUrl":"10.1016/j.jmb.2025.169059","url":null,"abstract":"<div><div>I was lucky to start my research career as the molecular biology revolution was taking hold, providing a constantly increasing set of tools and questions to investigate. Starting from a fascination with bacteria and their ability to adapt to different conditions, I’ve investigated post-translational mechanisms and their role in the ability of <em>E. coli</em> to respond to stress. My research career has been primarily at the National Institutes of Health, where I run a group within the Laboratory of Molecular Biology, NCI and hold the title of NIH Distinguished Investigator. Our lab has been interested in both energy-dependent proteolysis, discussed very briefly here, and small regulatory RNAs (sRNAs). The major group of such sRNAs act by pairing with target mRNAs with the aid of the RNA chaperone Hfq, mediating both positive and negative regulation of translation and mRNA stability. Both in our own lab and in a continuing and highly productive collaboration with the laboratory of Gisela (Gigi) Storz, we have used global approaches to identify novel sRNAs, identified how many of them are regulated, both at the level of transcription and stability, and worked on understanding the role of these sRNAs in regulatory networks. Our continued work explores regulators of sRNA and Hfq function. Here, Gigi and I have split summaries of our findings, and hope that our two chapters will be read together.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 11","pages":"Article 169059"},"PeriodicalIF":4.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Structural Plasticity of Plasmodium falciparum Plasmepsin X to Accommodate Binding of Potent Macrocyclic Hydroxyethylamine Inhibitors 恶性疟原虫Plasmodium plasmepsin X的结构可塑性以适应强效大环羟乙胺抑制剂的结合。
IF 4.7 2区 生物学
Journal of Molecular Biology Pub Date : 2025-03-03 DOI: 10.1016/j.jmb.2025.169062
Chrislaine Withers-Martinez , Roger George , Roksana Ogrodowicz , Simone Kunzelmann , Andrew G. Purkiss , Svend Kjaer , Philip A. Walker , Vadims Kovada , Aigars Jirgensons , Michael J. Blackman
{"title":"Structural Plasticity of Plasmodium falciparum Plasmepsin X to Accommodate Binding of Potent Macrocyclic Hydroxyethylamine Inhibitors","authors":"Chrislaine Withers-Martinez ,&nbsp;Roger George ,&nbsp;Roksana Ogrodowicz ,&nbsp;Simone Kunzelmann ,&nbsp;Andrew G. Purkiss ,&nbsp;Svend Kjaer ,&nbsp;Philip A. Walker ,&nbsp;Vadims Kovada ,&nbsp;Aigars Jirgensons ,&nbsp;Michael J. Blackman","doi":"10.1016/j.jmb.2025.169062","DOIUrl":"10.1016/j.jmb.2025.169062","url":null,"abstract":"<div><div><em>Plasmodium falciparum</em> plasmepsin X (PMX) has become a target of choice for the development of new antimalarial drugs due to its essential role across the parasite life cycle. Here we describe the 1.7 Å crystallographic structure of PMX noncovalently bound to a potent macrocyclic peptidomimetic inhibitor (<strong>7k</strong>) possessing a hydroxyethylamine (HEA) scaffold. Upon <strong>7k</strong> binding, the enzyme adopts a novel conformation, with significant involvement of the S2′S2 loop (M526-H536) and the S2 flap (F311-G314). This results in partial closure of the active site with widespread interactions in both the prime (S′) and the non-prime (S) sites of PMX. The catalytic aspartate residues D266 and D467 directly interact with the HEA pharmacophore. Docking of a <strong>7k</strong> derivative, compound <strong>7a</strong>, highlights a region in the S3 pocket near the S3 flexible loop (H242-F248) that may be key for ligand stabilisation. The dynamic nature of PMX and its propensity to undergo distinct types of induced fit upon inhibitor binding enables generation of potent inhibitors that target this essential malarial aspartic protease.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 10","pages":"Article 169062"},"PeriodicalIF":4.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
TamL is a Key Player of the Outer Membrane Homeostasis in Bacteroidota TamL是拟杆菌属外膜稳态的关键分子。
IF 4.7 2区 生物学
Journal of Molecular Biology Pub Date : 2025-03-03 DOI: 10.1016/j.jmb.2025.169063
Fabio Giovannercole , Tom De Smet , Miguel Ángel Vences-Guzmán , Frédéric Lauber , Rémy Dugauquier , Marc Dieu , Laura Lizen , Jonas Dehairs , Gipsi Lima-Mendez , Ziqiang Guan , Christian Sohlenkamp , Francesco Renzi
{"title":"TamL is a Key Player of the Outer Membrane Homeostasis in Bacteroidota","authors":"Fabio Giovannercole ,&nbsp;Tom De Smet ,&nbsp;Miguel Ángel Vences-Guzmán ,&nbsp;Frédéric Lauber ,&nbsp;Rémy Dugauquier ,&nbsp;Marc Dieu ,&nbsp;Laura Lizen ,&nbsp;Jonas Dehairs ,&nbsp;Gipsi Lima-Mendez ,&nbsp;Ziqiang Guan ,&nbsp;Christian Sohlenkamp ,&nbsp;Francesco Renzi","doi":"10.1016/j.jmb.2025.169063","DOIUrl":"10.1016/j.jmb.2025.169063","url":null,"abstract":"<div><div>In Proteobacteria, the outer membrane protein TamA and the inner membrane-anchored protein TamB form the Translocation and Assembly Module (TAM) complex, which facilitates the transport of autotransporters, virulence factors, and likely lipids across the two membranes. In Bacteroidota, TamA is replaced by TamL, a TamA-like lipoprotein with a lipid modification at its N-terminus that likely anchors it to the outer membrane. This structural difference suggests that TamL may have a distinct function compared to TamA. However, the role of TAM in bacterial phyla other than Proteobacteria remains unexplored.</div><div>Our study aimed to elucidate the function of TamL in <em>Flavobacterium johnsoniae</em>, an environmental Bacteroidota. Unlike its homologs in Proteobacteria, we found that TamL and TamB are essential in <em>F. johnsoniae</em>. Through genetic, phenotypic, proteomic, and lipidomic analyses, we show that TamL depletion severely compromises outer membrane integrity, as evidenced by reduced cell viability, altered cell shape, increased susceptibility to membrane-disrupting agents, and elevated levels of outer membrane lipoproteins. Notably, we did not observe an overall decrease in the levels of β-barrel outer membrane proteins, nor substantial alterations in outer membrane lipid composition.</div><div>By pull-down assays, we found TamL co-purifying with TamB in <em>F. johnsoniae</em>, suggesting an interaction. Furthermore, we found that while TamL and TamB monocistronic genes are conserved among Bacteroidota, only some species encode multiple TamL, TamB and TamA proteins.</div><div>To our knowledge, this study is the first to provide functional insights into a TAM subunit beyond Proteobacteria.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 10","pages":"Article 169063"},"PeriodicalIF":4.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
From Rat Tails to Glycoproteostasis: Motivated by Biology, Enabled by Biophysics, and Lucky 从大鼠尾巴到糖蛋白平衡:由生物学驱动、由生物物理学实现和幸运。
IF 4.7 2区 生物学
Journal of Molecular Biology Pub Date : 2025-02-28 DOI: 10.1016/j.jmb.2025.169055
Lila M. Gierasch
{"title":"From Rat Tails to Glycoproteostasis: Motivated by Biology, Enabled by Biophysics, and Lucky","authors":"Lila M. Gierasch","doi":"10.1016/j.jmb.2025.169055","DOIUrl":"10.1016/j.jmb.2025.169055","url":null,"abstract":"<div><div>In this article I tell the story of my career path and how I have come to focus my research on protein folding in the cell. My early fascination with protein folding began during my undergraduate research. My graduate work exploited reductionist approaches to explore structural features in proteins by using cyclic peptide models of<!--> <!-->β-turns. My career trajectory from these early days to present, described in the first section of this article, illustrates the importance of pursuing the scientific questions that one finds most exciting and seizing professional opportunities that enable these questions to be tackled productively. In addition, this trajectory shows how serendipity can shape a career path. The second section describes the extraordinary scientific discoveries I have witnessed in protein folding during my career. Here I explain how I was drawn into the world of protein folding in the<!--> <!-->cell. This turning point allowed me to participate in the explosion of research on molecular chaperones in the early 90′s and to help elucidate the nature of chaperone-substrate recognition, a problem I continue to focus on. Examples of our research contributions are presented in the third section, with a perspective on major challenges for the future offered in the last section. Throughout my career I have engaged in many collaborations;<!--> <!-->each has opened new scientific doors. Importantly, I seek to instill in my trainees the same excitement about research that I feel and to foster their growth as scientists and their discovery of their own passions and talents.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 11","pages":"Article 169055"},"PeriodicalIF":4.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Mechanistic Insights into Protein Biogenesis and Maturation on the Ribosome. 核糖体上蛋白质生物发生和成熟的机制见解。
IF 4.7 2区 生物学
Journal of Molecular Biology Pub Date : 2025-02-28 DOI: 10.1016/j.jmb.2025.169056
Alfred M Lentzsch, Jae Ho Lee, Shu-Ou Shan
{"title":"Mechanistic Insights into Protein Biogenesis and Maturation on the Ribosome.","authors":"Alfred M Lentzsch, Jae Ho Lee, Shu-Ou Shan","doi":"10.1016/j.jmb.2025.169056","DOIUrl":"10.1016/j.jmb.2025.169056","url":null,"abstract":"<p><p>The ribosome is a major cellular machine that converts genetic information into biological function. Emerging data show that the ribosome is not only a protein synthesis machine, but also participates in the maturation of the nascent protein into properly folded and active molecules. The ribosome surface near the opening of the polypeptide exit tunnel can interact directly with the newly synthesized proteins and, more importantly, provides a platform where numerous protein biogenesis factors assemble, gain access to the nascent chain, and direct them into diverse biogenesis pathways. In this article, we review the current understanding of cotranslational protein maturation pathways, with an emphasis on systems in which biochemical studies provided a high-resolution molecular understanding and yielded generalizable mechanistic principles.</p>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169056"},"PeriodicalIF":4.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
High Risk, High Reward: By Selecting Tsg101, A Protein That Sorts The Trash, As Our Personal ESCRT, Both HIV And I Were Able To Bud 高风险,高回报:通过选择Tsg101,一种分类垃圾的蛋白质,作为我们的个人ESCRT, HIV和我都能够发芽。
IF 4.7 2区 生物学
Journal of Molecular Biology Pub Date : 2025-02-28 DOI: 10.1016/j.jmb.2025.169053
Carol A. Carter
{"title":"High Risk, High Reward: By Selecting Tsg101, A Protein That Sorts The Trash, As Our Personal ESCRT, Both HIV And I Were Able To Bud","authors":"Carol A. Carter","doi":"10.1016/j.jmb.2025.169053","DOIUrl":"10.1016/j.jmb.2025.169053","url":null,"abstract":"<div><div>Being asked to write this “<em>Reflections</em>”-type article is a special honor offered at the end of one’s career and I am grateful for the opportunity to think back over the more than 4-decade span of my career in the field of HIV/AIDS Retrovirology. Although at this point in time there is still no vaccine or curative therapy for HIV/AIDS, this invitation to reminiscence comes in the year of FDA approval of Lenacapavir, the first-in-class anti-HIV agent targeting the viral capsid. This triumph in the field is the culmination of efforts of many, including some in my own laboratory, who were among the first to produce recombinant capsid protein (CAp24) for structural and biochemical studies. A current drawback of this drug is its low genetic barrier to viral resistance. The research finding considered to be our most important contribution to the field of HIV research was framed by the challenge to suppress the emergence of resistant variants, and I describe the paths that drove me to risk exploration of the non-traditional for potential solutions. Finally, I share my views on what I consider to be an important open question for the future: how to achieve greater diversity and inclusion in Science.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 11","pages":"Article 169053"},"PeriodicalIF":4.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The Elements of Life, Photosynthesis and Genomics 生命的要素,光合作用和基因组学。
IF 4.7 2区 生物学
Journal of Molecular Biology Pub Date : 2025-02-28 DOI: 10.1016/j.jmb.2025.169054
Sabeeha S. Merchant
{"title":"The Elements of Life, Photosynthesis and Genomics","authors":"Sabeeha S. Merchant","doi":"10.1016/j.jmb.2025.169054","DOIUrl":"10.1016/j.jmb.2025.169054","url":null,"abstract":"<div><div>I am a Professor of Biochemistry, Biophysics and Structural Biology and Plant and Microbial Biology at the University of California in Berkeley. I was born and raised in India, emigrated to the United States to attend university, earning a B.S. in Molecular Biology and a Ph.D. in Biochemistry at the University of Wisconsin in Madison. Following post-doctoral studies with Lawrence Bogorad at Harvard University where I became interested in genetic control of trace element quotas, I joined the department of Chemistry and Biochemistry at UCLA. One of the first to appreciate essential trace metals as potential regulators of gene expression, I articulated the details of the nutritional Cu regulon in Chlamydomonas. In parallel, I used genetic approaches to discover the genes governing missing steps in tetrapyrrole metabolism, including the attachment of heme to apocytochromes in the thylakoid lumen and the factors catalyzing the formation of ring V in chlorophyll. After biochemistry and classical genetics, I embraced genomics, taking a leadership role on the Joint Genome Institute’s efforts on the Chlamydomonas genome and more recently, contributing to high quality assemblies of several genomes in the green algal radiation, and large transcriptomic and proteomic datasets — focusing on the diel metabolic cycle in synchronized cultures and acclimation to key environmental and nutritional stressors — that are well-used and appreciated by the community. A new venture in Berkeley is the promotion of <em>Auxenochlorella protothecoides</em> as the true “green yeast” and as a platform for engineering algae to produce useful bioproducts.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 11","pages":"Article 169054"},"PeriodicalIF":4.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A BiP-centric View of Endoplasmic Reticulum Functions and of My Career 从内质网功能和我的职业生涯的角度来看,这是一个以bp为中心的观点。
IF 4.7 2区 生物学
Journal of Molecular Biology Pub Date : 2025-02-28 DOI: 10.1016/j.jmb.2025.169052
Linda M. Hendershot
{"title":"A BiP-centric View of Endoplasmic Reticulum Functions and of My Career","authors":"Linda M. Hendershot","doi":"10.1016/j.jmb.2025.169052","DOIUrl":"10.1016/j.jmb.2025.169052","url":null,"abstract":"<div><div>After completing my post-doctoral training at the University of Alabama, Birmingham and a brief period on the faculty there, I joined the Department of Tumor Cell Biology at St. Jude Children’s Research Hospital in 1987 as an Assistant Member and started my independent research program. For the following 37 years, I led a relatively small basic research group comprised at various times of post-doctoral fellows, graduate students, undergraduate students, and research technicians; many of whom I am still in contact. Last year I closed the lab and transitioned to an emeritus position at St. Jude. I continue to maintain several research collaborations covering areas of research that have long been dear to my heart.</div><div>My post-doctoral studies on BiP revealed that it controlled immunoglobulin assembly and transport, and as such, played a critical role in the fidelity of the immune response. My lab continued to define BiP’s functions in protein folding and subunit assembly, as well as, in degradation of proteins that failed to mature properly using biochemical, cell-based, and biophysical analyses. Several ER localized co-factors that regulate the activity of BiP and allow it to contribute to its multiple ER functions were identified by our group. These include DnaJ family members and nucleotide change factors. Through a variety of collaborative studies, we pursued BiP’s functions in maintaining the permeability barrier of the translocon, contributing to ER calcium stores, and regulating the up-stream transducers of the UPR, a stress response that is activated by the accumulation of unfolded proteins in the ER.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 11","pages":"Article 169052"},"PeriodicalIF":4.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Allostery in Disease: Anticancer Drugs, Pockets, and the Tumor Heterogeneity Challenge. 疾病中的变构:抗癌药物、口袋和肿瘤异质性挑战。
IF 4.7 2区 生物学
Journal of Molecular Biology Pub Date : 2025-02-26 DOI: 10.1016/j.jmb.2025.169050
Ruth Nussinov, Bengi Ruken Yavuz, Hyunbum Jang
{"title":"Allostery in Disease: Anticancer Drugs, Pockets, and the Tumor Heterogeneity Challenge.","authors":"Ruth Nussinov, Bengi Ruken Yavuz, Hyunbum Jang","doi":"10.1016/j.jmb.2025.169050","DOIUrl":"10.1016/j.jmb.2025.169050","url":null,"abstract":"<p><p>Charting future innovations is challenging. Yet, allosteric and orthosteric anticancer drugs are undergoing a revolution and taxing unresolved dilemmas await. Among the imaginative innovations, here we discuss cereblon and thalidomide derivatives as a means of recruiting neosubstrates and their degradation, allosteric heterogeneous bifunctional drugs like PROTACs, drugging phosphatases, inducers of targeted posttranslational protein modifications, antibody-drug conjugates, exploiting membrane interactions to increase local concentration, stabilizing the folded state, and more. These couple with harnessing allosteric cryptic pockets whose discovery offers more options to modulate the affinity of orthosteric, active site inhibitors. Added to these are strategies to counter drug resistance through drug combinations co-targeting pathways to bypass signaling blockades. Here, we discuss on the molecular and cellular levels, such inspiring advances, provide examples of their applications, their mechanisms and rational. We start with an overview on difficult to target proteins and their properties-rarely, if ever-conceptualized before, discuss emerging innovative drugs, and proceed to the increasingly popular allosteric cryptic pockets-their advantages-and critically, issues to be aware of. We follow with drug resistance and in-depth discussion of tumor heterogeneity. Heterogeneity is a hallmark of highly aggressive cancers, the core of drug resistance unresolved challenge. We discuss potential ways to target heterogeneity by predicting it. The increase in experimental and clinical data, computed (cell-type specific) interactomes, capturing transient cryptic pockets, learned drug resistance, workings of regulatory mechanisms, heterogeneity, and resistance-based cell signaling drug combinations, assisted by AI-driven reasoning and recognition, couple with creative allosteric drug discovery, charting future innovations.</p>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169050"},"PeriodicalIF":4.7,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Structures of ΔD421 Truncated Tau Fibrils Δ D421 截短 Tau 纤维的结构。
IF 4.7 2区 生物学
Journal of Molecular Biology Pub Date : 2025-02-26 DOI: 10.1016/j.jmb.2025.169051
Nadia El Mammeri, Pu Duan, Mei Hong
{"title":"Structures of ΔD421 Truncated Tau Fibrils","authors":"Nadia El Mammeri,&nbsp;Pu Duan,&nbsp;Mei Hong","doi":"10.1016/j.jmb.2025.169051","DOIUrl":"10.1016/j.jmb.2025.169051","url":null,"abstract":"<div><div>The microtubule-associated protein tau aggregates into pathological β-sheet amyloid fibrils in Alzheimer’s disease (AD) and other neurodegenerative diseases. In these aggregates, tau is chemically modified, including abnormal hyperphosphorylation and truncation. Truncation after D421 in the C-terminal domain occurs at early stages of AD. Here we investigate the structures of ΔD421-truncated 0N4R tau fibrils assembled <em>in vitro</em> in the absence of anionic cofactors. Using solid-state NMR spectroscopy and cryoelectron microscopy, we show that ΔD421-truncated 0N4R tau forms homogeneous fibrils whose rigid core adopts a three-layered β-sheet structure that spans R2, R3 and R4 repeats. This structure is essentially identical to that of full-length tau containing phospho-mimetic mutations at the PHF1 epitope in the C-terminal domain. In comparison, a ΔD421-truncated tau that additionally contains three phospho-mimetic mutations at the AT8 epitope in the proline-rich region forms a fibril core that includes the first half of the C-terminal domain, which is excluded from all known pathological tau fibril cores. These results indicate that the posttranslational modification code of tau contains redundancy: both charge modification and truncation of the C-terminal domain promote a three-layered β-sheet structure, which resembles pathological four-repeat tau structures in several tauopathies. In comparison, reducing the positive charges at the AT8 epitope in ΔD421-truncated tau promotes a fibril core that includes an immobilized C-terminal domain. The absence of this structure in tauopathy brains implies that ΔD421 truncation does not occur in conjunction with AT8 phosphorylation in diseased brains.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 10","pages":"Article 169051"},"PeriodicalIF":4.7,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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