Journal of Molecular Biology最新文献

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Conformations of Linker Histone H1 Bound to Nucleosome Arrays 连接体组蛋白H1与核小体阵列结合的构象。
IF 4.5 2区 生物学
Journal of Molecular Biology Pub Date : 2026-03-15 Epub Date: 2026-01-21 DOI: 10.1016/j.jmb.2026.169655
Bo Yuan , Subhra Kanti Das , Weilin Wang , Gillian Camacho , Ashok Kumar , Jeffrey J. Hayes , Tae-Hee Lee
{"title":"Conformations of Linker Histone H1 Bound to Nucleosome Arrays","authors":"Bo Yuan ,&nbsp;Subhra Kanti Das ,&nbsp;Weilin Wang ,&nbsp;Gillian Camacho ,&nbsp;Ashok Kumar ,&nbsp;Jeffrey J. Hayes ,&nbsp;Tae-Hee Lee","doi":"10.1016/j.jmb.2026.169655","DOIUrl":"10.1016/j.jmb.2026.169655","url":null,"abstract":"<div><div>Linker histone H1 plays crucial roles in nucleosome compaction and chromatin condensation. The highly basic C-terminal domain (CTD) of H1 interacts strongly with DNA, a critical aspect of its contribution to H1 function. Despite its critical roles in gene packaging in chromatin where nucleosomes are linked as an array, how H1 CTD interacts with nucleosome arrays remain poorly understood. Here we report a single-molecule FRET study of the conformation and conformational dynamics of the CTD of H1 bound to a 12-mer nucleosome array. According to our results, H1 CTDs within a nucleosome array show signs of highly heterogeneous conformations that are overall more extended and dynamic than that bound to a mono-nucleosome. This observation suggests that H1 CTD interacts randomly with two or more DNA linkers across nucleosomes in an array. This suggestion is further supported by our observation that these domains become more condensed and less dynamic as the arrays become less condensed at a lower NaCl concentration. Our results also suggest that histone H3 and H4 acetylation mimetics and tailless H3 result in H1 CTD interacting less with multiple linkers as they induce a less condensed structure of nucleosome arrays, thereby driving H1 CTD back to its own nucleosome. Our data support that H1 CTD interacts non-specifically with DNA linkers that are either local or distal and that modifications of the H3 and H4 tail domains can regulate H1-mediated chromatin condensation at both the nucleosome and nucleosome array levels.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 6","pages":"Article 169655"},"PeriodicalIF":4.5,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040102","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
Multivalent AMOTL1 Engages NEDD4-1 and KIBRA Through Distinct Cooperative Binding Mechanisms 多价AMOTL1通过不同的合作结合机制参与NEDD4-1和KIBRA。
IF 4.5 2区 生物学
Journal of Molecular Biology Pub Date : 2026-03-15 Epub Date: 2026-01-22 DOI: 10.1016/j.jmb.2026.169652
Amber Vogel , Matthew McWhorter , Ethiene Kwok , Afua Nyarko
{"title":"Multivalent AMOTL1 Engages NEDD4-1 and KIBRA Through Distinct Cooperative Binding Mechanisms","authors":"Amber Vogel ,&nbsp;Matthew McWhorter ,&nbsp;Ethiene Kwok ,&nbsp;Afua Nyarko","doi":"10.1016/j.jmb.2026.169652","DOIUrl":"10.1016/j.jmb.2026.169652","url":null,"abstract":"<div><div>The Hippo signaling pathway regulates the homeostatic balance between cell growth and apoptosis through intricate networks of multivalent protein complexes. How multivalency modulates the assembly and stability of these protein complexes remains poorly understood. Here, we show that Angiomotin-like 1 (AMOTL1), a scaffold protein containing three PPxY motifs, employs distinct cooperative binding mechanisms to engage two WW domain–containing partners: NEDD4-1, which promotes AMOTL1 degradation, and KIBRA, which protects AMOTL1 from degradation. Using quantitative molecular biophysical analyses, including isothermal titration calorimetry and nuclear magnetic resonance spectroscopy, we demonstrate that AMOTL1 forms a cooperatively stabilized complex with NEDD4-1 through simultaneous engagement of all three PPxY motifs with three of the four NEDD4-1 WW domains. This cooperative binding mode produces approximately ten-fold enhancement in affinity compared to the primary anchor interaction alone. In contrast, KIBRA engages AMOTL1 primarily through high-affinity binding at the C-terminal PPxY motif, with transient secondary interactions at the other PPxY sites that do not enhance overall binding strength. These contrasting mechanisms demonstrate that multivalency within the Hippo pathway serves as a tunable regulatory feature, where cooperative interactions can either enhance or minimally contribute to binding strength, explaining how a single scaffold protein can be differentially regulated to achieve opposing functional outcomes.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 6","pages":"Article 169652"},"PeriodicalIF":4.5,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043713","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
Self-Assembling RNA Nanostructures are Highly Sensitive to Environmental Conditions 自组装纳米结构对环境条件高度敏感。
IF 4.5 2区 生物学
Journal of Molecular Biology Pub Date : 2026-03-01 Epub Date: 2025-12-19 DOI: 10.1016/j.jmb.2025.169601
Jordan Aposhian , Surya Pratap S. Deopa , Scott Horowitz , Joseph D. Yesselman
{"title":"Self-Assembling RNA Nanostructures are Highly Sensitive to Environmental Conditions","authors":"Jordan Aposhian ,&nbsp;Surya Pratap S. Deopa ,&nbsp;Scott Horowitz ,&nbsp;Joseph D. Yesselman","doi":"10.1016/j.jmb.2025.169601","DOIUrl":"10.1016/j.jmb.2025.169601","url":null,"abstract":"<div><div>Recent developments in RNA nanotechnology have led to an increase in the design of specific, higher-order RNA structures, which will ultimately be used in drug delivery and immunomodulation applications. As researchers create RNA nanostructures with the intention of making them a standard tool in molecular biologists’ toolkits, further investigation is required into the robustness of RNA designs. Primarily, in what different molecular contexts are the designed and intended nanostructures stable? In this work, we show that RNA nanostructure self-assembly is highly sensitive to environmental conditions by using second-order right-angle light scattering. While a test RNA hexagonal grid nanostructure forms correctly through 120° kissing loops under ideal conditions, small variations in salt conditions and annealing times cause the nanostructure to form less structured variants. Tertiary contacts for self-assembly require magnesium and break over a broad range of low temperatures, melting at 43 °C. In contrast, this was found to be considerably lower than the secondary structure melting, which occurred at 75 °C. This work highlights the importance of quantitatively and thermodynamically characterizing self-assembling nanostructures as they are increasingly deployed for engineering and therapeutic applications.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 5","pages":"Article 169601"},"PeriodicalIF":4.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145802915","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
Conformational Changes in Type IA Topoisomerases Facilitate Strand Passage IA型拓扑异构酶的构象改变促进了链的通过。
IF 4.5 2区 生物学
Journal of Molecular Biology Pub Date : 2026-03-01 Epub Date: 2025-08-21 DOI: 10.1016/j.jmb.2025.169402
Deepesh Sigdel, Dillon Balthrop, Maria Mills
{"title":"Conformational Changes in Type IA Topoisomerases Facilitate Strand Passage","authors":"Deepesh Sigdel,&nbsp;Dillon Balthrop,&nbsp;Maria Mills","doi":"10.1016/j.jmb.2025.169402","DOIUrl":"10.1016/j.jmb.2025.169402","url":null,"abstract":"<div><div>Type IA topoisomerases are present in all kingdoms of life and are responsible for simplifying torsionally strained DNA structures during fundamental cellular processes. The common model for this simplification is based upon the concept of passage of an intact DNA strand through a transient cut in another single DNA strand. This process requires the protein to undergo several conformational changes. In this review, we discuss these conformational changes across the strand passage cycle from DNA binding through opening and closing of a protein mediated DNA gate. We also examine the involvement of the diverse C-terminal domains of these enzymes during strand-passage and current open questions in the field.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 5","pages":"Article 169402"},"PeriodicalIF":4.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937822","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 Analysis of GodF, an O-glutamylation Enzyme Involved in Goadsporin Biosynthesis 参与抗生素素生物合成的o -谷氨酰化酶GodF的结构分析。
IF 4.5 2区 生物学
Journal of Molecular Biology Pub Date : 2026-03-01 Epub Date: 2025-12-30 DOI: 10.1016/j.jmb.2025.169619
Akiko Shimizu-Ibuka , Yoshiki Kato , Shumpei Asamizu , Hiroyasu Onaka
{"title":"Structural Analysis of GodF, an O-glutamylation Enzyme Involved in Goadsporin Biosynthesis","authors":"Akiko Shimizu-Ibuka ,&nbsp;Yoshiki Kato ,&nbsp;Shumpei Asamizu ,&nbsp;Hiroyasu Onaka","doi":"10.1016/j.jmb.2025.169619","DOIUrl":"10.1016/j.jmb.2025.169619","url":null,"abstract":"<div><div>Goadsporin is one of linear azole-containing peptides (LAPs) that form a subgroup within ribosomally synthesized and post-translationally modified peptides (RiPPs). It contains two dehydroalanine residues formed through the action of two enzymes, GodF and GodG, in a two-step process involving serine <em>O</em>-glutamylation followed by elimination. Here, we report the X-ray crystal structure of GodF, which catalyzes the tRNA-dependent glutamylation of target serine residues, resolved at a 2.34-Å resolution. Although GodF exhibits low homology at the primary sequence level, its overall structure closely resembles that of TbtB, a tRNA<sup>Glu</sup>-dependent enzyme involved in thiopeptide biosynthesis, as well as the <em>O</em>-glutamylation domains of NisB and MibB, which serve as dehydroalanine synthases in lanthipeptide biosynthesis. The residues and structural elements forming the active site are well-aligned among these enzymes, while regions outside the active site are poorly conserved. Like TbtB, GodF features a coiled-coil subdomain at its N-terminus, and AlphaFold3 predicts this region plays a key role in recognizing the substrate tRNA<sup>Glu</sup>. GodF also contains a typical RiPP recognition element (RRE) motif; however, the spatial arrangement of the secondary structural elements comprising this motif differs notably from those in other <em>O</em>-glutamylating enzymes. These structural characteristics of GodF highlight the diversity of substrate-binding pockets among RiPP-modifying enzymes, reflecting the variability in their substrate peptides and the necessity to accommodate distinct conformational and physicochemical properties.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 5","pages":"Article 169619"},"PeriodicalIF":4.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888414","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
Ancestral Sequence Reconstruction Reveals CTP-dependent Loading of the Bacterial Centromere-binding Protein ParB as an Ancient Evolutionary Feature 祖先序列重建揭示了细菌着丝粒结合蛋白ParB的ctp依赖负载是一种古老的进化特征。
IF 4.5 2区 生物学
Journal of Molecular Biology Pub Date : 2026-03-01 Epub Date: 2025-12-23 DOI: 10.1016/j.jmb.2025.169611
Juri Hanßmann , Stefano Lometto , Wieland Steinchen , Lucas Schnabel , Gert Bange , Georg K.A. Hochberg , Martin Thanbichler
{"title":"Ancestral Sequence Reconstruction Reveals CTP-dependent Loading of the Bacterial Centromere-binding Protein ParB as an Ancient Evolutionary Feature","authors":"Juri Hanßmann ,&nbsp;Stefano Lometto ,&nbsp;Wieland Steinchen ,&nbsp;Lucas Schnabel ,&nbsp;Gert Bange ,&nbsp;Georg K.A. Hochberg ,&nbsp;Martin Thanbichler","doi":"10.1016/j.jmb.2025.169611","DOIUrl":"10.1016/j.jmb.2025.169611","url":null,"abstract":"<div><div>In most bacteria, chromosome and low-copy plasmid segregation are mediated by the ParAB<em>S</em> system. Its component ParB functions as a DNA sliding clamp that assembles on centromere-like <em>parS</em> sites to form large nucleoprotein complexes, which are subsequently positioned by the ATPase ParA. Loading of ParB onto DNA is regulated by a recently discovered conserved CTPase domain, yet the evolutionary origin of this regulatory module remains unclear. Here, we apply ancestral sequence reconstruction to resurrect ancient ParB proteins dating back to the early origins of the bacterial domain. Biochemical, structural, and cell biological analyses demonstrate that these reconstructed proteins display all core activities of their modern counterparts, suggesting that the ParAB<em>S</em> system emerged early during bacterial evolution and has essentially remained unchanged ever since. More broadly, our findings indicate that regulatory CTPases represent an ancient molecular innovation, whose origins can be traced back to the earliest stages of life.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 5","pages":"Article 169611"},"PeriodicalIF":4.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145832018","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
Rising Star Engineering the Genome for Curative Futures 明日之星:基因工程的未来治疗。
IF 4.5 2区 生物学
Journal of Molecular Biology Pub Date : 2026-03-01 Epub Date: 2026-01-02 DOI: 10.1016/j.jmb.2025.169618
Dali Li
{"title":"Rising Star Engineering the Genome for Curative Futures","authors":"Dali Li","doi":"10.1016/j.jmb.2025.169618","DOIUrl":"10.1016/j.jmb.2025.169618","url":null,"abstract":"<div><div>As a professor of biomedicine in the School of Life Sciences at East China Normal University (ECNU), I am dedicated to developing advanced genome editing technologies for disease modeling and precise gene therapy. My foundational training at Hunan Normal University and Texas A&amp;M University cultivated a deep interest in using engineered cellular and animal models to understand human diseases. Since 2013, my laboratory at ECNU has pioneered the use of TALEN and CRISPR/Cas9 for the rapid generation of knockout mouse and rat models for disease studies. Once stepped in genome editing field, I shifted my focus to advancing editing tools and developing gene therapy strategies for genetic disorders and cancer. My team has developed a suite of high-performance base editors for nuclear DNA, mitochondrial DNA, and RNA, broadening editing capabilities while enhancing precision and safety. Leveraging these technologies, we have designed several therapeutic strategies that have shown efficacy in cellular and animal models of genetic diseases. Through collaborative efforts, we have successfully translated genome editing into clinical applications, contributing to the treatment of patients with <em>β</em>-thalassemia. Additionally, we have developed a non-viral, site-specific CAR-T platform for lymphoma therapy. Looking forward, I aim to develop the next generation of long-fragment, site-specific integration technologies and accelerate clinical translation to bring transformative cures to more patients.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 5","pages":"Article 169618"},"PeriodicalIF":4.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145899115","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
Post-Translational Modifications Orchestrate Repair of Trapped Topoisomerase-Induced DNA Breaks via TDP1 and TDP2 翻译后修饰通过TDP1和TDP2协调被困拓扑异构酶诱导的DNA断裂的修复。
IF 4.5 2区 生物学
Journal of Molecular Biology Pub Date : 2026-03-01 Epub Date: 2025-06-26 DOI: 10.1016/j.jmb.2025.169309
Benu Brata Das, Saini Basu , Abhik Sengupta , Arpan Bhattacharyya
{"title":"Post-Translational Modifications Orchestrate Repair of Trapped Topoisomerase-Induced DNA Breaks via TDP1 and TDP2","authors":"Benu Brata Das,&nbsp;Saini Basu ,&nbsp;Abhik Sengupta ,&nbsp;Arpan Bhattacharyya","doi":"10.1016/j.jmb.2025.169309","DOIUrl":"10.1016/j.jmb.2025.169309","url":null,"abstract":"<div><div>DNA topoisomerases are critical for maintaining DNA topology and facilitating replication, transcription, and chromatin organization in both nuclear and mitochondrial genomes. When covalently trapped on DNA as topoisomerase cleavage complexes (Topcc’s), notably Top1ccs and Top2ccs, these enzymes generate cytotoxic DNA lesions that disrupt genomic integrity and threaten cell viability. Tyrosyl-DNA phosphodiesterase (TDP1 and TDP2) has emerged as key player in the resolution of these lesions, with broader roles in the repair of diverse DNA end structures. Post-translational modifications (PTMs) dynamically regulate the DNA damage response by modulating the activity, localization, and interactions of repair factors. This review provides a comprehensive overview of the mechanisms by which PTMs modulate the activity of Top1<span> and Top2, and the repair of their covalently trapped complexes. We further delineate how PTMs fine-tune the functional networks of TDP1 and TDP2, enhancing their efficiency in resolving Topccs and preserving genome stability. Together, these insights highlight the multilayered regulatory mechanisms that safeguard genomic integrity and offer potential avenues for therapeutic intervention.</span></div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 5","pages":"Article 169309"},"PeriodicalIF":4.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525839","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
Pioneers: Glucose Sensing and Control of Health-span and Lifespan 先驱者:葡萄糖感知和控制健康跨度和寿命。
IF 4.5 2区 生物学
Journal of Molecular Biology Pub Date : 2026-03-01 Epub Date: 2026-01-09 DOI: 10.1016/j.jmb.2026.169634
Sheng-Cai Lin
{"title":"Pioneers: Glucose Sensing and Control of Health-span and Lifespan","authors":"Sheng-Cai Lin","doi":"10.1016/j.jmb.2026.169634","DOIUrl":"10.1016/j.jmb.2026.169634","url":null,"abstract":"<div><div>My independent career started based on a simple doctrine of protein multifunctionality, by intuitively choosing the protein called AXIN, which has turned out to be the protagonist of my scientific life. This led us to discover the sensing pathway for glucose, which links to AMPK and mTORC1, two master metabolic controllers. We found that AXIN binds LKB1, an upstream kinase of AMPK, and that the AXIN:LKB1 complex translocates to the lysosomal surface after the lysosomal aldolase senses low glucose (fructose-1,6-bisphosphate as the direct signal) to activate AMPK and concomitantly inhibit mTORC1. Remarkably, we found that the lysosomal glucose-sensing AMPK pathway is shared by metformin, a glucose-lowering drug known to also extend lifespan and reduce cancer risk. In search of metabolites enriched in calorie-restricted mice and able to activate AMPK via the lysosomal pathway, we identified that lithocholic acid (LCA) as such a factor. We also identified TULP3 as the LCA receptor, which signals to activate sirtuins, increase NAD<sup>+</sup>, activate AMPK and inhibit mTORC1. In translation, we have identified an aldolase inhibitor termed aldometanib, which mimics glucose starvation to activate AMPK. Aldometanib can alleviate fatty liver, lower blood glucose, and extend lifespan in animals. Surprisingly, aldometanib can also mobilize tumoricidal CD8<sup>+</sup> T cells to infiltrate and contain hepatocellular carcinomas (HCC), enabling HCC-bearing mice to live to ripe ages, the endpoint of cancer therapy. Our work has thus revealed that glucose acts as a messenger that signals through a specialized route to control health-span and lifespan. We will continue to explore the teleological meaning of glucose as a “chosen” molecule.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 5","pages":"Article 169634"},"PeriodicalIF":4.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951111","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
Multivalency in Tau–Microtubule Interactions: Heterogeneous Association and Functional Implications tau -微管相互作用的多价性:异质关联和功能意义。
IF 4.5 2区 生物学
Journal of Molecular Biology Pub Date : 2026-03-01 Epub Date: 2025-12-19 DOI: 10.1016/j.jmb.2025.169600
Segev Naveh-Tassa, Yaakov Levy
{"title":"Multivalency in Tau–Microtubule Interactions: Heterogeneous Association and Functional Implications","authors":"Segev Naveh-Tassa,&nbsp;Yaakov Levy","doi":"10.1016/j.jmb.2025.169600","DOIUrl":"10.1016/j.jmb.2025.169600","url":null,"abstract":"<div><div>Tau is a dynamic microtubule-associated protein essential for maintaining microtubule (MT) stability and neuronal function. Its intrinsically disordered nature, combined with its multivalent binding capacity, makes it challenging to characterize structurally. Governed largely by electrostatic interactions, both in solution and when bound to MTs, Tau exhibits highly transient and heterogeneous behavior. Here, we apply coarse-grained molecular dynamics simulations to investigate tau–MT interactions and uncover how multivalent binding is regulated at the sub-regional level. Our simulations capture interactions both with the flexible, disordered C-terminal tails of tubulin and with the structured tubulin surface. We show that distinct tau sub-regions contribute differentially to binding. Isoform variation, defined by the presence or absence of specific sub-regions, further modulates tau’s interaction with tubulin, influencing both MT stability and dimer polymerization rates through electrostatic tuning. Our simulations also reveal how Alzheimer’s disease-associated phosphorylation disrupts tau–MT interactions by weakening multivalent engagement. Together, our findings provide new mechanistic insight into how electrostatics and sub-regional composition regulate the dynamic, multivalent nature of tau–MT interactions, with implications for neuronal integrity and tauopathy-related dysfunction.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 5","pages":"Article 169600"},"PeriodicalIF":4.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145802907","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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