Journal of Molecular Biology最新文献_第3页

The HSP90/R2TP Quaternary Chaperone Scaffolds Assembly of the TSC Complex HSP90/R2TP四级伴侣支架了TSC复合体的组装。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-10-26 DOI: 10.1016/j.jmb.2024.168840

Claire Abéza , Philipp Busse , Ana C.F. Paiva , Marie-Eve Chagot , Justine Schneider , Marie-Cécile Robert , Franck Vandermoere , Christine Schaeffer , Bruno Charpentier , Pedro M.F. Sousa , Tiago M. Bandeiras , Xavier Manival , Sarah Cianferani , Edouard Bertrand , Céline Verheggen

{"title":"The HSP90/R2TP Quaternary Chaperone Scaffolds Assembly of the TSC Complex","authors":"Claire Abéza , Philipp Busse , Ana C.F. Paiva , Marie-Eve Chagot , Justine Schneider , Marie-Cécile Robert , Franck Vandermoere , Christine Schaeffer , Bruno Charpentier , Pedro M.F. Sousa , Tiago M. Bandeiras , Xavier Manival , Sarah Cianferani , Edouard Bertrand , Céline Verheggen","doi":"10.1016/j.jmb.2024.168840","DOIUrl":"10.1016/j.jmb.2024.168840","url":null,"abstract":"<div><div>The R2TP chaperone is composed of the RUVBL1/RUVBL2 AAA+ ATPases and two adapter proteins, RPAP3 and PIH1D1. Together with HSP90, it functions in the assembly of macromolecular complexes that are often involved in cell proliferation. Here, proteomic experiments using the isolated PIH domain reveals additional R2TP partners, including the Tuberous Sclerosis Complex (TSC) and many transcriptional complexes. The TSC is a key regulator of mTORC1 and is composed of TSC1, TSC2 and TBC1D7. We show a direct interaction of TSC1 with the PIH phospho-binding domain of PIH1D1, which is, surprisingly, phosphorylation independent. Via the use of mutants and KO cell lines, we observe that TSC2 makes independent interactions with HSP90 and the TPR domains of RPAP3. Moreover, inactivation of PIH1D1 or the RUVBL1/2 ATPase activity inhibits the association of TSC1 with TSC2. Taken together, these data suggest a model in which the R2TP recruits TSC1 via PIH1D1 and TSC2 via RPAP3 and HSP90, and use the chaperone-like activities of RUVBL1/2 to stimulate their assembly.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"436 23","pages":"Article 168840"},"PeriodicalIF":4.7,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566756","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

GEMimp: An Accurate and Robust Imputation Method for Microbiome Data Using Graph Embedding Neural Network GEMimp：利用图嵌入神经网络对微生物组数据进行准确而稳健的估算方法。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-10-26 DOI: 10.1016/j.jmb.2024.168841

Ziwei Sun, Kai Song

{"title":"GEMimp: An Accurate and Robust Imputation Method for Microbiome Data Using Graph Embedding Neural Network","authors":"Ziwei Sun, Kai Song","doi":"10.1016/j.jmb.2024.168841","DOIUrl":"10.1016/j.jmb.2024.168841","url":null,"abstract":"<div><div>Microbiome research has increasingly underscored the profound link between microbial compositions and human health, with numerous studies establishing a strong correlation between microbiome characteristics and various diseases. However, the analysis of microbiome data is frequently compromised by inherent sparsity issues, characterized by a substantial presence of observed zeros. These zeros not only skew the abundance distribution of microbial species but also undermine the reliability of scientific conclusions drawn from such data. Addressing this challenge, we introduce GEMimp, an innovative imputation method designed to infuse robustness into microbiome data analysis. GEMimp leverages the node2vec algorithm, which incorporates both Breadth-First Search (BFS) and Depth-First Search (DFS) strategies in its random walks sampling process. This approach enables GEMimp to learn nuanced, low-dimensional representations of each taxonomic unit, facilitating the reconstruction of their similarity networks with unprecedented accuracy.</div><div>Our comparative analysis pits GEMimp against state-of-the-art imputation methods including SAVER, MAGIC and mbImpute. The results unequivocally demonstrate that GEMimp outperforms its counterparts by achieving the highest Pearson correlation coefficient when compared to the original raw dataset. Furthermore, GEMimp shows notable proficiency in identifying significant taxa, enhancing the detection of disease-related taxa and effectively mitigating the impact of sparsity on both simulated and real-world datasets, such as those pertaining to Type 2 Diabetes (T2D) and Colorectal Cancer (CRC). These findings collectively highlight the strong effectiveness of GEMimp, allowing for better analysis on microbial data. With alleviation of sparsity issues, it could be greatly facilitated in downstream analyses and even in the field of microbiology.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"436 23","pages":"Article 168841"},"PeriodicalIF":4.7,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566750","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

Optogenetic Control of Condensates: Principles and Applications 冷凝物的光遗传学控制：原理与应用。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-10-24 DOI: 10.1016/j.jmb.2024.168835

Zikang Dennis Huang , Lukasz J. Bugaj

引用次数: 0

Cryo-EM Structure of raiA ncRNA From Clostridium Reveals a New RNA 3D Fold 梭状芽孢杆菌 raiA ncRNA 的低温电子显微镜结构揭示了一种新的 RNA 3D 折叠。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-10-24 DOI: 10.1016/j.jmb.2024.168833

Nagendar Goud Badepally, Tales Rocha de Moura, Elżbieta Purta, Eugene F. Baulin, Janusz M. Bujnicki

引用次数: 0

Unraveling the Membrane Topology of TMEM151A: A Step Towards Understanding its Cellular Role 揭示 TMEM151A 的膜拓扑结构：了解其细胞作用的一步。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-10-23 DOI: 10.1016/j.jmb.2024.168834

Lisastella Morinelli , Beatrice Corradi , Pietro Arnaldi , Katia Cortese , Martina Muià , Federico Zara , Luca Maragliano , Bruno Sterlini , Anna Corradi

{"title":"Unraveling the Membrane Topology of TMEM151A: A Step Towards Understanding its Cellular Role","authors":"Lisastella Morinelli , Beatrice Corradi , Pietro Arnaldi , Katia Cortese , Martina Muià , Federico Zara , Luca Maragliano , Bruno Sterlini , Anna Corradi","doi":"10.1016/j.jmb.2024.168834","DOIUrl":"10.1016/j.jmb.2024.168834","url":null,"abstract":"<div><div>Transmembrane protein 151A (TMEM151A) has been identified as a causative gene for paroxysmal kinesigenic dyskinesia, though its molecular function remains almost completely unknown. Understanding the membrane topology of transmembrane proteins is crucial for elucidating their functions and possible interacting partners. In this study, we utilized molecular dynamics simulations, immunocytochemistry, and electron microscopy to define the topology of TMEM151A. Our results validate a starting AlphaFold model of TMEM151A and reveal that it comprises a transmembrane domain with two membrane-spanning alpha helices connected by a short extracellular loop and an intramembrane helix-hinge-helix structure. Notably, most of the protein is oriented towards the intracellular side of the membranes with a large cytosolic domain featuring a combination of alpha-helix and beta-sheet structures, as well as the protein N- and C-termini. These insights into TMEM151A’s topology and orientation of its domains with respect of the cell membranes provide essential information for future functional studies and represent a first fundamental step for understanding its role in the pathogenesis of paroxysmal kinesigenic dyskinesia.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"436 23","pages":"Article 168834"},"PeriodicalIF":4.7,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492283","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

Disruption of CAD Oligomerization by Pathogenic Variants 致病变体对 CAD 寡聚化的破坏。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-10-22 DOI: 10.1016/j.jmb.2024.168832

Francisco Del Caño-Ochoa , Lobna Ramadane-Morchadi , Lluís Eixerés , María Moreno-Morcillo , Rafael Fernández-Leiro , Santiago Ramón-Maiques

{"title":"Disruption of CAD Oligomerization by Pathogenic Variants","authors":"Francisco Del Caño-Ochoa , Lobna Ramadane-Morchadi , Lluís Eixerés , María Moreno-Morcillo , Rafael Fernández-Leiro , Santiago Ramón-Maiques","doi":"10.1016/j.jmb.2024.168832","DOIUrl":"10.1016/j.jmb.2024.168832","url":null,"abstract":"<div><div>CAD, the multi-enzymatic protein essential for initiating the <em>de novo</em> biosynthesis of pyrimidine nucleotides, forms large hexamers whose structure and function are not fully understood. Defects in CAD cause a severe neurometabolic disorder that is challenging to diagnose. We developed a cellular functional assay to identify defective CAD variants, and in this study, we characterized five pathogenic missense mutations in CAD’s dihydroorotase (DHO) and aspartate transcarbamoylase (ATC) domains. All mutations impaired enzymatic activities, with two notably disrupting the formation of DHO dimers and ATC trimers. Combining crystal structures and AlphaFold predictions, we modeled the hexameric CAD complex, highlighting the central role of the DHO and ATC domains in its assembly. Our findings provide insight into CAD’s stability, function, and organization, revealing that correct oligomerization of CAD into a supramolecular complex is required for its function in nucleotide synthesis and that mutations affecting this assembly are potentially pathogenic.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"436 23","pages":"Article 168832"},"PeriodicalIF":4.7,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492280","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

Molecular Phenotypes Segregate Missense Mutations in SLC13A5 Epilepsy SLC13A5 癫痫错义突变的分子表型分离。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-10-22 DOI: 10.1016/j.jmb.2024.168820

Valeria Jaramillo-Martinez, Souad R. Sennoune, Elena B. Tikhonova, Andrey L. Karamyshev, Vadivel Ganapathy, Ina L. Urbatsch

{"title":"Molecular Phenotypes Segregate Missense Mutations in SLC13A5 Epilepsy","authors":"Valeria Jaramillo-Martinez, Souad R. Sennoune, Elena B. Tikhonova, Andrey L. Karamyshev, Vadivel Ganapathy, Ina L. Urbatsch","doi":"10.1016/j.jmb.2024.168820","DOIUrl":"10.1016/j.jmb.2024.168820","url":null,"abstract":"<div><div>The sodium-coupled citrate transporter (NaCT, SLC13A5) mediates citrate uptake across the plasma membrane via an inward Na<sup>+</sup> gradient. Mutations in SLC13A5 cause early infantile epileptic encephalopathy type-25 (EIEE25, SLC13A5 Epilepsy) due to impaired citrate uptake in neurons and astrocytes. Despite clinical identification of disease-causing mutations, underlying mechanisms and cures remain elusive. Here we mechanistically classify six frequent SLC13A5 mutations by phenotyping their protein cell surface expression and citrate transport functions. Mutants C50R, T142M, and T227M exhibit impaired citrate transport despite normal expression at the cell surface. In contrast, mutations G219R, S427L, and L488P show low total protein expression levels, absence of mature, glycosylated proteins at the cell surface, retention of the proteins in the endoplasmic reticulum, and diminished transport activity. This mechanistic classification divides SLC13A5 mutants into two groups, Class I (C50R, T142M, and T227M) and Class II (G219R, S427L, and L488P). Importantly, mutants’ mRNA levels resemble wildtype, suggesting post-translational defects. Class II mutations display immature core-glycosylation and shortened half-lives, indicating protein folding defects. Together, these experiments provide a comprehensive understanding of the disease-causing mutation’s defects in SLC13A5 Epilepsy at the biochemical and molecular level and shed light into the trafficking pathway(s) of NaCT. The two classes of mutations will require fundamentally different approaches for treatment to either restore transport function of the mutant protein that is capable of reaching the cell surface (Class I), or therapies that enable the correction of protein folding defects to enable escape to the cell surface where it may restore transport function (Class II).</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"436 22","pages":"Article 168820"},"PeriodicalIF":4.7,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492281","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

Engineered mRNAs With Stable Structures Minimize Double-stranded RNA Formation and Increase Protein Expression 具有稳定结构的工程 mRNA 可最大限度地减少双链 RNA 的形成，提高蛋白质的表达。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-10-19 DOI: 10.1016/j.jmb.2024.168822

Qianshan Qin , Huayuan Yan , Weixiang Gao , Ruyin Cao , Guopeng Liu , Xiaojing Zhang , Niangang Wang , Wenjie Zuo , Lei Yuan , Peng Gao , Qi Liu

{"title":"Engineered mRNAs With Stable Structures Minimize Double-stranded RNA Formation and Increase Protein Expression","authors":"Qianshan Qin , Huayuan Yan , Weixiang Gao , Ruyin Cao , Guopeng Liu , Xiaojing Zhang , Niangang Wang , Wenjie Zuo , Lei Yuan , Peng Gao , Qi Liu","doi":"10.1016/j.jmb.2024.168822","DOIUrl":"10.1016/j.jmb.2024.168822","url":null,"abstract":"<div><div>The therapeutic use of synthetic message RNA (mRNA) has been validated in COVID-19 vaccines and shows enormous potential in developing infectious and oncological vaccines. However, double-stranded RNA (dsRNA) byproducts generated during the <em>in vitro</em> transcription (IVT) process can diminish the efficacy of mRNA-based therapeutics and provoke innate immune responses. Existing methods to eliminate dsRNA byproducts are often cumbersome and labor-intensive. In this study, we revealed that a loose mRNA secondary structure and more unpaired U bases in the sequence generally lead to the formation of more dsRNA byproducts during the IVT process. We further developed a predictive model for dsRNA byproducts formation based on sequence characteristics to guide the optimization of mRNA sequences, helping to minimize unwanted immune response and improve the protein expression of mRNA products. Collectively, our study provides novel clues and methodologies for developing effective mRNA therapeutics with minimized dsRNA byproducts and increased protein expression.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"436 22","pages":"Article 168822"},"PeriodicalIF":4.7,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454992","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 Hydrophobic Core Stabilizes the Residual Structure in the RRM2 Intermediate State of the ALS-linked Protein TDP-43 疏水核心稳定了 ALS 链接蛋白 TDP-43 的 RRM2 中间状态的残余结构。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-10-18 DOI: 10.1016/j.jmb.2024.168823

Brian C. Mackness , Brittany R. Morgan , Laura M. Deveau , Sagar V. Kathuria , Jill A. Zitzewitz , Francesca Massi

{"title":"A Hydrophobic Core Stabilizes the Residual Structure in the RRM2 Intermediate State of the ALS-linked Protein TDP-43","authors":"Brian C. Mackness , Brittany R. Morgan , Laura M. Deveau , Sagar V. Kathuria , Jill A. Zitzewitz , Francesca Massi","doi":"10.1016/j.jmb.2024.168823","DOIUrl":"10.1016/j.jmb.2024.168823","url":null,"abstract":"<div><div>Folding intermediates mediate both protein folding and the misfolding and aggregation observed in human diseases, including amyotrophic lateral sclerosis (ALS), and are prime targets for therapeutic interventions. In this study, we identified the core nucleus of structure for a folding intermediate in the second RNA recognition motif (RRM2) of the ALS-linked RNA-binding protein, TDP-43 (TAR DNA-binding protein-43), using a combination of experimental and computational approaches. Urea equilibrium unfolding studies revealed that the RRM2 intermediate state consists of collapsed residual secondary structure localized to the N-terminal half of RRM2, while the C-terminus is largely disordered. Steered molecular dynamics simulations and mutagenesis studies yielded key stabilizing hydrophobic contacts that, when mutated to alanine, severely disrupt the overall fold of RRM2. In combination, these findings suggest a role for this RRM intermediate in normal TDP-43 function as well as serving as a template for misfolding and aggregation through the low stability and non-native secondary structure.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"436 22","pages":"Article 168823"},"PeriodicalIF":4.7,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454991","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

memerna: Sparse RNA Folding Including Coaxial Stacking. memerna：稀疏 RNA 折叠（包括同轴堆积）。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-10-18 DOI: 10.1016/j.jmb.2024.168819

Eliot Courtney, Amitava Datta, David H Mathews, Max Ward

{"title":"memerna: Sparse RNA Folding Including Coaxial Stacking.","authors":"Eliot Courtney, Amitava Datta, David H Mathews, Max Ward","doi":"10.1016/j.jmb.2024.168819","DOIUrl":"https://doi.org/10.1016/j.jmb.2024.168819","url":null,"abstract":"<p><p>Determining RNA secondary structure is a core problem in computational biology. Fast algorithms for predicting secondary structure are fundamental to this task.Department of Biochemistry & Biophysics, University of Rochester Medical Center, Rochester, NY, USA We describe a modified formulation of the Zuker-Stiegler algorithm with coaxial stacking, a stabilising interaction in which the ends of helices in multi-loops are stacked. In particular, optimal coaxial stacking is computed as part of the dynamic programming state, rather than in an inner loop. We introduce a new notion of sparsity, which we call replaceability. Replaceability is a more general condition and applicable in more places than the triangle inequality that is used by previous sparse folding methods. We also introduce non-monotonic candidate lists as an additional sparsification tool. Existing usages of the triangle inequality for sparsification can be thought of as an application of both replaceability and monotonicity together. The modified recurrences along with replaceability allows sparsification to be applied to coaxial stacking as well, which increases the speed of the algorithm. We implemented this algorithm in software we call memerna, which we show to have the fastest exact (non-heuristic) implementation of RNA folding under the complete Turner 2004 model with coaxial stacking, out of several popular RNA folding tools supporting coaxial stacking. We also introduce a new notation for secondary structure which includes coaxial stacking, terminal mismatches, and dangles (CTDs) information. The memerna package 0.1 release is available at https://github.com/Edgeworth/memerna/tree/release/0.1.</p>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"168819"},"PeriodicalIF":4.7,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454993","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