Journal of Molecular Biology最新文献_第8页

Tracing the Origin of the Genetic Code and Thermostability to Dipeptide Sequences in Proteomes 追踪遗传密码和热稳定性的起源到蛋白质组中的二肽序列。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2026-02-15 Epub Date: 2025-08-14 DOI: 10.1016/j.jmb.2025.169396

Minglei Wang, M. Fayez Aziz, Gustavo Caetano-Anollés

{"title":"Tracing the Origin of the Genetic Code and Thermostability to Dipeptide Sequences in Proteomes","authors":"Minglei Wang, M. Fayez Aziz, Gustavo Caetano-Anollés","doi":"10.1016/j.jmb.2025.169396","DOIUrl":"10.1016/j.jmb.2025.169396","url":null,"abstract":"<div><div>The safekeeping of the genetic code has been entrusted to interactions between aminoacyl-tRNA synthetases and their cognate tRNA. In a previous phylogenomic study, chronologies of RNA substructures, protein domains and dipeptide sequences uncovered the early emergence of an ‘operational’ code in the acceptor arm of tRNA prior to the implementation of the 'standard' genetic code in the anticodon loop of the molecule. This history likely originated in peptide–synthesizing urzymes but was driven by episodes of molecular co-evolution and recruitment that promoted flexibility and protein folding. Here, we show that dipeptide sequences offer deep-time insights into the chronology of code emergence. A phylogeny describing the evolution of the repertoire of 400 canonical dipeptides reconstructed from an analysis of 4.3 billion dipeptide sequences across 1,561 proteomes revealed the overlapping temporal emergence of dipeptides containing Leu, Ser and Tyr, followed by those containing Val, Ile, Met, Lys, Pro, and Ala, all of which supported the operational RNA code. This strengthened a timeline of genetic code entry. The synchronous appearance of dipeptide–antidipeptide sequences along the dipeptide chronology supported an ancestral duality of bidirectional coding operating at the proteome level. Tracing determinants of thermal adaptation showed protein thermostability was a late evolutionary development and bolstered an origin of proteins in the mild environments typical of the Archaean eon. Our study uncovers a hidden evolutionary link between a protein code of dipeptides – arising from the structural demands of emerging proteins – and an early operational code shaped by co-evolution, editing, catalysis and specificity.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 4","pages":"Article 169396"},"PeriodicalIF":4.5,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144861993","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

Stability and Adaptation of Proteins, Membranes and Cells to Extreme Temperature and Pressure 蛋白质、膜和细胞对极端温度和压力的稳定性和适应性。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2026-02-15 Epub Date: 2025-10-06 DOI: 10.1016/j.jmb.2025.169477

J. Peters , J.G. LoRicco , M. Saracco , A. Caliò , P. Oger

引用次数: 0

Unraveling the Link Between Thermal Adaptation and Latent Allostery in Malate Dehydrogenase From Methanococcales 揭示甲烷球菌苹果酸脱氢酶的热适应与潜伏变构之间的联系。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2026-02-15 Epub Date: 2025-11-20 DOI: 10.1016/j.jmb.2025.169552

Caroline Simões Pereira , Sandrine Coquille , Céline Brochier-Armanet , Fabio Sterpone , Dominique Madern

{"title":"Unraveling the Link Between Thermal Adaptation and Latent Allostery in Malate Dehydrogenase From Methanococcales","authors":"Caroline Simões Pereira , Sandrine Coquille , Céline Brochier-Armanet , Fabio Sterpone , Dominique Madern","doi":"10.1016/j.jmb.2025.169552","DOIUrl":"10.1016/j.jmb.2025.169552","url":null,"abstract":"<div><div>Malate dehydrogenase (MalDH) (EC.1.1.1.37) is an enzyme engaged in the central metabolism of cells, catalyzing the interconversion between oxaloacetate and malate using NADH or NADPH as coenzyme. These enzymes are particularly interesting models for studying how proteins adapt to physical and chemical environmental constraints. In this study, we investigated the molecular mechanisms that have enabled MalDHs to adapt to changes in temperature, using <em>Methanococcales</em> archaea as a model organism. We solved the crystal structure of ancestral MalDHs in these archaea. Structural comparison with present-day MalDHs such as those from <em>Methanocaldococcus infernus</em> (M. inf) and <em>Methanocaldococcus jannaschii</em> (M. jan), highlights the role salt-bridges in thermal adaptation. We also found that present-day MalDHs from M. inf and M. jan, show structural features that resemble the extended or compact states typical of allosteric lactate dehydrogenases. To test hypotheses about a possible link between thermal adaptation and the emergence of allosteric regulation, we characterized structurally two M. jan MalDH mesophilic-like mutants. Molecular dynamics simulations using the Wt M. jan and mutant MalDHs were used to rationalize the experimental data. The results indicate that uncompetent and competent catalytic site configurations are in an equilibrium that depends on temperature conditions. At low temperature the Wt M. jan MalDH select non-competent conformers, whereas high temperature favors active conformers. In contrast, the M. jan MalDH mutants explore competent conformers for catalysis at a lowest temperature, a phenomenon that fits well with their biochemical behavior. Our work reveals that thermal adaptation and evolution of allostery are strongly linked via the modulation of the protein conformational landscape.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 4","pages":"Article 169552"},"PeriodicalIF":4.5,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145581550","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 Biomolecular Condensates 生物分子凝聚体中的变构。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2026-02-15 Epub Date: 2025-09-15 DOI: 10.1016/j.jmb.2025.169446

Ruth Nussinov , Clil Regev , Hyunbum Jang

{"title":"Allostery in Biomolecular Condensates","authors":"Ruth Nussinov , Clil Regev , Hyunbum Jang","doi":"10.1016/j.jmb.2025.169446","DOIUrl":"10.1016/j.jmb.2025.169446","url":null,"abstract":"<div><div>Allosteric proteins and membrane-less biomolecular condensates are physics-governed pivotal functional components. Allosteric regulation is an inherent physical property of dynamic proteins, and dynamic proteins are allosteric. <em>Thus, in biomolecular condensates (like everywhere else in the cell), allostery is at play</em>, and often missing in condensate descriptions is that the cooperative transitions can involve allosteric effects. The condensate environment can be especially conducive to allostery. Condensed settings can increase the chance of protein interaction and allosteric encounters in function-specific condensates. Specific protein–protein interactions provide the structural framework for signals to transmit cooperatively and dynamically, ultimately modulating cell activity. Their interfaces are commonly enriched in nonpolar (hydrophobic) surface. With abundant functionally specific proteins, and surfaces accommodating multiple hydrophobic patches, interconnected multivalent molecular networks are expected. Lacking hydrophobic cores, disordered proteins’ folding-upon-binding scenarios often form strong hydrophobic interfaces, and cooperative (partially disordered) multimers are also common. Repelling water is a major force in condensate formation, albeit not the sole. <em>Here we emphasize dilution as functional and allosteric determinant</em>. Extremely high dilution in rapidly growing proliferating cells can stimulate senescence; lower dilution increases concentration, thus, higher probability of increased proximity and reduced separation, driving protein–protein interactions, and allostery. <em>Is there then effective allostery in condensates</em>? We believe that it depends on the cell state. Under normal physiological conditions, with condensates water content around 40% of total cell mass–yes; over 70% could be too diluted. If too low—it can become function-poor aggregate-like. Effective allostery and signaling require specific interactions, extending from clustered receptors to the cytoskeleton.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 4","pages":"Article 169446"},"PeriodicalIF":4.5,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079259","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

Adaptation of Folding and Function of a Nuclease from the Cold Deep Sea 一种低温深海核酸酶的折叠适应性及其功能。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2026-02-15 Epub Date: 2025-12-22 DOI: 10.1016/j.jmb.2025.169602

Tejaswi Koduru , Philippe Barthe , Noam Hantman , Karine De Guillen , Scott A. McCallum , Joel E. Morgan , Estella F. Yee , Pierce Leonardi , Jack Foland , Christian Roumestand , Catherine A. Royer

{"title":"Adaptation of Folding and Function of a Nuclease from the Cold Deep Sea","authors":"Tejaswi Koduru , Philippe Barthe , Noam Hantman , Karine De Guillen , Scott A. McCallum , Joel E. Morgan , Estella F. Yee , Pierce Leonardi , Jack Foland , Christian Roumestand , Catherine A. Royer","doi":"10.1016/j.jmb.2025.169602","DOIUrl":"10.1016/j.jmb.2025.169602","url":null,"abstract":"<div><div>The majority of the Earth’s microbial biomass is found in high pressure environments, raising the question of how protein sequences adapt to such environments. Pressure adaptation is more complex, and less well-understood, than adaptation to extreme temperatures since in high pressure environments, these two thermodynamic parameters are often coupled, as in the cold deep-sea or at hydrothermal vents. To begin to address this question, we investigated the functional and folding properties of an exonuclease, Cnase, from the first Gram positive piezophile to be sequenced, <em>Carnobacterium</em> sp. <em>AT7</em>, isolated at 2500 m depth and at ∼2 °C in the Aleutian trench in the North Pacific. We find that Cnase is a bonafide exonuclease, despite its high negative charge. We also find that Cnase largely conserves the structure and folding mechanism of its mesophilic and well-studied homolog, staphylococcal nuclease, Snase, despite significant differences in their sequences.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 4","pages":"Article 169602"},"PeriodicalIF":4.5,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145825549","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

Protein Intrinsic Disorder and Adaptation to Extreme Environments: Resilience of Chaos 蛋白质内在紊乱和对极端环境的适应：混乱的恢复力。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2026-02-15 Epub Date: 2025-11-14 DOI: 10.1016/j.jmb.2025.169547

Vladimir N. Uversky

{"title":"Protein Intrinsic Disorder and Adaptation to Extreme Environments: Resilience of Chaos","authors":"Vladimir N. Uversky","doi":"10.1016/j.jmb.2025.169547","DOIUrl":"10.1016/j.jmb.2025.169547","url":null,"abstract":"<div><div>Extremophiles are organisms adapted not only to survive in harsh conditions but thrive in environments considered extreme or uninhabitable by most life forms. They serve as a living reflection of a popular motto “What doesn’t kill you makes you stronger” and show that life on Earth is spread well outside the human-centric comfort zone. In fact, extremophiles, being found in deep crustal and oceanic depths, outer space, highly acidic and basic conditions, extreme temperatures (+122 °C to −20 °C), and in the presence of toxins and high radiation, demonstrate life’s remarkable adaptability. Polyextremophiles, capable of enduring multiple extreme conditions, further highlight this adaptability, whereas super-extremophiles, exhibiting resilience in seemingly impossible environments, showcase the extraordinary capacity of life to endure and thrive. Even though they inhabit vastly different environments, extremophiles, polyextremophiles, and super-extremophiles are all Earth organisms. They are made of the same elements found on our planet and share basic biological similarities with other life forms. Their survival in extreme conditions is due to adaptations and changes in their existing cellular structures and metabolic processes, and not because they use entirely new fundamental components or chemical reactions. While extremophiles employ a multitude of factors, mechanisms, and survival strategies to withstand harsh environments, this study addresses a specific aspect of extremophile adaptation by concentrating solely on the functions of intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs).</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 4","pages":"Article 169547"},"PeriodicalIF":4.5,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534015","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

From Extreme Environments in Nature to Molecular and Cellular Adaptation and Functional Regulation 从自然界的极端环境到分子和细胞的适应和功能调节。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2026-02-15 Epub Date: 2026-01-12 DOI: 10.1016/j.jmb.2026.169639

Igor N. Berezovsky , Ruth Nussinov

引用次数: 0

Integrating Sequence, Structure, and Graph-based Features for Elucidating the Stability of Thermophilic Proteins 整合序列、结构和基于图的特征来阐明嗜热蛋白的稳定性。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2026-02-15 Epub Date: 2025-12-12 DOI: 10.1016/j.jmb.2025.169593

P. Ramakrishna Reddy, Fathima Ridha, M. Michael Gromiha

{"title":"Integrating Sequence, Structure, and Graph-based Features for Elucidating the Stability of Thermophilic Proteins","authors":"P. Ramakrishna Reddy, Fathima Ridha, M. Michael Gromiha","doi":"10.1016/j.jmb.2025.169593","DOIUrl":"10.1016/j.jmb.2025.169593","url":null,"abstract":"<div><div>Proteins from thermophilic organisms exhibit remarkable stability under extreme thermal conditions. Understanding the molecular mechanisms underlying thermostability is essential for studying protein evolution and engineering robust enzymes. In this study, we systematically analyzed four sets of mesophilic–thermophilic protein pairs to investigate the molecular basis of thermal adaptation. We have constructed independent datasets of mesophilic–thermophilic protein pairs defined by sequence identity and optimal growth temperature (OGT): (a) >90% identity and 60–80 °C OGT, (b) 50–90% identity and >80 °C OGT, (c) 50–90% identity and 60–80 °C OGT, and (d) 50–90% identity and 40–60 °C OGT. Mutational analysis revealed that thermophilic proteins consistently reduced polar, uncharged residues while enriching charged, hydrophobic, and aromatic residues, particularly in extreme thermophiles (>80 °C). Further, by integrating multiple known protein features into a hierarchical rule-based classifier, we identified the thermostable protein from a pair of sequences and also assessed the relative importance of features across datasets to provide interpretable insights into protein thermostability. The hierarchical rule-based method identified stabilizing residues as the primary distinguishing factor, followed by electrostatic energy, volume, and localized electrical effects, which correctly classified 99% of thermophilic proteins. A bagging model trained on the same features achieved a balanced accuracy of 92% in 5-fold cross-validation and 91% on the 20% hold-out test set. Furthermore, independent validation using multiple mutations in proteins accurately identified 94% of stabilizing and destabilizing mutations. The results obtained in this work provide valuable insights to understand the thermal adaptation of proteins and reliably identify thermostable proteins.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 4","pages":"Article 169593"},"PeriodicalIF":4.5,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145754843","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

On the Molecular Basis of the Hypersaline Adaptation of Halophilic Proteins 嗜盐蛋白适应高盐环境的分子基础。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2026-02-15 Epub Date: 2025-09-13 DOI: 10.1016/j.jmb.2025.169439

Gabriel Ortega-Quintanilla , Oscar Millet

引用次数: 0

Sequence Engineering at Non-motif Modulator Residues Yields a Peptide That Effectively Targets a Single PDZ Protein in a Disease-relevant Cellular Context 序列工程在非基序调节残基产生肽，有效地针对一个单一的PDZ蛋白在疾病相关的细胞环境。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2026-02-01 Epub Date: 2025-12-17 DOI: 10.1016/j.jmb.2025.169597

Jeanine F. Amacher , Patrick R. Cushing , Lars Vouilleme , Sierra N. Cullati , Bin Deng , Scott A. Gerber , Prisca Boisguerin , Dean R. Madden

{"title":"Sequence Engineering at Non-motif Modulator Residues Yields a Peptide That Effectively Targets a Single PDZ Protein in a Disease-relevant Cellular Context","authors":"Jeanine F. Amacher , Patrick R. Cushing , Lars Vouilleme , Sierra N. Cullati , Bin Deng , Scott A. Gerber , Prisca Boisguerin , Dean R. Madden","doi":"10.1016/j.jmb.2025.169597","DOIUrl":"10.1016/j.jmb.2025.169597","url":null,"abstract":"<div><div>PDZ interaction networks are finely-tuned products of evolution. These widespread binding domains recognize short linear motifs (SLiMs), usually at the C-terminus of their interacting partners, and are involved in trafficking and signaling pathways, the formation of tight junctions, and scaffolding of the post-synaptic density of neurons, amongst other roles. Typically, a single PDZ domain binds multiple targets; conversely, each PDZ-binding protein engages several PDZ domains, dependent on cellular conditions. Historical PDZ binding motifs rely on two key positions for binding. However, previous insights on modulator, or non-motif, selectivity preferences reveal that these limited motifs are insufficient to describe PDZ-mediated interactomes, consistent with the observation that the degree of promiscuity is much more limited than predicted by defined binding classes. Here, we use these principles to engineer and test a peptide-based inhibitor capable of interacting with a single PDZ domain-containing protein in a disease-relevant cellular system. We first interrogate a previously developed sequence selective for cystic fibrosis transmembrane conductance regulator (CFTR)-Associated Ligand (CAL), one of five PDZ domains known to bind the CFTR C-terminus, probing for off-target PDZ partners. Once identified, we use parallel biochemical and structural refinement to eliminate these interactions and introduce a CAL PDZ inhibitor with unprecedented PDZ domain selectivity. We test and verify specificity using relevant cellular PDZ target networks in a mass spectrometry-based approach. Our resultant selective inhibitor enhances chloride efflux when applied to polarized patient bronchial epithelial cells, as well as confirms that engineering an effectively single-PDZ peptide is possible when modulator preferences are applied.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 3","pages":"Article 169597"},"PeriodicalIF":4.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145792920","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