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ProHistoneDB: A database of prokaryotic and viral histones. ProHistoneDB:原核和病毒组蛋白数据库。
IF 4.5 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-16 DOI: 10.1016/j.jmb.2026.169644
Samuel Schwab, Michel Olsthoorn, Tim Jansen, Remus T Dame

Histones are one of the fundamental chromatin proteins of life. In eukaryotes and megaviruses, they form nucleosome structures that wrap DNA. However, in prokaryotes, histones are much more diverse in how they organize DNA. In bacteria, histones bend and wrap DNA while in archaea they wrap and bridge DNA. These differences in DNA organizing properties are primarily due to distinct modes of histone multimerization. Here we present ProHistoneDB, an online database describing and categorizing prokaryotic and viral histones. For each histone, monomer, dimer, tetramer, and hexamer predictions are viewable and downloadable. ProHistoneDB contains 7334 histones, categorized into 24 groups based on the multimer predictions. For each category, interactive phylogenetic trees and HMM profile logos are available to identify conserved residues and explore the relative evolutionary relationships of histones. ProHistoneDB can be accessed at https://prohistonedb.org/.

组蛋白是生命的基本染色质蛋白之一。在真核生物和巨病毒中,它们形成包裹DNA的核小体结构。然而,在原核生物中,组蛋白组织DNA的方式要多样化得多。在细菌中,组蛋白弯曲并包裹DNA,而在古细菌中,组蛋白包裹并连接DNA。这些DNA组织特性的差异主要是由于组蛋白多聚的不同模式。在这里,我们提出了ProHistoneDB,一个描述和分类原核和病毒组蛋白的在线数据库。对于每个组蛋白,单体,二聚体,四聚体和六聚体的预测是可见和可下载的。ProHistoneDB包含7334个组蛋白,根据多时间预测分为24组。对于每个类别,可使用交互系统发育树和HMM配置文件标识来识别保守残基并探索组蛋白的相对进化关系。ProHistoneDB可以访问:http://www.prohistonedb.org/。
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引用次数: 0
The Structure of a Thermostable Phage’s Portal Vertex and Neck Complex Illuminates the Headful Maturation Mechanism 耐热噬菌体的入口顶点和颈部复合体的结构阐明了头部成熟机制。
IF 4.5 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-14 DOI: 10.1016/j.jmb.2026.169641
Emma L. Sedivy, Emily Agnello , Julia E. Hobaugh, Rakeyah Ahsan, Kangkang Song , Chen Xu, Brian A. Kelch
Viruses assemble from component parts inside their host cells, but the mechanisms coordinating this complex process are not completely understood. In tailed bacteriophages, the genome is packaged into its capsid shell through the portal complex. The portal complex then closes to retain DNA and connects to the tail, which is required for host recognition and infection. The trigger to stop pumping DNA and assemble the mature virus has been a longstanding conundrum in the field. We determined the structure of the portal, the proteins that connect it to the tail, and portal vertex in the hyperthermophilic phage Oshimavirus using cryo-Electron Microscopy (cryo-EM). We find highly intertwined loop structures, like in a wicker basket, potentially stabilizing the portal vertex against high temperatures. Moreover, we observe that the portal protrudes from the capsid in mature virions. We propose that portal is repositioned by packaged DNA, forming a pressure-sensitive switch that terminates genome packaging and triggers tail attachment in headful phages.
病毒从宿主细胞内的组成部分组装,但协调这一复杂过程的机制尚不完全清楚。在尾部噬菌体中,基因组通过门脉复合体被包装到衣壳中。然后,门脉复合体关闭以保留DNA并连接到宿主识别和感染所需的尾部。停止注入DNA并组装成熟病毒的触发因素一直是该领域的一个长期难题。我们利用低温电子显微镜(cryo-EM)测定了嗜热噬菌体奥岛病毒的门脉结构、连接门脉尾部的蛋白质和门脉顶点。我们发现高度缠绕的环状结构,就像在柳条篮子里一样,可能会稳定传送门顶点,抵抗高温。此外,我们还观察到成熟病毒粒子的入口从衣壳中突出。我们提出,门蛋白被包装的DNA重新定位,形成一个压力敏感开关,终止基因组包装并触发头部噬菌体的尾部附着。
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引用次数: 0
Structure of Two Tandem-Repeat Galectin Proteins Binding a Model Glycolipid Membrane 两个串联重复凝集素蛋白结合模型糖脂膜的结构。
IF 4.5 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-14 DOI: 10.1016/j.jmb.2026.169638
William R.K. Talley , Daniel Bazan , Jaroslaw Majewski , Herbert Kaltner , Crystal M. Vander Zanden
Tandem-repeat galectins are a family of proteins containing two carbohydrate recognition domains (CRDs) with affinity to various glycoproteins and glycolipids involved in cell signaling. Galectin-4 is expressed in intestinal epithelial cells, and galectin-8 is essential in regulating cell adhesion and immune response. Misregulation of both tandem-repeat galectins is linked to variable cancer cell behavior. Structure models for the membrane-bound forms of galectin-4 and galectin-8 were constructed from X-ray reflectivity measurements coupled with molecular dynamics for galectin-4. The proteins were bound to lipid monolayers containing their respective ligands, gangliosides GM1 or GM3, to determine the membrane-bound structure. Galectin-4 contains two CRDs with weak affinity for GM1, and it bound with both CRDs arranged near the membrane while dynamically sampling alternative conformations. Galectin-8, in contrast, contains only one CRD with tight binding to GM3, and one CRD was pointed towards the membrane while the other oriented away from the membrane. Shortening the peptide linker between the CRDs altered protein binding to the membrane, suggesting the linker likely facilitates stabilizing contacts between the CRDs. Overall, this work helps to illustrate the conformational dynamics of tandem-repeat galectins, emphasizing the roles of ligand affinity, linker peptide dynamics, and contacts between CRDs.
串联重复半乳糖凝集素是一个包含两个碳水化合物识别结构域(CRDs)的蛋白家族,与参与细胞信号传导的各种糖蛋白和糖脂具有亲和力。半乳糖凝集素-4在肠上皮细胞中表达,而半乳糖凝集素-8在调节细胞粘附和免疫应答中起重要作用。这两种串联重复凝集素的错误调控与癌细胞的可变行为有关。半乳糖凝集素-4和半乳糖凝集素-8膜结合形式的结构模型是通过x射线反射率测量结合半乳糖凝集素-4的分子动力学构建的。将蛋白质结合到含有其各自配体神经节苷GM1或GM3的脂质单层上,以确定膜结合结构。半乳糖凝集素-4含有两个对GM1亲和力较弱的crd,并与这两个排列在膜附近的crd结合,同时动态采样不同的构象。相比之下,半乳糖凝集素-8只含有一个与GM3紧密结合的CRD,其中一个CRD指向膜,而另一个则远离膜。缩短crd之间的肽连接改变了蛋白质与膜的结合,表明连接可能有助于稳定crd之间的接触。总的来说,这项工作有助于阐明串联重复集集素的构象动力学,强调配体亲和力,连接体肽动力学和crd之间的接触的作用。
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引用次数: 0
BusR is a Bifunctional Transcription Factor Coordinating Both Osmotic Response and Amino Sugar Metabolism in Streptococcus mutans BusR是一种双功能转录因子,在变形链球菌中协调渗透反应和氨基糖代谢。
IF 4.5 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-14 DOI: 10.1016/j.jmb.2026.169640
Xin Li , Nan Liu , Kaiyu Gao , Carina Muyao Gu , Zhihao Cui , Kundi Zhang , Sujuan Xu , Lichuan Gu
Streptococcus mutans, the major causative agent of dental plaque and caries, maintains osmotic balance under hyperosmotic conditions by transporting glycine betaine into the cytoplasm via the BusAB transporter system. This mechanism is coordinated by the c-di-AMP-responsive transcriptional regulator BusR, which represses busAB expression in the absence of osmotic stress. In this study, we systematically characterized the function of BusR in S. mutans UA159. Our experiments showed that deletion of busR resulted not only in high expression of busAB but also in upregulated GlcNAc metabolic genes, specifically nagA/nagB and glmS, which are known to be regulated by transcriptional regulator NagR. The ΔbusR strain utilized GlcNAc as a nutrient more efficiently and exhibited a faster growth rate than the wild-type strain. Combined with results from further experimentation, this suggests that, BusR assumes a dual regulatory role under high-osmolarity conditions: it relieves repression of busAB to increase the transport of the osmoprotectant betaine into cytoplasm, and cooperates with NagR to regulate amino sugar metabolism by regulating the transcription of nagA/nagB and glmS. Consistent with the molecular ruler mechanism previously described for BusR homologs from Streptococcus agalactiae, we observe a similar structural basis that enables BusR to mediate precise, c-di-AMP–dependent modulation of gene transcription. This coordinated regulation of osmoprotection and amino sugar metabolism by BusR may give S. mutans a significant advantage for dealing with osmotic stress within the oral environment.
变形链球菌是牙菌斑和龋齿的主要病原体,它通过BusAB转运系统将甘氨酸甜菜碱转运到细胞质中,维持高渗条件下的渗透平衡。这一机制是由c-二磷酸腺苷响应转录调节因子BusR协调的,BusR在没有渗透胁迫的情况下抑制busAB的表达。在这项研究中,我们系统地表征了BusR在S. mutans UA159中的功能。我们的实验表明,缺失busR不仅导致了busAB的高表达,还导致了GlcNAc代谢基因的上调,特别是nagA/nagB和glmS,这些基因已知受转录调节因子NagR的调控。ΔbusR菌株比野生型菌株更有效地利用了GlcNAc作为营养物质,并且表现出更快的生长速度。结合进一步的实验结果,这表明BusR在高渗透压条件下具有双重调节作用:它减轻对busAB的抑制,增加渗透保护剂甜菜碱向细胞质的运输,并通过调节nagA/nagB和glmS的转录与NagR合作,调节氨基糖代谢。与之前描述的无乳链球菌的BusR同源物的分子调控机制一致,我们观察到类似的结构基础,使BusR能够介导精确的,依赖于c-二磷酸腺肽的基因转录调节。BusR对渗透保护和氨基糖代谢的协调调节可能使变形链球菌在处理口腔环境中的渗透应激方面具有显着优势。
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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 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-12 DOI: 10.1016/j.jmb.2026.169639
Igor N Berezovsky, Ruth Nussinov
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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 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-09 DOI: 10.1016/j.jmb.2026.169634
Sheng-Cai Lin
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+, 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+ 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.
我的独立职业生涯是基于一个简单的蛋白质多功能性原则开始的,我直觉地选择了一种叫做AXIN的蛋白质,它后来成为我科学生活的主角。这使我们发现了与AMPK和mTORC1这两个主要代谢控制器相连的葡萄糖传感途径。我们发现,AXIN结合AMPK的上游激酶LKB1,并且在溶酶体醛缩酶感知低葡萄糖(果糖-1,6-二磷酸为直接信号)后,AXIN:LKB1复合体易位到溶酶体表面,激活AMPK并同时抑制mTORC1。值得注意的是,我们发现溶酶体葡萄糖感应AMPK通路与二甲双胍共享,二甲双胍是一种已知的降血糖药物,也可以延长寿命并降低癌症风险。为了寻找富含热量限制小鼠并能够通过溶酶体途径激活AMPK的代谢物,我们确定了石胆酸(LCA)是这样一个因素。我们还确定了TULP3作为LCA受体,其信号激活sirtuins,增加NAD+,激活AMPK并抑制mTORC1。在翻译中,我们已经确定了一种醛缩酶抑制剂aldometanib,它模拟葡萄糖饥饿来激活AMPK。Aldometanib对动物有缓解脂肪肝、降低血糖、延长寿命的作用。令人惊讶的是,aldometanib还可以动员杀瘤性CD8+ T细胞浸润并抑制肝细胞癌(HCC),使携带HCC的小鼠活到成熟年龄,这是癌症治疗的终点。因此,我们的工作揭示了葡萄糖作为一个信使,通过一个特殊的途径来控制健康寿命和寿命。我们将继续探索葡萄糖作为“被选择的”分子的目的论意义。
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引用次数: 0
CovInter 2.0: Comprehensive Molecular Interactome of Coronavirus Infection. CovInter 2.0:冠状病毒感染的综合分子相互作用。
IF 4.5 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-09 DOI: 10.1016/j.jmb.2026.169633
Weimin Lu, Yintao Zhang, Kuerbannisha Amahong, Sisi Zhu, Xiuwen Li, Ying Zhou, Feng Zhu, Lin Tao

The ongoing evolution of coronaviruses (CoVs) poses a long-term threat to global public health, requiring dissection of virus-host interactions to develop broad-spectrum antivirals. Existing data resources are often limited to specific interaction types, hindering a systematic understanding of the complete viral life cycle. To address this, CovInter 2.0 (https://idrblab.org/COVINTER) has been developed as a comprehensively upgraded database of coronavirus interactomics, which is the first to systematically integrate the six major classes of molecular interactions that drive the viral life cycle, compiling over 61,000 entries. Furthermore, data for 229 potential anti-CoV drugs and their targets have been included, bridging molecular interactions with therapeutic development. The platform features an interactive network visualization tool for intuitive exploration of these complex relationships. As an open-access resource, CovInter 2.0 provides a powerful tool for virology and drug discovery, computational biology, designed to accelerate the identification of novel antiviral targets and the development of next-generation therapeutics.

冠状病毒(cov)的持续进化对全球公共卫生构成了长期威胁,需要解剖病毒与宿主的相互作用以开发广谱抗病毒药物。现有的数据资源通常局限于特定的交互类型,阻碍了对完整病毒生命周期的系统理解。为了解决这一问题,CovInter 2.0 (https://idrblab.org/COVINTER)是一个全面升级的冠状病毒相互作用组数据库,它是第一个系统整合驱动病毒生命周期的六大类分子相互作用的数据库,汇编了61,000多个条目。此外,还包括229种潜在抗冠状病毒药物及其靶点的数据,将分子相互作用与治疗开发联系起来。该平台的特点是一个交互式网络可视化工具,用于直观地探索这些复杂的关系。作为一个开放获取的资源,CovInter 2.0为病毒学和药物发现、计算生物学提供了一个强大的工具,旨在加速新的抗病毒靶点的识别和下一代治疗方法的开发。
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引用次数: 0
Rising Star: Folding Pattern and Working Mechanism of Functional RNA Molecules 新星:功能性RNA分子的折叠模式和工作机制。
IF 4.5 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-08 DOI: 10.1016/j.jmb.2026.169635
Aiming Ren
Aiming Ren obtained her Ph.D. in Structural Biology and Chemical Biology from the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, and conducted postdoctoral research at the Memorial Sloan Kettering Cancer Center, where she investigated RNA molecules involved in gene expression regulation (riboswitches) and self-cleavage catalysis (ribozymes). Ren later established her independent laboratory at Zhejiang University, focusing on the structural and mechanistic understanding of functional RNAs—particularly riboswitches, self-cleaving ribozymes, and RNA fluorogenic aptamers (FLAP). These RNA molecules represent elegant examples of RNA nature’s regulatory, catalytic, and fluorescence activation strategies, performing precise chemical transformations and sophisticated functional control through dynamic structural rearrangements. The Ren laboratory combines biochemical and molecular biological approaches with high-resolution structural techniques, including X-ray crystallography and cryo-electron microscopy, to elucidate how RNA architectures encode regulatory, catalytic, and activation functions. Through systematic investigations, Ren and her team have explored how riboswitches couple ligand recognition to gene regulation via dynamic conformational shifts, uncovered the catalytic mechanisms of several newly discovered self-cleaving ribozymes, revealing both shared structural principles and unique chemical strategies underlying RNA self-scission. The group also investigated how RNA aptamers fold to stabilize the bound dyes and enhance their fluorescence by several thousand-fold. By bridging RNA chemistry, structure, and dynamics, Aiming Ren’s research aims to illuminate the fundamental principles governing RNA function and evolution. Her work provides deep insights into RNA-based regulation, catalysis, and fluorescence activation, offering important implications for understanding ancient biochemical systems and for the development of novel RNA-based tools and therapeutics.
任志玲博士毕业于中国科学院上海有机化学研究所,获得结构生物学和化学生物学博士学位,并在纪念斯隆凯特琳癌症中心进行博士后研究,研究参与基因表达调控(核开关)和自裂催化(核酶)的RNA分子。她后来在浙江大学建立了自己的独立实验室,专注于对功能性RNA的结构和机制的理解,特别是核开关、自切割核酶和RNA荧光适体(FLAP)。这些RNA分子代表了RNA自然调控、催化和荧光激活策略的优雅例子,通过动态结构重排执行精确的化学转化和复杂的功能控制。Ren实验室将生物化学和分子生物学方法与高分辨率结构技术(包括x射线晶体学和低温电子显微镜)相结合,阐明RNA结构如何编码调节、催化和激活功能。通过系统的研究,Ren和她的团队探索了核糖体开关如何通过动态构象转移将配体识别与基因调控结合起来,揭示了几种新发现的自切割核糖酶的催化机制,揭示了RNA自切割的共同结构原理和独特的化学策略。该小组还研究了RNA适体如何折叠以稳定结合的染料并将其荧光增强数千倍。通过连接RNA化学、结构和动力学,任志明的研究旨在阐明控制RNA功能和进化的基本原理。她的工作为基于rna的调控、催化和荧光激活提供了深刻的见解,为理解古代生化系统和开发新的基于rna的工具和治疗方法提供了重要的意义。
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引用次数: 0
TLSEA 2.0: an updated tool for lncRNA enrichment analysis. TLSEA 2.0:更新的lncRNA富集分析工具。
IF 4.5 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-07 DOI: 10.1016/j.jmb.2026.169630
Yunhe Tian, Ziyu Li, Jialin Yang, Jianwei Li

Long non-coding RNAs (lncRNAs) regulate gene expression, cellular functions, and disease-related processes through extensive and diverse interactions with various molecules, thereby forming heterogeneous functional regulatory networks. LncRNAs often exert their regulatory effects in a cooperative manner, functional enrichment analysis is considered a powerful approach for systematically elucidating their functions. However, most existing methods focus on the functions of individual lncRNAs, overlooking complex interactions among them, which limits the scope of enrichment analysis. In this paper, we developed TLSEA 2.0 (http://www.lirmed.com/tlsea2/), an updated web-based tool with an expanded repository of functional lncRNA sets, for enhancing enrichment analysis capabilities. Compared with the earlier version of TLSEA, TLSEA 2.0 has tripled its reference lncRNA sets and expanded enrichment analysis categories from one to five: Disease, Drug, RNA-RNA Interaction, RNA-Protein Interaction, and Cancer Phenotype. TLSEA 2.0 introduces an Expansion option, which extends the user-submitted lncRNA list by incorporating additional lncRNAs that exhibit strong association with the input set based on similarity networks, thereby expanding the user-submitted lncRNA list and enabling the discovery of more potential associations. Additional functional similarity networks have been incorporated, including lncRNA-protein interactions and co-expression data. Furthermore, TLSEA 2.0 employs combining Graph Attention Networks (GAT) and Graph Convolutional Networks (GCN) to replace traditional graph representation learning during the process of extracting lncRNA features. These enhancements make TLSEA 2.0 a more comprehensive and robust online platform for functional enrichment analysis, facilitating deeper insights into the complex biological regulatory functions of lncRNAs.

长链非编码rna (lncRNAs)通过与各种分子广泛而多样的相互作用,调控基因表达、细胞功能和疾病相关过程,从而形成异质的功能调控网络。lncrna通常以合作的方式发挥其调控作用,功能富集分析被认为是系统阐明其功能的有力方法。然而,大多数现有的方法都集中在单个lncrna的功能上,忽略了它们之间复杂的相互作用,这限制了富集分析的范围。在本文中,我们开发了TLSEA 2.0 (http://www.lirmed.com/tlsea2/),这是一个更新的基于web的工具,具有扩展的功能性lncRNA集存储库,用于增强富集分析能力。与早期版本的TLSEA相比,TLSEA 2.0将其参考lncRNA集增加了两倍,并将富集分析类别从一种扩展到五种:疾病、药物、RNA-RNA相互作用、rna -蛋白质相互作用和癌症表型。TLSEA 2.0引入了一个扩展选项,该选项通过纳入基于相似性网络的与输入集表现出强关联的额外lncRNA来扩展用户提交的lncRNA列表,从而扩展用户提交的lncRNA列表,并能够发现更多潜在的关联。其他功能相似网络也被纳入,包括lncrna -蛋白相互作用和共表达数据。此外,TLSEA 2.0在提取lncRNA特征的过程中,采用了图注意网络(GAT)和图卷积网络(GCN)相结合的方法来代替传统的图表示学习。这些改进使TLSEA 2.0成为一个更全面、更强大的功能富集分析在线平台,有助于更深入地了解lncrna的复杂生物调控功能。
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引用次数: 0
A Survey of Predicted Protein–Protein Interactions Involving Disordered Regions in Humans 一项涉及人类无序区域的预测蛋白质-蛋白质相互作用的调查。
IF 4.5 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-07 DOI: 10.1016/j.jmb.2026.169636
Jimin Pei, Jing Zhang, Qian Cong
Intrinsically disordered regions (IDRs) in proteins play a pivotal role in protein–protein interactions (PPIs). Using AlphaFold2 and enriched multiple sequence alignments, we predicted and investigated PPIs across the human proteome, focusing on those involving disordered regions. Our predictions show that disordered regions predominantly interact with ordered domains, whereas predicted disordered–disordered interactions are relatively rare. Although disordered regions typically lack annotated domains, certain regions—such as the keratin type II head domain and the Krüppel-associated box (KRAB)—mediate specific interactions. In contrast, their predicted binding partners frequently feature diverse Pfam domains, including protein kinase, WD40 repeat, and nuclear hormone receptor domains. These domains are enriched in nuclear localization and α-helical repeat motifs. Disordered regions involved in predicted PPIs exhibit higher sequence conservation than non-interacting disordered regions, suggesting evolutionary constraints at interaction interfaces. Moreover, certain posttranslational modifications (e.g., phosphorylation and acetylation) in disordered regions are enriched within predicted interaction interfaces, likely modulating binding affinities. Notably, we identified a significant enrichment of disease-associated mutations in predicted PPI interfaces involving disordered regions, underscoring their functional and pathological relevance. Together, these findings highlight the intricate interplay between disordered and ordered regions in mediating PPIs and provide insights into their structural and functional contributions to human health and disease.
蛋白质的内在无序区(IDRs)在蛋白质-蛋白质相互作用(PPIs)中起着关键作用。利用AlphaFold2和富集的多序列比对,我们预测并研究了整个人类蛋白质组的ppi,重点关注那些涉及无序区域的ppi。我们的预测表明,无序区域主要与有序区域相互作用,而预测的无序-无序相互作用相对较少。虽然紊乱区域通常缺乏注释结构域,但某些区域-如角蛋白II型头部结构域和kr ppel相关框(KRAB)-介导特异性相互作用。相比之下,他们预测的结合伙伴通常具有不同的Pfam结构域,包括蛋白激酶、WD40重复和核激素受体结构域。这些结构域富含核定位和α-螺旋重复基序。与非相互作用的无序区相比,参与预测ppi的无序区表现出更高的序列保守性,表明相互作用界面存在进化约束。此外,某些翻译后修饰(例如,磷酸化和乙酰化)在预测的相互作用界面内富集,可能调节结合亲和力。值得注意的是,我们在涉及无序区域的预测PPI界面中发现了疾病相关突变的显著富集,强调了它们的功能和病理相关性。总之,这些发现突出了介导PPIs的无序区和有序区之间复杂的相互作用,并提供了它们对人类健康和疾病的结构和功能贡献的见解。
{"title":"A Survey of Predicted Protein–Protein Interactions Involving Disordered Regions in Humans","authors":"Jimin Pei,&nbsp;Jing Zhang,&nbsp;Qian Cong","doi":"10.1016/j.jmb.2026.169636","DOIUrl":"10.1016/j.jmb.2026.169636","url":null,"abstract":"<div><div>Intrinsically disordered regions (IDRs) in proteins play a pivotal role in protein–protein interactions (PPIs). Using AlphaFold2 and enriched multiple sequence alignments, we predicted and investigated PPIs across the human proteome, focusing on those involving disordered regions. Our predictions show that disordered regions predominantly interact with ordered domains, whereas predicted disordered–disordered interactions are relatively rare. Although disordered regions typically lack annotated domains, certain regions—such as the keratin type II head domain and the Krüppel-associated box (KRAB)—mediate specific interactions. In contrast, their predicted binding partners frequently feature diverse Pfam domains, including protein kinase, WD40 repeat, and nuclear hormone receptor domains. These domains are enriched in nuclear localization and α-helical repeat motifs. Disordered regions involved in predicted PPIs exhibit higher sequence conservation than non-interacting disordered regions, suggesting evolutionary constraints at interaction interfaces. Moreover, certain posttranslational modifications (e.g., phosphorylation and acetylation) in disordered regions are enriched within predicted interaction interfaces, likely modulating binding affinities. Notably, we identified a significant enrichment of disease-associated mutations in predicted PPI interfaces involving disordered regions, underscoring their functional and pathological relevance. Together, these findings highlight the intricate interplay between disordered and ordered regions in mediating PPIs and provide insights into their structural and functional contributions to human health and disease.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 5","pages":"Article 169636"},"PeriodicalIF":4.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941994","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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Journal of Molecular Biology
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