Journal of Molecular Biology最新文献_第8页

Mycobacterial Methionine Aminopeptidase Type 1c Moonlights as an Anti-association Factor on the 30S Ribosomal Subunit 分枝杆菌蛋氨酸氨基肽酶1c型作为30S核糖体亚基的抗关联因子。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-05-27 DOI: 10.1016/j.jmb.2025.169230

Aneek Banerjee, Krishnamoorthi Srinivasan, Jayati Sengupta

{"title":"Mycobacterial Methionine Aminopeptidase Type 1c Moonlights as an Anti-association Factor on the 30S Ribosomal Subunit","authors":"Aneek Banerjee, Krishnamoorthi Srinivasan, Jayati Sengupta","doi":"10.1016/j.jmb.2025.169230","DOIUrl":"10.1016/j.jmb.2025.169230","url":null,"abstract":"<div><div>Methionine aminopeptidase (MetAP) is a vital metalloprotease that plays a crucial role in protein synthesis by binding to the 70S ribosome at the peptide exit tunnel and removing the N-terminal methionine from nascent polypeptide chains. In <em>Escherichia coli</em>, a single subclass of type 1 MetAP is present, whereas mycobacteria possess two subclasses, MetAP1a and MetAP1c. The key difference between these two is the presence of an additional 40 amino acid-long N-terminal extension in MetAP1c, which may contribute to distinct functional properties. In this study, we have uncovered a previously unrecognized “moonlighting” function of MetAP1c in mycobacteria. Interestingly, our results show that MetAP1c expression is specifically enhanced during the stationary phase of bacterial growth. Moreover, we identify a unique interaction between MetAP1c and the 30S ribosomal subunit, revealing its distinctive affinity for the small subunit. A 4.7 Å cryo-EM map of the <em>Mycobacterium smegmatis</em> MetAP1c-30S subunit complex demonstrates for the first time that MetAP1c binds at the inter-subunit face of the 30S subunit head region. The binding of MetAP1c induces conformational changes in the 30S subunit, impairing its ability to associate with the 50S subunit, thus imparting an anti-association property to MetAP1c. To further understand the role of the N-terminal extension, we constructed two mutant variants of MetAP1c, which confirmed its critical involvement in this moonlighting function. This anti-association activity of MetAP1c is likely one of the energy conservation mechanisms in mycobacteria where MetAP1c is involved in translation down regulation during stationary phase.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 17","pages":"Article 169230"},"PeriodicalIF":4.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179563","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 key region of Tau that is able to drive assembly and modulate inhibition by Hydromethylthionine Tau（350-362）是驱动调节氢甲基硫氨酸抑制纤维形成的关键区域。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-05-27 DOI: 10.1016/j.jmb.2025.169231

Youssra K. Al-Hilaly , Janet E. Rickard , Michael Simpson , John M.D. Storey , Charles R. Harrington , Claude M. Wischik , Louise C. Serpell

{"title":"A key region of Tau that is able to drive assembly and modulate inhibition by Hydromethylthionine","authors":"Youssra K. Al-Hilaly , Janet E. Rickard , Michael Simpson , John M.D. Storey , Charles R. Harrington , Claude M. Wischik , Louise C. Serpell","doi":"10.1016/j.jmb.2025.169231","DOIUrl":"10.1016/j.jmb.2025.169231","url":null,"abstract":"<div><div>Tau<sub>297–391</sub> (dGAE) forms paired helical filaments <em>in vitro</em> that resemble those deposited in Alzheimer’s disease brain tissue. We have previously shown that hydromethylthionine (HMT) has the ability to inhibit dGAE self-assembly at sub-stoichiometric ratios. Here, we examined two regions of tau within the core filament-forming region that possess high self-assembly propensity sequences and have explored their ability to form filaments and whether their self-assembly can be inhibited by HMT. We confirm that tau<sub>306–323</sub> self-assembles to form filaments but that fibrillogenesis is not inhibited by HMT. Previous work by others has shown that tau<sub>350–362</sub> (PAM4) forms assemblies that recapitulate the C-shaped structure of paired helical filaments. Here, a chiral spectral circular dichroism fingerprint shows that HMT binds to tau350–362 and we reveal that HMT inhibits assembly. We conclude that the region important for assembly and inhibition is formed by the inner C-shaped region of tau and suggest that the central region involved in filament assembly may associate with HMT to prevent self-assembly.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 17","pages":"Article 169231"},"PeriodicalIF":4.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179771","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 Insights into Autophagy in the AlphaFold Era AlphaFold时代自噬的结构洞察。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-05-27 DOI: 10.1016/j.jmb.2025.169235

Tatsuro Maruyama , Nobuo N. Noda

引用次数: 0

Structural Plasticity and Functional Dynamics of Pigeon Cryptochrome 4 as Avian Magnetoreceptor. 鸽子隐色素4作为鸟类磁受体的结构可塑性和功能动力学。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-05-27 DOI: 10.1016/j.jmb.2025.169233

Chuanye Xiong, Palanisamy Kandhan, Brian D Zoltowski, Peng Tao

{"title":"Structural Plasticity and Functional Dynamics of Pigeon Cryptochrome 4 as Avian Magnetoreceptor.","authors":"Chuanye Xiong, Palanisamy Kandhan, Brian D Zoltowski, Peng Tao","doi":"10.1016/j.jmb.2025.169233","DOIUrl":"10.1016/j.jmb.2025.169233","url":null,"abstract":"<p><p>Cryptochromes (CRYs) are key flavoproteins involved in biological processes such as circadian rhythm regulation and magnetoreception. Type IV CRYs have been identified as primary candidates for avian magnetoreception. However, their structural flexibility, particularly within the cryptochrome C-terminal extension (CCE) and phosphate-binding loop (PBL), remains poorly understood. In this study, we employed temperature replica exchange molecular dynamics (T-REMD) simulations combined with advanced dimensionality reduction techniques, including autoencoder and time-lagged independent component analysis (t-ICA), to explore the conformational space of Columba livia cryptochrome 4 (ClCRY4), as the only available crystal structure of Type IV CRYs to date. By using Drosophila cryptochrome (dCRY) as a reference structure, we assessed the reliability of T-REMD sampling in capturing key states of ClCRY4. Our results indicate that the CCE region of ClCRY4 displays unique conformational dynamics and cooperative interactions with the PBL, highlighting the need for further investigation. The clustering analysis of ClCRY4 conformations revealed multiple structural states, underscoring the functional significance of its intrinsically disordered regions (IDRs). This study provides a novel computational approach for studies of CRYs dynamics, through which the modeling of one CRY with full structure could be used to benchmark the computational study of another CRY only with partial structural information available.</p>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169233"},"PeriodicalIF":4.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12276989/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179849","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

Immunoproteasome-specific Subunit Alterations as a Potential Therapeutic Target for Mitochondriopathies 免疫蛋白酶体特异性亚基改变作为线粒体病的潜在治疗靶点。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-05-23 DOI: 10.1016/j.jmb.2025.169229

Agata Kodroń , Konrad Kowalski , Ben Hur Marins Mussulini , Cem Hazir , Mayra A. Borrero-Landazabal , Sonia Ngati , Michal Wasilewski , Agnieszka Chacinska

{"title":"Immunoproteasome-specific Subunit Alterations as a Potential Therapeutic Target for Mitochondriopathies","authors":"Agata Kodroń , Konrad Kowalski , Ben Hur Marins Mussulini , Cem Hazir , Mayra A. Borrero-Landazabal , Sonia Ngati , Michal Wasilewski , Agnieszka Chacinska","doi":"10.1016/j.jmb.2025.169229","DOIUrl":"10.1016/j.jmb.2025.169229","url":null,"abstract":"<div><div>Mitochondria are double-membrane organelles crucial for eukaryotic cells due to their role in ATP production by oxidative phosphorylation (OXPHOS). Most of the ∼1500 proteins of the mitochondrial proteome are encoded in the nuclear genome, synthesized in the cytosol, and actively transported into mitochondria. The proteasome, a major cellular proteolytic machinery, plays an important role in the quality control of their transport by degradation of inefficiently imported mitochondrial proteins in the cytosol. Proteasome inhibition by bortezomib was described as a strategy to alleviate deficiencies stemming from an inefficient import of proteins into the mitochondria. Notably, an impairment of the respiratory complexes was shown to induce a rearrangement of the proteasome composition to incorporate some of the immunoproteasome catalytic subunits, such as PSMB9. In this study, we demonstrated that targeting immunoproteasome inhibited degradation, and thus restored the abundance of inefficiently imported respiratory complex IV proteins in the patient derived fibroblasts. Furthermore, we demonstrated that the immunoproteasome-specific inhibitors displayed a decreased toxicity compared to bortezomib. Our results indicate that immunoproteasome subunits present a novel molecular target for future therapies of mitochondriopathies.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 17","pages":"Article 169229"},"PeriodicalIF":4.7,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144140952","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

Interplay Between tRNA Modifications and Processing tRNA修饰与加工之间的相互作用。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-05-22 DOI: 10.1016/j.jmb.2025.169198

Jirka Peschek , Francesca Tuorto

引用次数: 0

Structural Impact of Ex Vivo Resistance Mutations on HIV-1 Integrase Polymers Induced by Allosteric Inhibitors 变构抑制剂诱导的HIV-1整合酶聚合物的体外耐药突变的结构影响

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-05-21 DOI: 10.1016/j.jmb.2025.169224

Saira Montermoso , Grant Eilers , Audrey Allen , Robert Sharp , Young Hwang , Frederic D. Bushman , Kushol Gupta , Gregory Van Duyne

{"title":"Structural Impact of Ex Vivo Resistance Mutations on HIV-1 Integrase Polymers Induced by Allosteric Inhibitors","authors":"Saira Montermoso , Grant Eilers , Audrey Allen , Robert Sharp , Young Hwang , Frederic D. Bushman , Kushol Gupta , Gregory Van Duyne","doi":"10.1016/j.jmb.2025.169224","DOIUrl":"10.1016/j.jmb.2025.169224","url":null,"abstract":"<div><div>HIV-1 integrase (IN) is targeted by two classes of antivirals: integrase strand transfer inhibitors (INSTIs), which bind to the active site within the catalytic core domain (CCD), and allosteric integrase inhibitors (ALLINIs), which bind at the CCD dimer interface. ALLINIs were initially designed to disrupt interactions with the cellular cofactor LEDGF/p75, but it has become clear that ALLINIs primarily act by promoting formation of aberrant integrase polymers. The ALLINIs achieve this by stabilizing ectopic intermolecular interactions between the CCD dimer and the integrase carboxy-terminal domain (CTD), which disrupts viral maturation. Previously, we determined the structure of full-length HIV-1 IN bound to the ALLINI GSK1264 at 4.4 Å resolution, revealing its polymerization mechanism. More recently, we reported the X-ray crystal structure of a minimal ternary complex between CCD, CTD, and the ALLINI BI-224436 at a higher resolution. In this study, we improve the original 4.4 Å structure using this higher-resolution information and report two new structures of full-length HIV-1 IN harboring escape mutations in the CCD (Trp131Cys) or CTD (Asn222Lys) bound with the prototype ALLINI BI-D at 4.5 Å. These structures reveal perturbations to the tertiary organization associated with escape substitutions, which correlate with their reduced ability to form ectopic ALLINI-induced polymers <em>in vitro</em>. These findings suggest a general structural mechanism of ALLINI resistance and provide insights for the design of improved ALLINIs.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 17","pages":"Article 169224"},"PeriodicalIF":4.7,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144131950","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

Rest, Repair, Repeat: The Complex Relationship of Autophagy and Sleep 休息、修复、重复：自噬与睡眠的复杂关系。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-05-21 DOI: 10.1016/j.jmb.2025.169227

Halvor Ullern , Paulina Schnur , Charlotte N Boccara , Helene Knævelsrud

{"title":"Rest, Repair, Repeat: The Complex Relationship of Autophagy and Sleep","authors":"Halvor Ullern , Paulina Schnur , Charlotte N Boccara , Helene Knævelsrud","doi":"10.1016/j.jmb.2025.169227","DOIUrl":"10.1016/j.jmb.2025.169227","url":null,"abstract":"<div><div>Autophagy and sleep are two evolutionary conserved mechanisms across the animal kingdom. Autophagy is a pathway for the degradation of cytoplasmic material in the lysosome, playing important roles in the homeostasis and health of the organism. On the other hand, sleep is a homeostatically regulated state with numerous presumed essential roles, including the restoration of tissue and physiological functions, such as brain waste clearance via the activation of the glymphatic systems. Given that sleep and autophagy are crucial processes tightly linked to homeostasis and maintenance of good health, understanding how they interact is of great interest, especially as sleep quality decreases in our modern 24-hour societies. Autophagy represents a promising target for therapeutic interventions in this context. Here, we review the contrasted and complementary roles of autophagy and sleep in maintaining homeostasis. Specifically, we focus on recent evidence suggesting that sleep impairment may increase autophagy, while autophagosome levels may modulate the amount of sleep. We discuss outstanding questions at the intersection of these two fields, highlighting methodological shortcomings in the current literature. Overcoming these limitations will be instrumental to design new experiments with the aim of answering one of the greatest mysteries of our time – why do we sleep?</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 18","pages":"Article 169227"},"PeriodicalIF":4.7,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144131946","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

Synthetic Biology for Designing Allostery and Its Potential Biomedical Applications. 设计变构的合成生物学及其潜在的生物医学应用。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-05-21 DOI: 10.1016/j.jmb.2025.169225

Tjaša Plaper, Urška Knez Štibler, Roman Jerala

{"title":"Synthetic Biology for Designing Allostery and Its Potential Biomedical Applications.","authors":"Tjaša Plaper, Urška Knez Štibler, Roman Jerala","doi":"10.1016/j.jmb.2025.169225","DOIUrl":"10.1016/j.jmb.2025.169225","url":null,"abstract":"<p><p>Allosteric regulation of protein function, where a perturbation at one site induces a conformational shift or alters dynamics at a distal functional site, plays a key role in numerous biological processes. The ability to introduce allostery using synthetic biology principles holds significant potential both for biomedical and biotechnological applications, and for advancing our understanding of natural allostery. By customizing target proteins for sensing specific chemical or physical signals, including ligand binding and environmental cues, we aim to allosterically modulate the function of a target protein depending on the selected triggers. This approach, unlike active-site targeting, offers greater specificity and selectivity and can allosterically couple diverse physiological processes. Synthetic biology strategies have been developed recently for designed allosteric protein regulation, including the design of allosteric modulators such as domain insertion, generation of de novo allosteric protein switches, and application of engineered allosteric mechanisms to control cellular functions. We examine the application of artificial intelligence (AI)-based generative protein design and other important milestones, challenges and opportunities in this field, highlighting how these approaches could be applied for the development of new therapeutic strategies.</p>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169225"},"PeriodicalIF":4.7,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144131877","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

Disease-associated Kv1.3 Variants are Energy Compromised with Impaired Nascent Chain Folding 疾病相关的Kv1.3变异与新生链折叠受损有关。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-05-21 DOI: 10.1016/j.jmb.2025.169226

Aaron Sykes , Lannawill Caruth , Sophia Gross , Shefali Setia Verma , Toshinori Hoshi , Carol Deutsch

{"title":"Disease-associated Kv1.3 Variants are Energy Compromised with Impaired Nascent Chain Folding","authors":"Aaron Sykes , Lannawill Caruth , Sophia Gross , Shefali Setia Verma , Toshinori Hoshi , Carol Deutsch","doi":"10.1016/j.jmb.2025.169226","DOIUrl":"10.1016/j.jmb.2025.169226","url":null,"abstract":"<div><div>Nascent proteins fold in a stepwise manner during all stages of biogenesis. This progression is particularly complex for ion channels composed of multiple biogenic and functional domains and subunits. The human Kv1.3 ion channel, encoded by <em>KCNA3</em>, is expressed in neuronal and immune cells. Its dysregulation produces chronic inflammatory disease and autoimmune disorders, which affect many in the US population, especially women. Using the unbiased ‘genome-first’ approach with integrated patient biobank databases, we identified <em>KCNA3</em> gene variants associated with human disease and examined their impact on Kv1.3 channel biogenesis. Our tertiary and quaternary folding assays and all-atom molecular dynamics simulations show that <em>KCNA3</em> gene variants in T1, the channel’s intersubunit recognition domain, manifest early-stage T1 folding defects, energetic instabilities, and conformational distortion of subunits concomitant with tertiary unwinding. These findings identify molecular mechanisms by which patient-associated variants influence channel assembly, potentially contributing to diverse clinical phenotypes underlying human disease.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 17","pages":"Article 169226"},"PeriodicalIF":4.7,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144131942","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