Journal of Molecular Biology最新文献

Multiply Perturbed Response to Disclose Allosteric Control of Conformational Change: Application to Fluorescent Biosensor Design. 揭示构象变化变构控制的多重摄动响应：在荧光生物传感器设计中的应用。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-05-28 DOI: 10.1016/j.jmb.2025.169234

Melike Berksoz, Ali Rana Atilgan, Burak Kocuk, Canan Atilgan

{"title":"Multiply Perturbed Response to Disclose Allosteric Control of Conformational Change: Application to Fluorescent Biosensor Design.","authors":"Melike Berksoz, Ali Rana Atilgan, Burak Kocuk, Canan Atilgan","doi":"10.1016/j.jmb.2025.169234","DOIUrl":"https://doi.org/10.1016/j.jmb.2025.169234","url":null,"abstract":"Proteins exhibit remarkable conformational flexibility, enabling precise functional regulation through allostery. A key application of allostery is in the design of protein-based sensors, which detect environmental changes-such as ligand binding or post-translational modifications-and convert these cues into measurable signals (e.g., fluorescence). Here, we investigate a series of ligand-binding proteins that serve as sensing domains in direct-response fluorescent biosensors, wherein ligand binding enhances fluorescence output. We employ a multiple force application approach which we term Multiply Perturbed Response (MPR) to identify \"hot spot\" residues that drive the conformational transition from an apo (inactive/OFF) to a holo (active/ON) state. We first present two efficient computational approaches to determine residues and forces that maximize the overlap of the observed conformational change. We then determine the overlap maximizer residues for up to five force insertion locations, and we compare them with actual insertion sites used in existing biosensors. Our analysis shows that the allosteric residues identified by MPR coincide with the fluorescent-protein insertion sites that were mapped experimentally through extensive trial-and-error. This work enhances the utility of linear response theory-based methods in uncovering multiple functionally significant regions that trigger a known conformational change. While the validity of the harmonic approximation in anharmonic conformational transitions needs additional validation, MPR gives a good starting point to explore allosteric sites. The approach might prove useful not only in the design of biosensors, but may also find applications in offering physics-based collective variables in mapping conformational transition pathways of proteins.","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169234"},"PeriodicalIF":4.7,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186145","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 links hACE2 binding, pan-variant neutralization and helical extension in the SARS-CoV-2 Spike protein. 在SARS-CoV-2刺突蛋白中，变构连接hACE2结合、泛变异中和和螺旋延伸。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-05-28 DOI: 10.1016/j.jmb.2025.169232

Alice Colyer, Esther Wolf, Cristina Lento, Mart Ustav, Adnan Sljoka, Derek J Wilson

{"title":"Allostery links hACE2 binding, pan-variant neutralization and helical extension in the SARS-CoV-2 Spike protein.","authors":"Alice Colyer, Esther Wolf, Cristina Lento, Mart Ustav, Adnan Sljoka, Derek J Wilson","doi":"10.1016/j.jmb.2025.169232","DOIUrl":"https://doi.org/10.1016/j.jmb.2025.169232","url":null,"abstract":"The SARS-CoV-2 spike protein is highly antigenic, with epitopes in three distinct regions of the receptor binding domain (RBD) alone that have known mechanisms of neutralization. In previous work, we predicted a fourth RBD epitope based on allosteric conformational perturbations measured by hydrogen-deuterium exchange mass spectrometry (HDX-MS) upon complexation with the canonical spike protein target, human angiotensin-converting enzyme 2 (hACE2). We subsequently identified a pan-neutralizing antibody (ICO-hu104) with the predicted epitope, however, as the epitope was somewhat distant from the hACE2 binding interface, and our previous work limited to the spike RBD, the neutralization mechanism was unclear. Using HDX-MS, we investigated the binding of ICO-hu104 to the full-length SARS-CoV-2 spike protein from Wuhan, Delta and Omicron variants. We demonstrate that binding of ICO-hu104 results in an increase in deuterium uptake in the distant HR1 domain in latter variants, which in a biological context could be indicative of destabilisation of the helices within this region, promoting premature S1 shedding or failure of helical extension during S2-mediated fusion. This is supported by our computational modelling, highlighting propagation of allosteric effects to the S2 coiled-coil region upon rigidification of the ICO-hu104 epitope. Collectively, this work demonstrates an alternative neutralization mechanism for ICO-hu104 which is distinct from its first-generation predecessors and thus opens alternative avenues targeting non-RBD epitopes through allosteric perturbations.","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169232"},"PeriodicalIF":4.7,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186144","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

pLMMoRF: A web server that accurately predicts membrane-interacting molecular recognition features by employing a protein language model. pLMMoRF：一个通过使用蛋白质语言模型准确预测膜相互作用分子识别特征的web服务器。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-05-27 DOI: 10.1016/j.jmb.2025.169236

Máté Csepi, Blanka Berta, Sushmita Basu, Lukasz Kurgan, Tamás Hegedűs

{"title":"pLMMoRF: A web server that accurately predicts membrane-interacting molecular recognition features by employing a protein language model.","authors":"Máté Csepi, Blanka Berta, Sushmita Basu, Lukasz Kurgan, Tamás Hegedűs","doi":"10.1016/j.jmb.2025.169236","DOIUrl":"https://doi.org/10.1016/j.jmb.2025.169236","url":null,"abstract":"Interactions between proteins and lipids are crucial for numerous cellular processes. Some of the lipid interacting segments in protein sequences are intrinsically disordered regions (IDRs), which may gain secondary structures upon binding. We collected experimentally annotated lipid-interacting IDRs, named membrane molecular recognition features (MemMoRFs). We used this dataset to develop and test an accurate and relatively fast sequence-based MemMoRF predictor, pLMMoRF, thereby supporting tedious and costly experimental identification of MemMoRFs. Our predictor utilizes a protein language model (pLM) which we processed to generate inputs to a deep convolutional neural network. We considered various pLMs (ESM-2, ProstT5, ProtT5 and Ankh) and applied feature selection to reduce their outputs, creating a more compact neural network model. pLMMoRF leverages the Ankh-based model, selected for its higher accuracy compared to our other models. Tests on low similarity test datasets demonstrate that pLMMoRF is more accurate than the sole current predictor of MemMoRFs, CoMemMoRFPred. Moreover, pLMMoRF has a relatively small computational footprint because of the compact network size and use of dedicated GPU nodes. This allowed us to make MemMoRF predictions for the human proteome. We analyzed these predictions and made them publicly available, facilitating an improved understanding of functions of membrane-coupled proteins. Our work underscores the importance of selecting key embedding features to enhance predictive performance and reduce computational footprint of sequence-based predictors of protein functions. The web server for the pLMMoRF predictor and the predictions for human proteins are freely available at https://plmmorf.hegelab.org.","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169236"},"PeriodicalIF":4.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179652","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

Decoding tRNA Modifications: Integrating Molecular, Biological, and Pathological Insights. 解码tRNA修饰：整合分子、生物学和病理学见解。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-05-27 DOI: 10.1016/j.jmb.2025.169238

Jane E Jackman, Ute Kothe

引用次数: 0

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":"https://doi.org/10.1016/j.jmb.2025.169230","url":null,"abstract":"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 Escherichia coli, 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 Mycobacterium smegmatis 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.","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"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

Tau(350-362) is a key region that drives modulates inhibition of fibrillogenesis 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":"Tau(350-362) is a key region that drives modulates inhibition of fibrillogenesis 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":"https://doi.org/10.1016/j.jmb.2025.169231","url":null,"abstract":"Tau297-391 (dGAE) forms paired helical filaments in vitro 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 are associated with self-assembly propensity and have explored their ability to form filaments and whether their self-assembly can be inhibited by HMT. We confirm that tau306-323 self-assembles to form filaments but that fibrillogenesis is not inhibited by HMT. Previous work by others has shown that tau350-362 (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.","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"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 Zoltowski, Peng Tao

{"title":"Structural Plasticity and Functional Dynamics of Pigeon Cryptochrome 4 as Avian Magnetoreceptor.","authors":"Chuanye Xiong, Palanisamy Kandhan, Brian Zoltowski, Peng Tao","doi":"10.1016/j.jmb.2025.169233","DOIUrl":"https://doi.org/10.1016/j.jmb.2025.169233","url":null,"abstract":"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.","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":"","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":"","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":"https://doi.org/10.1016/j.jmb.2025.169229","url":null,"abstract":"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.","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"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