Journal of Molecular Biology最新文献_第7页

Allostery in Disease: Anticancer Drugs, Pockets, and the Tumor Heterogeneity Challenge.

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-02-26 DOI: 10.1016/j.jmb.2025.169050

Ruth Nussinov, Bengi Ruken Yavuz, Hyunbum Jang

{"title":"Allostery in Disease: Anticancer Drugs, Pockets, and the Tumor Heterogeneity Challenge.","authors":"Ruth Nussinov, Bengi Ruken Yavuz, Hyunbum Jang","doi":"10.1016/j.jmb.2025.169050","DOIUrl":"10.1016/j.jmb.2025.169050","url":null,"abstract":"<p><p>Charting future innovations is challenging. Yet, allosteric and orthosteric anticancer drugs are undergoing a revolution and taxing unresolved dilemmas await. Among the imaginative innovations, here we discuss cereblon and thalidomide derivatives as a means of recruiting neosubstrates and their degradation, allosteric heterogeneous bifunctional drugs like PROTACs, drugging phosphatases, inducers of targeted posttranslational protein modifications, antibody-drug conjugates, exploiting membrane interactions to increase local concentration, stabilizing the folded state, and more. These couple with harnessing allosteric cryptic pockets whose discovery offers more options to modulate the affinity of orthosteric, active site inhibitors. Added to these are strategies to counter drug resistance through drug combinations co-targeting pathways to bypass signaling blockades. Here, we discuss on the molecular and cellular levels, such inspiring advances, provide examples of their applications, their mechanisms and rational. We start with an overview on difficult to target proteins and their properties-rarely, if ever-conceptualized before, discuss emerging innovative drugs, and proceed to the increasingly popular allosteric cryptic pockets-their advantages-and critically, issues to be aware of. We follow with drug resistance and in-depth discussion of tumor heterogeneity. Heterogeneity is a hallmark of highly aggressive cancers, the core of drug resistance unresolved challenge. We discuss potential ways to target heterogeneity by predicting it. The increase in experimental and clinical data, computed (cell-type specific) interactomes, capturing transient cryptic pockets, learned drug resistance, workings of regulatory mechanisms, heterogeneity, and resistance-based cell signaling drug combinations, assisted by AI-driven reasoning and recognition, couple with creative allosteric drug discovery, charting future innovations.</p>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169050"},"PeriodicalIF":4.7,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531153","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

Structures of ΔD421 Truncated Tau Fibrils Δ D421 截短 Tau 纤维的结构。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-02-26 DOI: 10.1016/j.jmb.2025.169051

Nadia El Mammeri, Pu Duan, Mei Hong

{"title":"Structures of ΔD421 Truncated Tau Fibrils","authors":"Nadia El Mammeri, Pu Duan, Mei Hong","doi":"10.1016/j.jmb.2025.169051","DOIUrl":"10.1016/j.jmb.2025.169051","url":null,"abstract":"<div><div>The microtubule-associated protein tau aggregates into pathological β-sheet amyloid fibrils in Alzheimer’s disease (AD) and other neurodegenerative diseases. In these aggregates, tau is chemically modified, including abnormal hyperphosphorylation and truncation. Truncation after D421 in the C-terminal domain occurs at early stages of AD. Here we investigate the structures of ΔD421-truncated 0N4R tau fibrils assembled <em>in vitro</em> in the absence of anionic cofactors. Using solid-state NMR spectroscopy and cryoelectron microscopy, we show that ΔD421-truncated 0N4R tau forms homogeneous fibrils whose rigid core adopts a three-layered β-sheet structure that spans R2, R3 and R4 repeats. This structure is essentially identical to that of full-length tau containing phospho-mimetic mutations at the PHF1 epitope in the C-terminal domain. In comparison, a ΔD421-truncated tau that additionally contains three phospho-mimetic mutations at the AT8 epitope in the proline-rich region forms a fibril core that includes the first half of the C-terminal domain, which is excluded from all known pathological tau fibril cores. These results indicate that the posttranslational modification code of tau contains redundancy: both charge modification and truncation of the C-terminal domain promote a three-layered β-sheet structure, which resembles pathological four-repeat tau structures in several tauopathies. In comparison, reducing the positive charges at the AT8 epitope in ΔD421-truncated tau promotes a fibril core that includes an immobilized C-terminal domain. The absence of this structure in tauopathy brains implies that ΔD421 truncation does not occur in conjunction with AT8 phosphorylation in diseased brains.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 10","pages":"Article 169051"},"PeriodicalIF":4.7,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531162","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

IsoTools 2.0: Software for Comprehensive Analysis of Long-read Transcriptome Sequencing Data.

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-02-26 DOI: 10.1016/j.jmb.2025.169049

Yalan Bi, Tom Lukas Lankenau, Matthias Lienhard, Ralf Herwig

{"title":"IsoTools 2.0: Software for Comprehensive Analysis of Long-read Transcriptome Sequencing Data.","authors":"Yalan Bi, Tom Lukas Lankenau, Matthias Lienhard, Ralf Herwig","doi":"10.1016/j.jmb.2025.169049","DOIUrl":"10.1016/j.jmb.2025.169049","url":null,"abstract":"<p><p>Direct, single molecule measurement of RNA by long-read transcriptome sequencing (LRTS) enables the reliable detection of transcripts and alternative splicing events, thus contributing to the identification of splicing mechanisms, improvement of current gene models, as well as to the prediction of more reliable protein isoforms. LRTS data comes from either PacBio's single-molecule real time sequencing or from Oxford Nanopore's nanopore sequencing. Previously, we developed IsoTools, a software originally designed for processing and analyzing PacBio data. IsoTools copes with the complexity of LRTS data and offers multiple functionality for transcript identification and quantification as well as the analysis of differential isoform usage and local differential splicing events. Here, we report an update of the software, IsoTools 2.0, and demonstrate its additional performance on Oxford Nanopore data from multiple experimental protocols. We present the IsoTools 2.0 workflow, highlighting novel functionalities with respect to reliable transcript detection as well as transcription start site prediction. Additionally, we show novel metrics for structural description and quantification of gene model variability based on the gene's transcripts. We demonstrate the performance of IsoTools 2.0 on a variety of experimental protocols for library construction from a recent LRTS challenge. We show that IsoTools 2.0 is able to cope with the inherent complexity of LRTS data and that the workflow generates meaningful hypotheses on biomarkers for alternative splicing. The software is available from https://github.com/HerwigLab/IsoTools2/.</p>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169049"},"PeriodicalIF":4.7,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531155","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

Off-pathway oligomers of α-synuclein and Aβ inhibit secondary nucleation of α-synuclein amyloid fibrils

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-02-25 DOI: 10.1016/j.jmb.2025.169048

Marie P. Schützmann , Wolfgang Hoyer

{"title":"Off-pathway oligomers of α-synuclein and Aβ inhibit secondary nucleation of α-synuclein amyloid fibrils","authors":"Marie P. Schützmann , Wolfgang Hoyer","doi":"10.1016/j.jmb.2025.169048","DOIUrl":"10.1016/j.jmb.2025.169048","url":null,"abstract":"<div><div><span><math><mrow><mi>α</mi></mrow></math></span>-Synuclein (<span><math><mrow><mi>α</mi></mrow></math></span>Syn) is a key culprit in the pathogenesis of synucleinopathies such as Parkinson’s Disease (PD), in which it forms not only insoluble aggregates called amyloid fibrils but also smaller, likely more detrimental species termed oligomers. This property is shared with other amyloidogenic proteins such as the Alzheimer’s Disease-associated amyloid-<span><math><mrow><mi>β</mi></mrow></math></span> (A<span><math><mrow><mi>β</mi></mrow></math></span>). We previously found an intriguing interplay between off-pathway A<span><math><mrow><mi>β</mi></mrow></math></span> oligomers and A<span><math><mrow><mi>β</mi></mrow></math></span> fibrils, in which the oligomers interfere with fibril formation via inhibition of secondary nucleation by blocking secondary nucleation sites on the fibril surface. Here, using ThT aggregation kinetics and atomic force microscopy (AFM), we tested if the same interplay applies to <span><math><mrow><mi>α</mi></mrow></math></span>Syn fibrils. Both homotypic (i.e. <span><math><mrow><mi>α</mi></mrow></math></span>Syn) and heterotypic (i.e. A<span><math><mrow><mi>β</mi></mrow></math></span>) off-pathway oligomers inhibited <span><math><mrow><mi>α</mi></mrow></math></span>Syn aggregation in kinetic assays of secondary nucleation. Initially soluble, kinetically trapped A<span><math><mrow><mi>β</mi></mrow></math></span> oligomers co-precipitated with <span><math><mrow><mi>α</mi></mrow></math></span>Syn(1–108) fibrils. The resulting co-assemblies were imaged as clusters of curvilinear oligomers by AFM. The results indicate that off-pathway oligomers have a general tendency to bind amyloid fibril surfaces, also in the absence of sequence homology between fibril and oligomer. The interplay between off-pathway oligomers and amyloid fibrils adds another level of complexity to the homo- and hetero-assembly processes of amyloidogenic proteins.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 10","pages":"Article 169048"},"PeriodicalIF":4.7,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522137","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

Unexpected Richness of the Bacterial Small RNA World.

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-02-25 DOI: 10.1016/j.jmb.2025.169045

Gisela Storz

{"title":"Unexpected Richness of the Bacterial Small RNA World.","authors":"Gisela Storz","doi":"10.1016/j.jmb.2025.169045","DOIUrl":"10.1016/j.jmb.2025.169045","url":null,"abstract":"<p><p>I stumbled onto a small RNA (sRNA) induced by oxidative stress when I did the \"wrong\" northern blot experiment as a second-year graduate student. I was so intrigued by the very strong induction of the 109 nt OxyS RNA that I kept working to elucidate its function while carrying out other projects. Over a decade after developing the first OxyS northern, I was able to document that the RNA acts as a regulator. This finding together with concurrent observations about the 91 nt DsrA RNA by Susan Gottesman's group led to the realization that regulatory sRNAs were far more prevalent in bacteria than initially imagined. I do not think we could have anticipated how integral sRNAs are to regulatory networks in bacteria and how much we would learn about the mechanisms by which these sRNAs regulate gene expression, most commonly through limited base pairing with target mRNAs, chaperoned by the Hfq protein. Our work was greatly facilitated by the collegiality in the bacterial sRNA field and the regular discussions and collaborations between my group and the Gottesman group. Susan and I are both writing overviews but have agreed to emphasize different aspects of the investigation into bacterial sRNAs with the intent that our articles are read in parallel.</p>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169045"},"PeriodicalIF":4.7,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522079","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

Pioneer in Molecular Biology: Conformational Ensembles in Molecular Recognition, Allostery, and Cell Function.

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-02-25 DOI: 10.1016/j.jmb.2025.169044

Ruth Nussinov

{"title":"Pioneer in Molecular Biology: Conformational Ensembles in Molecular Recognition, Allostery, and Cell Function.","authors":"Ruth Nussinov","doi":"10.1016/j.jmb.2025.169044","DOIUrl":"10.1016/j.jmb.2025.169044","url":null,"abstract":"<p><p>In 1978, for my PhD, I developed the efficient O(n<sup>3</sup>) dynamic programming algorithm for the-then open problem of RNA secondary structure prediction. This algorithm, now dubbed the \"Nussinov algorithm\", \"Nussinov plots\", and \"Nussinov diagrams\", is still taught across Europe and the U.S. As sequences started coming out in the 1980s, I started seeking genome-encoded functional signals, later becoming a bioinformatics trend. In the early 1990s I transited to proteins, co-developing a powerful computer vision-based docking algorithm. In the late 1990s, I proposed the foundational role of conformational ensembles in molecular recognition and allostery. At the time, conformational ensembles and free energy landscapes were viewed as physical properties of proteins but were not associated with function. The classical view of molecular recognition and binding was based on only two conformations captured by crystallography: open and closed. I proposed that all conformational states preexist. Proteins always have not one folded form-nor two-but many folded forms. Thus, rather than inducing fit, binding can work by shifting the ensembles between states, and this shifting, or redistributing the ensembles to maintain equilibrium, is the origin of the allosteric effect and protein, thus cell, function. This transformative paradigm impacted community views in allosteric drug design, catalysis, and regulation. Dynamic conformational ensemble shifts are now acknowledged as the origin of recognition, allostery, and signaling, underscoring that conformational ensembles-not proteins-are the workhorses of the cell, pioneering the fundamental idea that dynamic ensembles are the driving force behind cellular processes. Nussinov was recognized as pioneer in molecular biology by JMB.</p>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169044"},"PeriodicalIF":4.7,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522076","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

TGT Damages its Substrate tRNAs by the Formation of Abasic Sites in the Anticodon Loop.

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-02-25 DOI: 10.1016/j.jmb.2025.169000

Kevin Kopietz, Kasturi Raorane, Wei Guo, Florian Flegler, Valérie Bourguignon, Quentin Thuillier, Lea-Marie Kilz, Marlies Weber, Virginie Marchand, Klaus Reuter, Francesca Tuorto, Mark Helm, Yuri Motorin

{"title":"TGT Damages its Substrate tRNAs by the Formation of Abasic Sites in the Anticodon Loop.","authors":"Kevin Kopietz, Kasturi Raorane, Wei Guo, Florian Flegler, Valérie Bourguignon, Quentin Thuillier, Lea-Marie Kilz, Marlies Weber, Virginie Marchand, Klaus Reuter, Francesca Tuorto, Mark Helm, Yuri Motorin","doi":"10.1016/j.jmb.2025.169000","DOIUrl":"https://doi.org/10.1016/j.jmb.2025.169000","url":null,"abstract":"<p><p>RNA modification is a well-recognized way for gene expression regulation in a living cell. Natural enzymatic RNA modifications have been characterized for decades. Recently, additional mechanisms, more related to RNA damage, have emerged, which do not involve targeted enzymatic activity but nonetheless alter the chemical structure of nucleosides. Aberrantly modified RNA may also appear due to incomplete or erroneous enzymatic reactions. We demonstrate that tRNA-guanine transglycosylase (TGT) in bacteria and eukaryotes accidentally leaves RNA abasic sites (rAP) in the anticodon loop of substrate tRNAs. The formation of an rAP site is a part of the TGT catalytic mechanism, involving the cleavage of the N-glycosidic bond, and the formation of a covalent enzyme-tRNA adduct. The phenomenon of rAP site formation is readily detectable for tRNA<sup>Tyr</sup>(GUA) in bacteria and tRNA<sup>Asp</sup>(GUC) in eukaryotes and is amplified when the supply for preQ<sub>1</sub> in bacteria is compromised. The TGT-mediated accumulation of rAP sites in tRNAs is strongly induced upon stress, and most prominent upon oxidative stress in bacteria. Polysome profiling in bacteria points out the partial exclusion of rAP-containing tRNAs from the translating ribosome fraction, prompting a consideration of these tRNA species as \"damaged\" and most likely non-functional. The exploratory analysis of rAP tRNA(GUN) sites in mice demonstrates a substantial variability among different tissues, with the highest accumulation of damaged tRNA observed in the brain, the lung and the spleen. Altogether, these results uncover a unique molecular mechanism of RNA modification that, via a presumably erroneous reaction, diminishes RNA function rather than enhancing it.</p>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169000"},"PeriodicalIF":4.7,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514314","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

SAMD12 as a Master Regulator of MAP4Ks by Decoupling Kinases From the CNKSR2 Scaffold

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-02-24 DOI: 10.1016/j.jmb.2025.169034

Wen Pan , Zhijie Lin , Shiwen Chen , Jiahui Li , Yu Wang , Keyu Chen , Mingjie Zhang

{"title":"SAMD12 as a Master Regulator of MAP4Ks by Decoupling Kinases From the CNKSR2 Scaffold","authors":"Wen Pan , Zhijie Lin , Shiwen Chen , Jiahui Li , Yu Wang , Keyu Chen , Mingjie Zhang","doi":"10.1016/j.jmb.2025.169034","DOIUrl":"10.1016/j.jmb.2025.169034","url":null,"abstract":"<div><div>The MAP4K member TNIK and the multi-domain scaffold protein CNKSR2, both of which are clustered at neuronal synapses, interact with each other and are closely associated with neurodevelopmental disorders, although the mechanism underlying their interaction is unclear. In this study, we characterized the interaction mechanisms between MAP4K kinases (MAP4K4, MINK1 and TNIK) and the CNKSR1/2/3 scaffold proteins, and discovered that SAMD12, a familial adult myoclonic epilepsy disease gene product, or its close homolog SAMD10, binds to CNKSR1/2/3 with exceptionally strong affinities and can quantitatively displace MAP4K from CNKSR1/2/3 scaffolds. Additionally, we demonstrated that CNKSR2 acts as both a scaffold and an activator of TNIK during neuronal synapse development. Ectopic expression of SAMD12 can effectively alter synapse development, likely by inhibiting TNIK activity through the dissociation of the kinase from CNKSR2. Our findings may have broad implications on the roles of MAP4Ks and CNKSR1/2/3 in the nervous system and in other tissues under physiological and pathophysiological processes.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 9","pages":"Article 169034"},"PeriodicalIF":4.7,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514312","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

Timestamp calibration for time-series single cell RNA-seq expression data

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-02-24 DOI: 10.1016/j.jmb.2025.169021

Xiran Chen , Sha Lin , Xiaofeng Chen , Weikai Li , Yifei Li

{"title":"Timestamp calibration for time-series single cell RNA-seq expression data","authors":"Xiran Chen , Sha Lin , Xiaofeng Chen , Weikai Li , Yifei Li","doi":"10.1016/j.jmb.2025.169021","DOIUrl":"10.1016/j.jmb.2025.169021","url":null,"abstract":"<div><div>Timestamp automatic annotation (TAA) is a crucial procedure for analyzing time-series scRNA-seq data, as they unveil dynamic biological developments and cell regeneration processes. However, current TAA methods heavily rely on manual timestamps, often overlooking their reliability. This oversight can significantly degrade the performance of timestamp automatic annotation due to noisy timestamps. Nevertheless, the current approach for addressing this issue tends to select less critical cleaned samples for timestamp calibration. To tackle this challenge, we have developed a novel timestamp calibration model called ScPace for handling noisy labeled time-series scRNA-seq data. This approach incorporates a latent variable indicator within a base classifier instead of probability sampling to detect noisy samples effectively. To validate our proposed method, we conducted experiments on both simulated and real time-series scRNA-seq datasets. Cross validation experiments with different artificial mislabeling rates demonstrate that ScPace outperforms previous approaches. Furthermore, after calibrating the timestamps of the original time-series scRNA-seq data using our method, we performed supervised pseudotime analysis, revealing that ScPace enhances its performance significantly. These findings suggest that ScPace is an effective tool for timestamp calibration by enabling reclassification and deletion of detected noisy labeled samples while maintaining robustness across diverse ranges of time-series scRNA-seq datasets. The source code is available at https://github.com/OPUS-Lightphenexx/ScPace.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 9","pages":"Article 169021"},"PeriodicalIF":4.7,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514130","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

Investigation of Domain Interaction in the Apolipoprotein E Isoforms by HDX-MS

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-02-24 DOI: 10.1016/j.jmb.2025.169036

Sudip Pal, Subhrajyoti Dolai, Deepa S., Kanchan Garai

{"title":"Investigation of Domain Interaction in the Apolipoprotein E Isoforms by HDX-MS","authors":"Sudip Pal, Subhrajyoti Dolai, Deepa S., Kanchan Garai","doi":"10.1016/j.jmb.2025.169036","DOIUrl":"10.1016/j.jmb.2025.169036","url":null,"abstract":"<div><div>Involvement of apoE4 in the pathology of Alzheimer’s disease (AD) is hypothesized to arise from its unique structural properties, most importantly the interactions between the N- and C-terminal domains. However, structural understanding of the domain interaction is still lacking. Here, we use Hydrogen-Deuterium Exchange Mass Spectrometry (HDX-MS) to study domain interactions by measuring the effect of the C-terminal domain (CTD) on the solvent accessibility of the N-terminal domain (NTD) in both apoE3 and apoE4. Our results indicate that the presence of CTD enhances the solvent accessibility of all the four helices in the NTD in apoE4, but only two helices, specifically Helix-1 and 4 in apoE3. Therefore, the allosteric changes in the conformational ensemble of the NTD induced by the CTD is more extensive in apoE4 than in apoE3. Moreover, strong pH dependence suggests role of the salt bridges in the interdomain interactions. Since the NTD harbors the receptor binding region, the destabilizing effect of CTD on it provides a structural basis for the role of interdomain interactions on the pathological functions of apoE4. Furthermore, we propose HDX-MS as a methodology for screening and assessing the efficacy of ‘structure corrector’ molecules targeting apoE4 to mitigate its pathological effects in AD.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 10","pages":"Article 169036"},"PeriodicalIF":4.7,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514310","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