eLife最新文献_第6页

Induction of hepatitis B core protein aggregation targeting an unconventional binding site.

IF 6.4 1区生物学

eLife Pub Date : 2025-03-26 DOI: 10.7554/eLife.98827

Vladimir Khayenko, Cihan Makbul, Clemens Schulte, Naomi Hemmelmann, Sonja Kachler, Bettina Böttcher, Hans Michael Maric

{"title":"Induction of hepatitis B core protein aggregation targeting an unconventional binding site.","authors":"Vladimir Khayenko, Cihan Makbul, Clemens Schulte, Naomi Hemmelmann, Sonja Kachler, Bettina Böttcher, Hans Michael Maric","doi":"10.7554/eLife.98827","DOIUrl":"10.7554/eLife.98827","url":null,"abstract":"The hepatitis B virus (HBV) infection is a major global health problem, with chronic infection leading to liver complications and high death toll. Current treatments, such as nucleos(t)ide analogs and interferon-α, effectively suppress viral replication but rarely cure the infection. To address this, new antivirals targeting different components of the HBV molecular machinery are being developed. Here we investigated the hepatitis B core protein (HBc) that forms the viral capsids and plays a vital role in the HBV life cycle. We explored two distinct binding pockets on the HBV capsid: the central hydrophobic pocket of HBc-dimers and the pocket at the tips of capsid spikes. We synthesized a geranyl dimer that binds to the central pocket with micromolar affinity, and dimeric peptides that bind the spike-tip pocket with sub-micromolar affinity. Cryo-electron microscopy further confirmed the binding of peptide dimers to the capsid spike tips and their capsid-aggregating properties. Finally, we show that the peptide dimers induce HBc aggregation in vitro and in living cells. Our findings highlight two tractable sites within the HBV capsid and provide an alternative strategy to affect HBV capsids.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11942178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143709171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Network segregation is associated with processing speed in the cognitively healthy oldest-ol.

IF 6.4 1区生物学

eLife Pub Date : 2025-03-26 DOI: 10.7554/eLife.78076

Sara A Nolin, Mary E Faulkner, Paul Stewart, Leland L Fleming, Stacy Merritt, Roxanne F Rezaei, Prad K Bharadwaj, Mary Kate Franchetti, David A Raichlen, Courtney J Jessup, Lloyd Edwards, G Alex Hishaw, Emily J Van Etten, Theodore P Trouard, David Geldmacher, Virginia G Wadley, Noam Alperin, Eric S Porges, Adam J Woods, Ron A Cohen, Bonnie E Levin, Tatjana Rundek, Gene E Alexander, Kristina Visscher

{"title":"Network segregation is associated with processing speed in the cognitively healthy oldest-ol.","authors":"Sara A Nolin, Mary E Faulkner, Paul Stewart, Leland L Fleming, Stacy Merritt, Roxanne F Rezaei, Prad K Bharadwaj, Mary Kate Franchetti, David A Raichlen, Courtney J Jessup, Lloyd Edwards, G Alex Hishaw, Emily J Van Etten, Theodore P Trouard, David Geldmacher, Virginia G Wadley, Noam Alperin, Eric S Porges, Adam J Woods, Ron A Cohen, Bonnie E Levin, Tatjana Rundek, Gene E Alexander, Kristina Visscher","doi":"10.7554/eLife.78076","DOIUrl":"https://doi.org/10.7554/eLife.78076","url":null,"abstract":"The brain is organized into systems and networks of interacting components. The functional connections among these components give insight into the brain's organization and may underlie some cognitive effects of aging. Examining the relationship between individual differences in brain organization and cognitive function in older adults who have reached oldest old ages with healthy cognition can help us understand how these networks support healthy cognitive aging. We investigated functional network segregation in 146 cognitively healthy participants aged 85+ in the McKnight Brain Aging Registry. We found that the segregation of the association system and the individual networks within the association system [the fronto-parietal network (FPN), cingulo-opercular network (CON) and default mode network (DMN)], has strong associations with overall cognition and processing speed. We also provide a healthy oldest-old (85+) cortical parcellation that can be used in future work in this age group. This study shows that network segregation of the oldest-old brain is closely linked to cognitive performance. This work adds to the growing body of knowledge about differentiation in the aged brain by demonstrating that cognitive ability is associated with differentiated functional networks in very old individuals representing successful cognitive aging.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143709180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

AI-based discovery and cryoEM structural elucidation of a K_ATP channel pharmacochaperone.

IF 6.4 1区生物学

eLife Pub Date : 2025-03-26 DOI: 10.7554/eLife.103159

Assmaa Elsheikh, Camden M Driggers, Ha H Truong, Zhongying Yang, John Allen, Niel M Henriksen, Katarzyna Walczewska-Szewc, Show-Ling Shyng

{"title":"AI-based discovery and cryoEM structural elucidation of a KATP channel pharmacochaperone.","authors":"Assmaa Elsheikh, Camden M Driggers, Ha H Truong, Zhongying Yang, John Allen, Niel M Henriksen, Katarzyna Walczewska-Szewc, Show-Ling Shyng","doi":"10.7554/eLife.103159","DOIUrl":"10.7554/eLife.103159","url":null,"abstract":"Pancreatic KATP channel trafficking defects underlie congenital hyperinsulinism (CHI) cases unresponsive to the KATP channel opener diazoxide, the mainstay medical therapy for CHI. Current clinically used KATP channel inhibitors have been shown to act as pharmacochaperones and restore surface expression of trafficking mutants; however, their therapeutic utility for KATP trafficking-impaired CHI is hindered by high affinity binding, which limits functional recovery of rescued channels. Recent structural studies of KATP channels employing cryo-electron microscopy (cryoEM) have revealed a promiscuous pocket where several known KATP pharmacochaperones bind. The structural knowledge provides a framework for discovering KATP channel pharmacochaperones with desired reversible inhibitory effects to permit functional recovery of rescued channels. Using an AI-based virtual screening technology AtomNet followed by functional validation, we identified a novel compound, termed Aekatperone, which exhibits chaperoning effects on KATP channel trafficking mutations. Aekatperone reversibly inhibits KATP channel activity with a half-maximal inhibitory concentration (IC50) ~9 μM. Mutant channels rescued to the cell surface by Aekatperone showed functional recovery upon washout of the compound. CryoEM structure of KATP bound to Aekatperone revealed distinct binding features compared to known high affinity inhibitor pharmacochaperones. Our findings unveil a KATP pharmacochaperone enabling functional recovery of rescued channels as a promising therapeutic for CHI caused by KATP trafficking defects.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11942174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143709150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Aβ-driven nuclear pore complex dysfunction alters activation of necroptosis proteins in a mouse model of Alzheimer's disease.

IF 6.4 1区生物学

eLife Pub Date : 2025-03-25 DOI: 10.7554/eLife.92069

Vibhavari Aysha Bansal, Jia Min Tan, Hui Rong Soon, Norliyana Zainolabidin, Takaomi Saido, Toh Hean Ch'ng

{"title":"Aβ-driven nuclear pore complex dysfunction alters activation of necroptosis proteins in a mouse model of Alzheimer's disease.","authors":"Vibhavari Aysha Bansal, Jia Min Tan, Hui Rong Soon, Norliyana Zainolabidin, Takaomi Saido, Toh Hean Ch'ng","doi":"10.7554/eLife.92069","DOIUrl":"10.7554/eLife.92069","url":null,"abstract":"The emergence of Aβ pathology is one of the hallmarks of Alzheimer's disease (AD), but the mechanisms and impact of Aβ in progression of the disease is unclear. The nuclear pore complex (NPC) is a multi-protein assembly in mammalian cells that regulates movement of macromolecules across the nuclear envelope; its function is shown to undergo age-dependent decline during normal aging and is also impaired in multiple neurodegenerative disorders. Yet not much is known about the impact of Aβ on NPC function in neurons. Here, we examined NPC and nucleoporin (NUP) distribution and nucleocytoplasmic transport using a mouse model of AD (AppNL-G-F/NL-G-F) that expresses Aβ in young animals. Our studies revealed that a time-dependent accumulation of intracellular Aβ corresponded with a reduction of NPCs and NUPs in the nuclear envelope which resulted in the degradation of the permeability barrier and inefficient segregation of nucleocytoplasmic proteins, and active transport. As a result of the NPC dysfunction App KI neurons become more vulnerable to inflammation-induced necroptosis - a programmed cell death pathway where the core components are activated via phosphorylation through nucleocytoplasmic shutting. Collectively, our data implicates Aβ in progressive impairment of nuclear pore function and further confirms that the protein complex is vulnerable to disruption in various neurodegenerative diseases and is a potential therapeutic target.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11936419/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143709167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

The NIH is a sound investment for the US taxpayer.

IF 6.4 1区生物学

eLife Pub Date : 2025-03-25 DOI: 10.7554/eLife.106710

Nicholas W Gilpin

引用次数: 0

Genomic and structural insights into Jyvaskylavirus, the first giant virus isolated from Finland.

IF 6.4 1区生物学

eLife Pub Date : 2025-03-25 DOI: 10.7554/eLife.103492

Gabriel Magno de Freitas Almeida, Iker Arriaga, Bruna Luiza de Azevedo, Miika Leppänen, Jonatas S Abrahão, Julien Andreani, Davide Zabeo, Janne J Ravantti, Nicola G A Abrescia, Lotta-Riina Sundberg

{"title":"Genomic and structural insights into Jyvaskylavirus, the first giant virus isolated from Finland.","authors":"Gabriel Magno de Freitas Almeida, Iker Arriaga, Bruna Luiza de Azevedo, Miika Leppänen, Jonatas S Abrahão, Julien Andreani, Davide Zabeo, Janne J Ravantti, Nicola G A Abrescia, Lotta-Riina Sundberg","doi":"10.7554/eLife.103492","DOIUrl":"10.7554/eLife.103492","url":null,"abstract":"Giant viruses of protists are a diverse and likely ubiquitous group of organisms. Here, we describe Jyvaskylavirus, the first giant virus isolated from Finland. This clade B marseillevirus was found in Acanthamoeba castellanii from a composting soil sample in Jyväskylä, Central Finland. Its genome shares similarities with other marseilleviruses. Helium ion microscopy and electron microscopy of infected cells unraveled stages of the Jyvaskylavirus life cycle. We reconstructed the Jyvaskylavirus particle to 6.3 Å resolution using cryo-electron microscopy. The ~2500 Å diameter virion displays structural similarities to other Marseilleviridae giant viruses. The capsid comprises of 9240 copies of the major capsid protein, encoded by open reading frame (ORF) 184, which possesses a double jellyroll fold arranged in trimers forming pseudo-hexameric capsomers. Below the capsid shell, the internal membrane vesicle encloses the genome. Through cross-structural and -sequence comparisons with other Marseilleviridae using AI-based software in model building and prediction, we elucidated ORF142 as the penton protein, which plugs the 12 vertices of the capsid. Five additional ORFs were identified, with models predicted and fitted into densities that either cap the capsomers externally or stabilize them internally. The isolation of Jyvaskylavirus suggests that these viruses may be widespread in the boreal environment and provide structural insights extendable to other marseilleviruses.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11936420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Feeling abandoned but energized.

IF 6.4 1区生物学

eLife Pub Date : 2025-03-25 DOI: 10.7554/eLife.106704

Vaughn S Cooper

引用次数: 0

Oxidized low-density lipoprotein potentiates angiotensin II-induced Gq activation through the AT1-LOX1 receptor complex.

IF 6.4 1区生物学

eLife Pub Date : 2025-03-25 DOI: 10.7554/eLife.98766

Jittoku Ihara, Yibin Huang, Yoichi Takami, Yoichi Nozato, Toshimasa Takahashi, Akemi Kakino, Cheng Wang, Ziwei Wang, Yu Guo, Weidong Liu, Nanxiang Yin, Ryoichi Ohara, Taku Fujimoto, Shino Yoshida, Kazuhiro Hongyo, Hiroshi Koriyama, Hiroshi Akasaka, Hikari Takeshita, Shinsuke Sakai, Kazunori Inoue, Yoshitaka Isaka, Hiromi Rakugi, Tatsuya Sawamura, Koichi Yamamoto

{"title":"Oxidized low-density lipoprotein potentiates angiotensin II-induced Gq activation through the AT1-LOX1 receptor complex.","authors":"Jittoku Ihara, Yibin Huang, Yoichi Takami, Yoichi Nozato, Toshimasa Takahashi, Akemi Kakino, Cheng Wang, Ziwei Wang, Yu Guo, Weidong Liu, Nanxiang Yin, Ryoichi Ohara, Taku Fujimoto, Shino Yoshida, Kazuhiro Hongyo, Hiroshi Koriyama, Hiroshi Akasaka, Hikari Takeshita, Shinsuke Sakai, Kazunori Inoue, Yoshitaka Isaka, Hiromi Rakugi, Tatsuya Sawamura, Koichi Yamamoto","doi":"10.7554/eLife.98766","DOIUrl":"10.7554/eLife.98766","url":null,"abstract":"Chronic kidney disease (CKD) and atherosclerotic heart disease, frequently associated with dyslipidemia and hypertension, represent significant health concerns. We investigated the interplay among these conditions, focusing on the role of oxidized low-density lipoprotein (oxLDL) and angiotensin II (Ang II) in renal injury via G protein αq subunit (Gq) signaling. We hypothesized that oxLDL enhances Ang II-induced Gq signaling via the AT1 (Ang II type 1 receptor)-LOX1 (lectin-like oxLDL receptor) complex. Based on CHO and renal cell model experiments, oxLDL alone did not activate Gq signaling. However, when combined with Ang II, it significantly potentiated Gq-mediated inositol phosphate 1 production and calcium influx in cells expressing both LOX-1 and AT1 but not in AT1-expressing cells. This suggests a critical synergistic interaction between oxLDL and Ang II in the AT1-LOX1 complex. Conformational studies using AT1 biosensors have indicated a unique receptor conformational change due to the oxLDL-Ang II combination. In vivo, wild-type mice fed a high-fat diet with Ang II infusion presented exacerbated renal dysfunction, whereas LOX-1 knockout mice did not, underscoring the pathophysiological relevance of the AT1-LOX1 interaction in renal damage. These findings highlight a novel mechanism of renal dysfunction in CKD driven by dyslipidemia and hypertension and suggest the therapeutic potential of AT1-LOX1 receptor complex in patients with these comorbidities.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11936421/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

How scientists and institutions should respond.

IF 6.4 1区生物学

eLife Pub Date : 2025-03-25 DOI: 10.7554/eLife.106702

Ran Blekhman

引用次数: 0

In vivo targeted and deterministic single-cell malignant transformation.

IF 6.4 1区生物学

eLife Pub Date : 2025-03-25 DOI: 10.7554/eLife.97650

Pierluigi Scerbo, Benjamin Tisserand, Marine Delagrange, Héloise Debare, David Bensimon, Bertrand Ducos

引用次数: 0