Ferdos Abid Ali, Alexander J. Zwetsloot, Caroline E. Stone, Tomos E. Morgan, Richard F. Wademan, Andrew P. Carter, Anne Straube
{"title":"KIF1C activates and extends dynein movement through the FHF cargo adapter","authors":"Ferdos Abid Ali, Alexander J. Zwetsloot, Caroline E. Stone, Tomos E. Morgan, Richard F. Wademan, Andrew P. Carter, Anne Straube","doi":"10.1038/s41594-024-01418-z","DOIUrl":"https://doi.org/10.1038/s41594-024-01418-z","url":null,"abstract":"<p>Cellular cargos move bidirectionally on microtubules by recruiting opposite polarity motors dynein and kinesin. These motors show codependence, where one requires the activity of the other, although the mechanism is unknown. Here we show that kinesin-3 KIF1C acts as both an activator and a processivity factor for dynein, using in vitro reconstitutions of human proteins. Activation requires only a fragment of the KIF1C nonmotor stalk binding the cargo adapter HOOK3. The interaction site is separate from the constitutive factors FTS and FHIP, which link HOOK3 to small G-proteins on cargos. We provide a structural model for the autoinhibited FTS–HOOK3–FHIP1B (an FHF complex) and explain how KIF1C relieves it. Collectively, we explain codependency by revealing how mutual activation of dynein and kinesin occurs through their shared adapter. Many adapters bind both dynein and kinesins, suggesting this mechanism could be generalized to other bidirectional complexes.</p>","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Intronic variant increases Parkinson disease risk by disrupting branchpoint sequence","authors":"","doi":"10.1038/s41594-024-01424-1","DOIUrl":"https://doi.org/10.1038/s41594-024-01424-1","url":null,"abstract":"A genetic variant specific to people of African ancestry increases the risk of neurodegenerative diseases, such as Parkinson disease (PD). This variant occurs in a noncoding region and interferes with the splicing of mRNA transcripts, resulting in lowered protein levels and activity. This work reveals a novel therapeutic target in an underserved and underrepresented population.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"26 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Arjun Bhatta, Bernhard Kuhle, Ryan D. Yu, Lucas Spanaus, Katja Ditter, Katherine E. Bohnsack, Hauke S. Hillen
{"title":"Molecular basis of human nuclear and mitochondrial tRNA 3′ processing","authors":"Arjun Bhatta, Bernhard Kuhle, Ryan D. Yu, Lucas Spanaus, Katja Ditter, Katherine E. Bohnsack, Hauke S. Hillen","doi":"10.1038/s41594-024-01445-w","DOIUrl":"https://doi.org/10.1038/s41594-024-01445-w","url":null,"abstract":"<p>Eukaryotic transfer RNA (tRNA) precursors undergo sequential processing steps to become mature tRNAs. In humans, ELAC2 carries out 3′ end processing of both nucleus-encoded (nu-tRNAs) and mitochondria-encoded (mt-tRNAs) tRNAs. ELAC2 is self-sufficient for processing of nu-tRNAs but requires TRMT10C and SDR5C1 to process most mt-tRNAs. Here we show that TRMT10C and SDR5C1 specifically facilitate processing of structurally degenerate mt-tRNAs lacking the canonical elbow. Structures of ELAC2 in complex with TRMT10C, SDR5C1 and two divergent mt-tRNA substrates reveal two distinct mechanisms of pre-tRNA recognition. While canonical nu-tRNAs and mt-tRNAs are recognized by direct ELAC2–RNA interactions, processing of noncanonical mt-tRNAs depends on protein–protein interactions between ELAC2 and TRMT10C. These results provide the molecular basis for tRNA 3′ processing in both the nucleus and the mitochondria and explain the organelle-specific requirement for additional factors. Moreover, they suggest that TRMT10C–SDR5C1 evolved as a mitochondrial tRNA maturation platform to compensate for the structural erosion of mt-tRNAs in bilaterian animals.</p>","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Targeted degradation of membrane proteins","authors":"Grace Hohman, Michael Shahid, Mohamed Eldeeb","doi":"10.1038/s41594-024-01461-w","DOIUrl":"https://doi.org/10.1038/s41594-024-01461-w","url":null,"abstract":"Targeted protein degradation is a promising drug discovery approach. A study now describes transferrin receptor targeting chimeras (TransTACS), which lysosomally degrade membrane proteins with potent specificity and efficacy. TransTACs reversibly regulate the tumor-killing activity of CAR-T cells and inhibit drug-resistant EGFR-driven cancers in mice.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142905035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Insights into phosphate homeostasis regulation by XPR1","authors":"Daniel P. Bondeson","doi":"10.1038/s41594-024-01460-x","DOIUrl":"https://doi.org/10.1038/s41594-024-01460-x","url":null,"abstract":"XPR1 is the only annotated phosphate exporter protein in humans. Recent studies provide mechanistic clues to its cellular function; three posit non-export mechanisms to regulate phosphate homeostasis, while six present high-resolution cryo-EM data supporting a bona fide phosphate channel mechanism controlled by intracellular phosphate levels.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"114 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142901591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Regina Mencia, Agustín L. Arce, Candela Houriet, Wenfei Xian, Adrián Contreras, Gautam Shirsekar, Detlef Weigel, Pablo A. Manavella
{"title":"Transposon-triggered epigenetic chromatin dynamics modulate EFR-related pathogen response","authors":"Regina Mencia, Agustín L. Arce, Candela Houriet, Wenfei Xian, Adrián Contreras, Gautam Shirsekar, Detlef Weigel, Pablo A. Manavella","doi":"10.1038/s41594-024-01440-1","DOIUrl":"https://doi.org/10.1038/s41594-024-01440-1","url":null,"abstract":"<p>Infectious diseases drive wild plant evolution and impact crop yield. Plants, like animals, sense biotic threats through pattern recognition receptors (PRRs). Overly robust immune responses can harm plants; thus, understanding the tuning of defense response mechanisms is crucial for developing pathogen-resistant crops. In this study, we found that an inverted-repeat transposon (<i>EFR-associated IR</i>, <i>Ea-IR</i>) located between the loci encoding PRRs ELONGATION FACTOR-TU RECEPTOR (<i>EFR</i>) and myosin XI-k (<i>XI-k</i>) in <i>Arabidopsis</i> affects chromatin organization, promoting the formation of a repressive chromatin loop. Upon pathogen infection, chromatin changes around <i>EFR</i> and <i>XI-k</i> correlate with increased <i>EFR</i> transcription. Pathogen-induced chromatin opening causes RNA polymerase II readthrough, producing a longer, <i>Ea-IR</i><i>-</i>containing <i>XI-k</i> transcript, processed by Dicer-like enzymes into small RNAs, which reset chromatin to a repressive state attenuating the immune response after infection. <i>Arabidopsis</i> accessions lacking <i>Ea-IR</i> have higher basal <i>EFR</i> levels and resistance to pathogens. We show a scenario in which a transposon, chromatin organization and gene expression interact to fine-tune immune responses, during both the course of infection and the course of evolution.</p>","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Wide-ranging cellular functions of ion channels and lipid scramblases in the structurally related TMC, TMEM16 and TMEM63 families","authors":"Lily Yeh Jan, Yuh Nung Jan","doi":"10.1038/s41594-024-01444-x","DOIUrl":"https://doi.org/10.1038/s41594-024-01444-x","url":null,"abstract":"<p>Calcium (Ca<sup>2+</sup>)-activated ion channels and lipid scramblases in the transmembrane protein 16 (TMEM16) family are structurally related to mechanosensitive ion channels in the TMEM63 and transmembrane channel-like (TMC) families. Members of this structurally related superfamily share similarities in gating transitions and serve a wide range of physiological functions, which is evident from their disease associations. The TMEM16, TMEM63 and TMC families include members with important functions in the cell membrane and/or intracellular organelles such as the endoplasmic reticulum, membrane contact sites, endosomes and lysosomes. Moreover, some members of the TMEM16 family and the TMC family perform dual functions of ion channel and lipid scramblase, leading to intriguing physiological implications. In addition to their physiological functions such as mediating phosphatidylserine exposure and facilitation of extracellular vesicle generation and cell fusion, scramblases are involved in the entry and replication of enveloped viruses. Comparisons of structurally diverse scramblases may uncover features in the lipid-scrambling mechanisms that are likely shared by scramblases.</p>","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142874436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Balancing reproductive pursuit and visual danger","authors":"Dimitris Typas","doi":"10.1038/s41594-024-01458-5","DOIUrl":"https://doi.org/10.1038/s41594-024-01458-5","url":null,"abstract":"<p>Humans and other animals wittingly or unwittingly run risk–benefit analyses daily. For animals of reproductive age, a prime example of such analysis is assessing the benefit of reproductive success versus the cost of being preyed upon. The scale needs to be sensitive: over-prioritize survival at the risk of a lack of progeny, or undermine danger at the risk of perishing. While previous studies and empirical knowledge have suggested that males become less preoccupied about potential danger upon permissive cues indicating increased probability of successful copulation, the molecular mechanisms orchestrating this behavior have remained ill-understood.</p><p>Writing in <i>Nature</i>, Cazalé-Debat et al. remedy this gap in understanding and provide notable mechanistic and functional insight into the neurons, receptors and signaling cascades that regulate the trade-off between survival and propagation in <i>Drosophila</i>. Using sex–danger conflict assays, the authors demonstrate that though male flies abort courtship upon danger cues at early stages, they increasingly disregard visual threats as courtship progresses and copulation becomes more likely. The initial abortive response seems to be regulated by visual activation of LC16 neurons, which then turn on 5-HT<sup>PMPD</sup> neurons (serotonin neurons in the posterior medial dorsal cluster) and activate the release of serotonin; the latter inhibits P1 and plP10 neurons, thus turning off key hubs that are known to be activated during courtship. This allows flies to prioritize survival over reproduction.</p>","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"51 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Miao Yu, Nathan R. Zemke, Ziyin Chen, Ivan Juric, Rong Hu, Ramya Raviram, Armen Abnousi, Rongxin Fang, Yanxiao Zhang, David U. Gorkin, Yang E. Li, Yuan Zhao, Lindsay Lee, Shreya Mishra, Anthony D. Schmitt, Yunjiang Qiu, Diane E. Dickel, Axel Visel, Len A. Pennacchio, Ming Hu, Bing Ren
{"title":"Integrative analysis of the 3D genome and epigenome in mouse embryonic tissues","authors":"Miao Yu, Nathan R. Zemke, Ziyin Chen, Ivan Juric, Rong Hu, Ramya Raviram, Armen Abnousi, Rongxin Fang, Yanxiao Zhang, David U. Gorkin, Yang E. Li, Yuan Zhao, Lindsay Lee, Shreya Mishra, Anthony D. Schmitt, Yunjiang Qiu, Diane E. Dickel, Axel Visel, Len A. Pennacchio, Ming Hu, Bing Ren","doi":"10.1038/s41594-024-01431-2","DOIUrl":"https://doi.org/10.1038/s41594-024-01431-2","url":null,"abstract":"<p>While a rich set of putative <i>cis</i>-regulatory sequences involved in mouse fetal development have been annotated recently on the basis of chromatin accessibility and histone modification patterns, delineating their role in developmentally regulated gene expression continues to be challenging. To fill this gap, here we mapped chromatin contacts between gene promoters and distal sequences across the genome in seven mouse fetal tissues and across six developmental stages of the forebrain. We identified 248,620 long-range chromatin interactions centered at 14,138 protein-coding genes and characterized their tissue-to-tissue variations and developmental dynamics. Integrative analysis of the interactome with previous epigenome and transcriptome datasets from the same tissues revealed a strong correlation between the chromatin contacts and chromatin state at distal enhancers, as well as gene expression patterns at predicted target genes. We predicted target genes of 15,098 candidate enhancers and used them to annotate target genes of homologous candidate enhancers in the human genome that harbor risk variants of human diseases. We present evidence that schizophrenia and other adult disease risk variants are frequently found in fetal enhancers, providing support for the hypothesis of fetal origins of adult diseases.</p>","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"253 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142825550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Visualizing antibiotic action in a pathogenic bacterium at atomic to cellular scale","authors":"","doi":"10.1038/s41594-024-01442-z","DOIUrl":"https://doi.org/10.1038/s41594-024-01442-z","url":null,"abstract":"The mechanisms of antibiotic action can be highly context specific. Using in-cell cryo-electron tomography (cryo-ET) of Mycoplasma pneumoniae — a causative agent of respiratory disease — we visualized the context-dependent action of the ribosome-targeting antibiotic chloramphenicol simultaneously at atomic, molecular and cellular levels. This work highlights how in-cell structural biology can expand our understanding of antibiotic mechanisms of action.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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