{"title":"Cryo-EM structures of Nipah virus polymerase complex reveal highly varied interactions between L and P proteins among paramyxoviruses.","authors":"Lu Xue, Tiancai Chang, Jiacheng Gui, Zimu Li, Heyu Zhao, Bingqian Zou, Junnan Lu, Mei Li, Xin Wen, Shenghua Gao, Peng Zhan, Lijun Rong, Liqiang Feng, Peng Gong, Jun He, Xinwen Chen, Xiaoli Xiong","doi":"10.1093/procel/pwaf014","DOIUrl":"https://doi.org/10.1093/procel/pwaf014","url":null,"abstract":"<p><p>Nipah virus (NiV) and related viruses form a distinct henipavirus genus within the Paramyxoviridae family. NiV continues to spillover into the humans causing deadly outbreaks with increasing human-bat interaction. NiV encodes the large protein (L) and phosphoprotein (P) to form the viral RNA polymerase machinery. Their sequences show limited homologies to those of non-henipavirus paramyxoviruses. We report two cryo-electron microscopy (cryo-EM) structures of the Nipah virus (NiV) polymerase L-P complex, expressed and purified in either its full-length or truncated form. The structures resolve the RNA-dependent RNA polymerase (RdRp) and polyribonucleotidyl transferase (PRNTase) domains of the L protein, as well as a tetrameric P protein bundle bound to the L-RdRp. L-protein C-terminal regions are unresolved, indicating flexibility. Two PRNTase domain zinc-binding sites, conserved in most Mononegavirales, are confirmed essential for NiV polymerase activity. The structures further reveal anchoring of the P protein bundle and P protein X domain (XD) linkers on L, via an interaction pattern distinct among Paramyxoviridae. These interactions facilitate binding of a P protein XD linker in the nucleotide entry channel and distinct positioning of other XD linkers. We show that the disruption of the L-P interactions reduces NiV polymerase activity. The reported structures should facilitate rational antiviral-drug discovery and provide a guide for the functional study of NiV polymerase.</p>","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143450206","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}
Protein & CellPub Date : 2025-02-01DOI: 10.1093/procel/pwae048
Heng Zhang, Zhiwei Zheng, Xiaoying Chen, Lizhen Xu, Chen Guo, Jiawei Wang, Yihui Cui, Fan Yang
{"title":"RADICAL: a rationally designed ion channel activated by ligand for chemogenetics.","authors":"Heng Zhang, Zhiwei Zheng, Xiaoying Chen, Lizhen Xu, Chen Guo, Jiawei Wang, Yihui Cui, Fan Yang","doi":"10.1093/procel/pwae048","DOIUrl":"10.1093/procel/pwae048","url":null,"abstract":"","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":" ","pages":"136-142"},"PeriodicalIF":13.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120399","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}
Protein & CellPub Date : 2025-02-01DOI: 10.1093/procel/pwae026
Qiuyang Zheng, Xin Wang
{"title":"Alzheimer's disease: insights into pathology, molecular mechanisms, and therapy.","authors":"Qiuyang Zheng, Xin Wang","doi":"10.1093/procel/pwae026","DOIUrl":"10.1093/procel/pwae026","url":null,"abstract":"<p><p>Alzheimer's disease (AD), the leading cause of dementia, is characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. This condition casts a significant shadow on global health due to its complex and multifactorial nature. In addition to genetic predispositions, the development of AD is influenced by a myriad of risk factors, including aging, systemic inflammation, chronic health conditions, lifestyle, and environmental exposures. Recent advancements in understanding the complex pathophysiology of AD are paving the way for enhanced diagnostic techniques, improved risk assessment, and potentially effective prevention strategies. These discoveries are crucial in the quest to unravel the complexities of AD, offering a beacon of hope for improved management and treatment options for the millions affected by this debilitating disease.</p>","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":" ","pages":"83-120"},"PeriodicalIF":13.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786724/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140909164","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}
Protein & CellPub Date : 2025-02-01DOI: 10.1093/procel/pwae056
Yao Liu, Senfeng Zhang, Chunyi Hu
{"title":"Cas7 meets Cas14: a strategic partnership in the type VII CRISPR-Cas.","authors":"Yao Liu, Senfeng Zhang, Chunyi Hu","doi":"10.1093/procel/pwae056","DOIUrl":"10.1093/procel/pwae056","url":null,"abstract":"","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":"16 2","pages":"79-82"},"PeriodicalIF":13.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216673","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}
Protein & CellPub Date : 2025-01-15DOI: 10.1093/procel/pwaf002
Han Liu,Hongye Zeng,Xiaojing Qin,Wenjing Ning,Lin Xu,Shiting Yang,Xue Liu,Wenxin Luo,Ningshao Xia
{"title":"The Icarian flight of antibody-drug conjugates: target selection amidst complexity and tackling adverse impacts.","authors":"Han Liu,Hongye Zeng,Xiaojing Qin,Wenjing Ning,Lin Xu,Shiting Yang,Xue Liu,Wenxin Luo,Ningshao Xia","doi":"10.1093/procel/pwaf002","DOIUrl":"https://doi.org/10.1093/procel/pwaf002","url":null,"abstract":"Antibody-drug conjugates (ADCs) represent a promising class of targeted cancer therapeutics that combine the specificity of monoclonal antibodies with the potency of cytotoxic payloads. Despite their therapeutic potential, the use of ADCs faces significant challenges, including off/on-target toxicity and resistance development. This review examines the current landscape of ADC development, focusing on the critical aspects of target selection and antibody engineering. We discuss strategies to increase ADC efficacy and safety, including multitarget approaches, pH-dependent antibodies, and masked peptide technologies. The importance of comprehensive antigen expression profiling in both tumor and normal tissues is emphasized, highlighting the role of advanced technologies, such as single-cell sequencing and artificial intelligence (AI), in optimizing target selection. Furthermore, we explore combination therapies and innovations in linker‒payload chemistry, which may provide approaches for expanding the therapeutic window of ADCs. These advances pave the way for the development of more precise and effective cancer treatments, potentially extending ADC applications beyond oncology.","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":"127 1","pages":""},"PeriodicalIF":21.1,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989315","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}
Protein & CellPub Date : 2025-01-13DOI: 10.1093/procel/pwaf003
Qiao Liu, Wei Dong, Rong Liu, Luming Xu, Ling Ran, Ziying Xie, Shun Lei, Xingxing Su, Zhengliang Yue, Dan Xiong, Lisha Wang, Shuqiong Wen, Yan Zhang, Jianjun Hu, Chenxi Qin, Yongchang Chen, Bo Zhu, Xiangyu Chen, Xia Wu, Lifan Xu, Qizhao Huang, Yingjiao Cao, Lilin Ye, Zhonghui Tang
{"title":"Chromatin landscape alteration uncovers multiple transcriptional circuits during memory CD8+ T cell differentiation.","authors":"Qiao Liu, Wei Dong, Rong Liu, Luming Xu, Ling Ran, Ziying Xie, Shun Lei, Xingxing Su, Zhengliang Yue, Dan Xiong, Lisha Wang, Shuqiong Wen, Yan Zhang, Jianjun Hu, Chenxi Qin, Yongchang Chen, Bo Zhu, Xiangyu Chen, Xia Wu, Lifan Xu, Qizhao Huang, Yingjiao Cao, Lilin Ye, Zhonghui Tang","doi":"10.1093/procel/pwaf003","DOIUrl":"https://doi.org/10.1093/procel/pwaf003","url":null,"abstract":"<p><p>Extensive epigenetic reprogramming involves in memory CD8+ T-cell differentiation. The elaborate epigenetic rewiring underlying the heterogeneous functional states of CD8+ T cells remains hidden. Here, we profile single-cell chromatin accessibility and map enhancer-promoter interactomes to characterize the differentiation trajectory of memory CD8+ T cells. We reveal that under distinct epigenetic regulations, the early activated CD8+ T cells divergently originated for short-lived effector and memory precursor effector cells. We also uncover a defined epigenetic rewiring leading to the conversion from effector memory to central memory cells during memory formation. Additionally, we illustrate chromatin regulatory mechanisms underlying long-lasting versus transient transcription regulation during memory differentiation. Finally, we confirm the essential roles of Sox4 and Nrf2 in developing memory precursor effector and effector memory cells, respectively, and validate cell state-specific enhancers in regulating Il7r using CRISPR-Cas9. Our data pave the way for understanding the mechanism underlying epigenetic memory formation in CD8+ T-cell differentiation.</p>","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971978","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}