Pub Date : 2024-08-20DOI: 10.1038/s41422-024-01018-y
George Hajishengallis, Triantafyllos Chavakis
{"title":"Stroke-induced trained immunity spells bad news for the heart","authors":"George Hajishengallis, Triantafyllos Chavakis","doi":"10.1038/s41422-024-01018-y","DOIUrl":"https://doi.org/10.1038/s41422-024-01018-y","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"95 1","pages":""},"PeriodicalIF":44.1,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142007530","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}
Pub Date : 2024-08-14DOI: 10.1038/s41422-024-01014-2
Ke Sun, Sicong Li, Bowen Zheng, Yanlei Zhu, Tongyue Wang, Mingfu Liang, Yue Yao, Kairan Zhang, Jizhong Zhang, Hongyong Li, Dongyang Han, Jishen Zheng, Brian Coventry, Longxing Cao, David Baker, Lei Liu, Peilong Lu
Abiotic D-proteins that selectively bind to natural L-proteins have gained significant biotechnological interest. However, the underlying structural principles governing such heterochiral protein-protein interactions remain largely unknown. In this study, we present the de novo design of D-proteins consisting of 50-65 residues, aiming to target specific surface regions of L-proteins or L-peptides. Our designer D-protein binders exhibit nanomolar affinity toward an artificial L-peptide, as well as two naturally occurring proteins of therapeutic significance: the D5 domain of human tropomyosin receptor kinase A (TrkA) and human interleukin-6 (IL-6). Notably, these D-protein binders demonstrate high enantiomeric specificity and target specificity. In cell-based experiments, designer D-protein binders effectively inhibited the downstream signaling of TrkA and IL-6 with high potency. Moreover, these binders exhibited remarkable thermal stability and resistance to protease degradation. Crystal structure of the designed heterochiral D-protein-L-peptide complex, obtained at a resolution of 2.0 Å, closely resembled the design model, indicating that the computational method employed is highly accurate. Furthermore, the crystal structure provides valuable information regarding the interactions between helical L-peptides and D-proteins, particularly elucidating a novel mode of heterochiral helix-helix interactions. Leveraging the design of D-proteins specifically targeting L-peptides or L-proteins opens up avenues for systematic exploration of the mirror-image protein universe, paving the way for a diverse range of applications.
选择性地与天然 L 蛋白结合的非生物 D 蛋白已引起生物技术的极大兴趣。然而，制约这种异手性蛋白-蛋白相互作用的基本结构原理在很大程度上仍不为人所知。在本研究中，我们从头开始设计了由 50-65 个残基组成的 D 蛋白，旨在靶向 L 蛋白或 L 肽的特定表面区域。我们设计的D蛋白结合剂对人工L肽以及两种具有治疗意义的天然蛋白（人肌钙蛋白受体激酶A（TrkA）的D5结构域和人白细胞介素-6（IL-6））具有纳摩尔级的亲和力。值得注意的是，这些 D 蛋白结合剂具有很高的对映体特异性和靶向特异性。在基于细胞的实验中，设计的 D 蛋白结合剂以高效力有效抑制了 TrkA 和 IL-6 的下游信号传导。此外，这些结合剂还具有显著的热稳定性和抗蛋白酶降解性。所设计的异手性 D 蛋白-L 肽复合物的晶体结构分辨率为 2.0 Å，与设计模型非常相似，表明所采用的计算方法非常精确。此外，该晶体结构还为螺旋 L 肽和 D 蛋白之间的相互作用提供了宝贵的信息，特别是阐明了一种新型的异螺旋-螺旋相互作用模式。利用专门针对 L 肽或 L 蛋白的 D 蛋白设计为系统探索镜像蛋白质宇宙开辟了途径，为各种应用铺平了道路。
{"title":"Accurate de novo design of heterochiral protein-protein interactions.","authors":"Ke Sun, Sicong Li, Bowen Zheng, Yanlei Zhu, Tongyue Wang, Mingfu Liang, Yue Yao, Kairan Zhang, Jizhong Zhang, Hongyong Li, Dongyang Han, Jishen Zheng, Brian Coventry, Longxing Cao, David Baker, Lei Liu, Peilong Lu","doi":"10.1038/s41422-024-01014-2","DOIUrl":"https://doi.org/10.1038/s41422-024-01014-2","url":null,"abstract":"<p><p>Abiotic D-proteins that selectively bind to natural L-proteins have gained significant biotechnological interest. However, the underlying structural principles governing such heterochiral protein-protein interactions remain largely unknown. In this study, we present the de novo design of D-proteins consisting of 50-65 residues, aiming to target specific surface regions of L-proteins or L-peptides. Our designer D-protein binders exhibit nanomolar affinity toward an artificial L-peptide, as well as two naturally occurring proteins of therapeutic significance: the D5 domain of human tropomyosin receptor kinase A (TrkA) and human interleukin-6 (IL-6). Notably, these D-protein binders demonstrate high enantiomeric specificity and target specificity. In cell-based experiments, designer D-protein binders effectively inhibited the downstream signaling of TrkA and IL-6 with high potency. Moreover, these binders exhibited remarkable thermal stability and resistance to protease degradation. Crystal structure of the designed heterochiral D-protein-L-peptide complex, obtained at a resolution of 2.0 Å, closely resembled the design model, indicating that the computational method employed is highly accurate. Furthermore, the crystal structure provides valuable information regarding the interactions between helical L-peptides and D-proteins, particularly elucidating a novel mode of heterochiral helix-helix interactions. Leveraging the design of D-proteins specifically targeting L-peptides or L-proteins opens up avenues for systematic exploration of the mirror-image protein universe, paving the way for a diverse range of applications.</p>","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":" ","pages":""},"PeriodicalIF":28.1,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981833","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}
Pub Date : 2024-08-07DOI: 10.1038/s41422-024-01011-5
Poonam S Jadhav, Shreya Mahajan, Si Ming Man
{"title":"NLRC5 PANoptosome: Aquaman of the Dead Sea.","authors":"Poonam S Jadhav, Shreya Mahajan, Si Ming Man","doi":"10.1038/s41422-024-01011-5","DOIUrl":"https://doi.org/10.1038/s41422-024-01011-5","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":" ","pages":""},"PeriodicalIF":28.1,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901089","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}
Pub Date : 2024-08-05DOI: 10.1038/s41422-024-01013-3
Bisi Miao, Ling Ge, Chenxi He, Xinghao Wang, Jibo Wu, Xiang Li, Kun Chen, Jinkai Wan, Shenghui Xing, Lingnan Ren, Zhennan Shi, Shengnan Liu, Yajun Hu, Jiajia Chen, Yanyan Yu, Lijian Feng, Natasha M. Flores, Zhihui Liang, Xinyi Xu, Ruoxin Wang, Jian Zhou, Jia Fan, Bin Xiang, En Li, Yuanhui Mao, Jingdong Cheng, Kehao Zhao, Pawel K. Mazur, Jiabin Cai, Fei Lan
While lysine methylation is well-known for regulating gene expression transcriptionally, its implications in translation have been largely uncharted. Trimethylation at lysine 22 (K22me3) on RPL40, a core ribosomal protein located in the GTPase activation center, was first reported 27 years ago. Yet, its methyltransferase and role in translation remain unexplored. Here, we report that SMYD5 has robust in vitro activity toward RPL40 K22 and primarily catalyzes RPL40 K22me3 in cells. The loss of SMYD5 and RPL40 K22me3 leads to reduced translation output and disturbed elongation as evidenced by increased ribosome collisions. SMYD5 and RPL40 K22me3 are upregulated in hepatocellular carcinoma (HCC) and negatively correlated with patient prognosis. Depleting SMYD5 renders HCC cells hypersensitive to mTOR inhibition in both 2D and 3D cultures. Additionally, the loss of SMYD5 markedly inhibits HCC development and growth in both genetically engineered mouse and patient-derived xenograft (PDX) models, with the inhibitory effect in the PDX model further enhanced by concurrent mTOR suppression. Our findings reveal a novel role of the SMYD5 and RPL40 K22me3 axis in translation elongation and highlight the therapeutic potential of targeting SMYD5 in HCC, particularly with concurrent mTOR inhibition. This work also conceptually broadens the understanding of lysine methylation, extending its significance from transcriptional regulation to translational control.
{"title":"SMYD5 is a ribosomal methyltransferase that catalyzes RPL40 lysine methylation to enhance translation output and promote hepatocellular carcinoma","authors":"Bisi Miao, Ling Ge, Chenxi He, Xinghao Wang, Jibo Wu, Xiang Li, Kun Chen, Jinkai Wan, Shenghui Xing, Lingnan Ren, Zhennan Shi, Shengnan Liu, Yajun Hu, Jiajia Chen, Yanyan Yu, Lijian Feng, Natasha M. Flores, Zhihui Liang, Xinyi Xu, Ruoxin Wang, Jian Zhou, Jia Fan, Bin Xiang, En Li, Yuanhui Mao, Jingdong Cheng, Kehao Zhao, Pawel K. Mazur, Jiabin Cai, Fei Lan","doi":"10.1038/s41422-024-01013-3","DOIUrl":"10.1038/s41422-024-01013-3","url":null,"abstract":"While lysine methylation is well-known for regulating gene expression transcriptionally, its implications in translation have been largely uncharted. Trimethylation at lysine 22 (K22me3) on RPL40, a core ribosomal protein located in the GTPase activation center, was first reported 27 years ago. Yet, its methyltransferase and role in translation remain unexplored. Here, we report that SMYD5 has robust in vitro activity toward RPL40 K22 and primarily catalyzes RPL40 K22me3 in cells. The loss of SMYD5 and RPL40 K22me3 leads to reduced translation output and disturbed elongation as evidenced by increased ribosome collisions. SMYD5 and RPL40 K22me3 are upregulated in hepatocellular carcinoma (HCC) and negatively correlated with patient prognosis. Depleting SMYD5 renders HCC cells hypersensitive to mTOR inhibition in both 2D and 3D cultures. Additionally, the loss of SMYD5 markedly inhibits HCC development and growth in both genetically engineered mouse and patient-derived xenograft (PDX) models, with the inhibitory effect in the PDX model further enhanced by concurrent mTOR suppression. Our findings reveal a novel role of the SMYD5 and RPL40 K22me3 axis in translation elongation and highlight the therapeutic potential of targeting SMYD5 in HCC, particularly with concurrent mTOR inhibition. This work also conceptually broadens the understanding of lysine methylation, extending its significance from transcriptional regulation to translational control.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"34 9","pages":"648-660"},"PeriodicalIF":28.1,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41422-024-01013-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892990","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}
The hierarchical packaging of chromatin fibers plays a critical role in gene regulation. The 30-nm chromatin fibers, a central-level structure bridging nucleosomal arrays to higher-order organizations, function as the first level of transcriptional dormant chromatin. The dynamics of 30-nm chromatin fiber play a crucial role in biological processes related to DNA. Here, we report a 3.6-angstrom resolution cryogenic electron microscopy structure of H5-bound dodecanucleosome, i.e., the chromatin fiber reconstituted in the presence of linker histone H5, which shows a two-start left-handed double helical structure twisted by tetranucleosomal units. An atomic structural model of the H5-bound chromatin fiber, including an intact chromatosome, is built, which provides structural details of the full-length linker histone H5, including its N-terminal domain and an HMG-motif-like C-terminal domain. The chromatosome structure shows that H5 binds the nucleosome off-dyad through a three-contact mode in the chromatin fiber. More importantly, the H5-chromatin structure provides a fine molecular basis for the intra-tetranucleosomal and inter-tetranucleosomal interactions. In addition, we systematically validated the physiological functions and structural characteristics of the tetranucleosomal unit through a series of genetic and genomic studies in Saccharomyces cerevisiae and in vitro biophysical experiments. Furthermore, our structure reveals that multiple structural asymmetries of histone tails confer a polarity to the chromatin fiber. These findings provide structural and mechanistic insights into how a nucleosomal array folds into a higher-order chromatin fiber with a polarity in vitro and in vivo.
染色质纤维的分级包装在基因调控中起着至关重要的作用。30纳米染色质纤维是连接核糖体阵列和高阶组织的中心层结构，是转录休眠染色质的第一层。30-nm 染色质纤维的动态在与 DNA 相关的生物过程中起着至关重要的作用。在此，我们报告了一个 3.6 埃的 H5 结合十二核小体低温电子显微镜结构，即在连接子组蛋白 H5 存在的情况下重组的染色质纤维，它显示了一个由四核小体单位扭曲的双起始左手双螺旋结构。我们建立了一个与 H5 结合的染色质纤维（包括一个完整的染色质体）的原子结构模型，该模型提供了全长连接组蛋白 H5 的结构细节，包括其 N 端结构域和一个类似 HMG-motif 的 C 端结构域。染色质结构显示，H5通过染色质纤维中的三接触模式与核小体偏离染色质结合。更重要的是，H5-染色质结构为核小体内和核小体间的相互作用提供了精细的分子基础。此外，我们通过在酿酒酵母中进行一系列遗传和基因组研究以及体外生物物理实验，系统地验证了四核体单元的生理功能和结构特征。此外，我们的结构揭示了组蛋白尾部的多种结构不对称性赋予了染色质纤维极性。这些发现从结构和机理上揭示了核糖体阵列如何在体外和体内折叠成具有极性的高阶染色质纤维。
{"title":"Structural basis for linker histone H5–nucleosome binding and chromatin fiber compaction","authors":"Wenyan Li, Jie Hu, Feng Song, Juan Yu, Xin Peng, Shuming Zhang, Lin Wang, Mingli Hu, Jia-Cheng Liu, Yu Wei, Xue Xiao, Yan Li, Dongyu Li, Hui Wang, Bing-Rui Zhou, Linchang Dai, Zongjun Mou, Min Zhou, Haonan Zhang, Zheng Zhou, Huidong Zhang, Yawen Bai, Jin-Qiu Zhou, Wei Li, Guohong Li, Ping Zhu","doi":"10.1038/s41422-024-01009-z","DOIUrl":"10.1038/s41422-024-01009-z","url":null,"abstract":"The hierarchical packaging of chromatin fibers plays a critical role in gene regulation. The 30-nm chromatin fibers, a central-level structure bridging nucleosomal arrays to higher-order organizations, function as the first level of transcriptional dormant chromatin. The dynamics of 30-nm chromatin fiber play a crucial role in biological processes related to DNA. Here, we report a 3.6-angstrom resolution cryogenic electron microscopy structure of H5-bound dodecanucleosome, i.e., the chromatin fiber reconstituted in the presence of linker histone H5, which shows a two-start left-handed double helical structure twisted by tetranucleosomal units. An atomic structural model of the H5-bound chromatin fiber, including an intact chromatosome, is built, which provides structural details of the full-length linker histone H5, including its N-terminal domain and an HMG-motif-like C-terminal domain. The chromatosome structure shows that H5 binds the nucleosome off-dyad through a three-contact mode in the chromatin fiber. More importantly, the H5-chromatin structure provides a fine molecular basis for the intra-tetranucleosomal and inter-tetranucleosomal interactions. In addition, we systematically validated the physiological functions and structural characteristics of the tetranucleosomal unit through a series of genetic and genomic studies in Saccharomyces cerevisiae and in vitro biophysical experiments. Furthermore, our structure reveals that multiple structural asymmetries of histone tails confer a polarity to the chromatin fiber. These findings provide structural and mechanistic insights into how a nucleosomal array folds into a higher-order chromatin fiber with a polarity in vitro and in vivo.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"34 10","pages":"707-724"},"PeriodicalIF":28.1,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41422-024-01009-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892991","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}
Pub Date : 2024-08-01DOI: 10.1038/s41422-024-01010-6
Tong Chen, Pranam Chatterjee
{"title":"Synergizing sequence and structure representations to predict protein variants","authors":"Tong Chen, Pranam Chatterjee","doi":"10.1038/s41422-024-01010-6","DOIUrl":"10.1038/s41422-024-01010-6","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"34 9","pages":"597-598"},"PeriodicalIF":28.1,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41422-024-01010-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141862135","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}
{"title":"Deciphering the role of immune system in the obesity-cancer relationship.","authors":"Camille Blériot, Gerasimos Anagnostopoulos, Florent Ginhoux","doi":"10.1038/s41422-024-01008-0","DOIUrl":"https://doi.org/10.1038/s41422-024-01008-0","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":" ","pages":""},"PeriodicalIF":28.1,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141854989","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}
Pub Date : 2024-07-29DOI: 10.1038/s41422-024-00998-1
Heng Liu, Shimeng Guo, Antao Dai, Peiyu Xu, Xin Li, Sijie Huang, Xinheng He, Kai Wu, Xinyue Zhang, Dehua Yang, Xin Xie, H. Eric Xu
{"title":"Author Correction: Structural and functional evidence that GPR30 is not a direct estrogen receptor","authors":"Heng Liu, Shimeng Guo, Antao Dai, Peiyu Xu, Xin Li, Sijie Huang, Xinheng He, Kai Wu, Xinyue Zhang, Dehua Yang, Xin Xie, H. Eric Xu","doi":"10.1038/s41422-024-00998-1","DOIUrl":"10.1038/s41422-024-00998-1","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"34 9","pages":"669-669"},"PeriodicalIF":28.1,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41422-024-00998-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792079","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}
Pub Date : 2024-07-26DOI: 10.1038/s41422-024-01007-1
Yaqiu Wang, Thirumala-Devi Kanneganti
{"title":"Yin and Yang of innate immune cell death.","authors":"Yaqiu Wang, Thirumala-Devi Kanneganti","doi":"10.1038/s41422-024-01007-1","DOIUrl":"https://doi.org/10.1038/s41422-024-01007-1","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":" ","pages":""},"PeriodicalIF":28.1,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141765635","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}
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