2016 Vol. 7, No. 12

NgAgo: a hope or a hype?
Xiaoxue Zhang
2016, 7(12): 849-849. doi: 10.1007/s13238-016-0344-8
The rising young scientist stars in China
Hao Cheng
2016, 7(12): 850-853. doi: 10.1007/s13238-016-0347-5
Amazing structure of respirasome: unveiling the secrets of cell respiration
Runyu Guo, Jinke Gu, Meng Wu, Maojun Yang
2016, 7(12): 854-865. doi: 10.1007/s13238-016-0329-7
Respirasome, a huge molecular machine that carries out cellular respiration, has gained growing attention since its discovery, because respiration is the most indispensable biological process in almost all living creatures. The concept of respirasome has renewed our understanding of the respiratory chain organization, and most recently, the structure of respirasome solved by Yang's group from Tsinghua University (Gu et al. Nature 237(7622):639-643, 2016) firstly presented the detailed interactions within this huge molecular machine, and provided important information for drug design and screening. However, the study of cellular respiration went through a long history. Here, we briefly showed the detoured history of respiratory chain investigation, and then described the amazing structure of respirasome.
Crystal clear: visualizing the intervention mechanism of the PD-1/PD-L1 interaction by two cancer therapeutic monoclonal antibodies
Shuguang Tan, Danqing Chen, Kefang Liu, Mengnan He, Hao Song, Yi Shi, Jun Liu, Catherine W. -H. Zhang, Jianxun Qi, Jinghua Yan, Shan Gao, George F. Gao
2016, 7(12): 866-877. doi: 10.1007/s13238-016-0337-7
Antibody-based PD-1/PD-L1 blockade therapies have taken center stage in immunotherapies for cancer, with multiple clinical successes. PD-1 signaling plays pivotal roles in tumor-driven T-cell dysfunction. In contrast to prior approaches to generate or boost tumor-specific T-cell responses, antibody-based PD-1/PD-L1 blockade targets tumor-induced T-cell defects and restores preexisting T-cell function to modulate antitumor immunity. In this review, the fundamental knowledge on the expression regulations and inhibitory functions of PD-1 and the present understanding of antibody-based PD-1/PD-L1 blockade therapies are briefly summarized. We then focus on the recent breakthrough work concerning the structural basis of the PD-1/PD-Ls interaction and how therapeutic antibodies, pembrolizumab targeting PD-1 and avelumab targeting PD-L1, compete with the binding of PD-1/PD-L1 to interrupt the PD-1/PD-L1 interaction. We believe that this structural information will benefit the design and improvement of therapeutic antibodies targeting PD-1 signaling.
Research articles
4.4 Å Resolution Cryo-EM structure of human mTOR Complex 1
Huirong Yang, Jia Wang, Mengjie Liu, Xizi Chen, Min Huang, Dan Tan, Meng-Qiu Dong, Catherine C. L. Wong, Jiawei Wang, Yanhui Xu, Hong-Wei Wang
2016, 7(12): 878-887. doi: 10.1007/s13238-016-0346-6
Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates signals from growth factors, cellular energy levels, stress and amino acids to control cell growth and proliferation through regulating translation, autophagy and metabolism. Here we determined the cryo-electron microscopy structure of human mTORC1 at 4.4 Å resolution. The mTORC1 comprises a dimer of heterotrimer (mTOR-Raptor-mLST8) mediated by the mTOR protein. The complex adopts a hollow rhomboid shape with 2-fold symmetry. Notably, mTORC1 shows intrinsic conformational dynamics. Within the complex, the conserved N-terminal caspaselike domain of Raptor faces toward the catalytic cavity of the kinase domain of mTOR. Raptor shows no caspase activity and therefore may bind to TOS motif for substrate recognition. Structural analysis indicates that FKBP12-Rapamycin may generate steric hindrance for substrate entry to the catalytic cavity of mTORC1. The structure provides a basis to understand the assembly of mTORC1 and a framework to characterize the regulatory mechanism of mTORC1 pathway.
In vitro assembly of Ebola virus nucleocapsid-like complex expressed in E. coli
Ruchao Peng, Tengfei Zhu, Babayemi Olawale Oladejo, Abednego Moki Musyoki, Yingzi Cui, Yi Shi, Peiyi Wang, George Fu Gao
2016, 7(12): 888-898. doi: 10.1007/s13238-016-0314-1
Ebola virus (EBOV) harbors an RNA genome encapsidated by nucleoprotein (NP) along with other viral proteins to form a nucleocapsid complex. Previous Cryoeletron tomography and biochemical studies have shown the helical structure of EBOV nucleocapsid at nanometer resolution and the first 450 amino-acid of NP (NPΔ451-739) alone is capable of forming a helical nucleocapsid-like complex (NLC). However, the structural basis for NP-NP interaction and the dynamic procedure of the nucleocapsid assembly is yet poorly understood. In this work, we, by using an E. coli expression system, captured a series of images of NPΔ451-739 conformers at different stages of NLC assembly by negative-stain electron microscopy, which allowed us to picture the dynamic procedure of EBOV nucleocapsid assembly. Along with further biochemical studies, we showed the assembly of NLC is salt-sensitive, and also established an indispensible role of RNA in this process. We propose the diverse modes of NLC elongation might be the key determinants shaping the plasticity of EBOV virions. Our findings provide a new model for characterizing the self-oligomerization of viral nucleoproteins and studying the dynamic assembly process of viral nucleocapsid in vitro.
miR-10a inhibits cell proliferation and promotes cell apoptosis by targeting BCL6 in diffuse large B-cell lymphoma
Qian Fan, Xiangrui Meng, Hongwei Liang, Huilai Zhang, Xianming Liu, Lanfang Li, Wei Li, Wu Sun, Haiyang Zhang, Ke Zen, Chen-Yu Zhang, Zhen Zhou, Xi Chen, Yi Ba
2016, 7(12): 899-912. doi: 10.1007/s13238-016-0316-z
The BCL6 (B-Cell Lymphoma 6) gene is a proto-oncogene that is often expressed in diffuse large B-cell lymphomas (DLBCLs). BCL6 loss of function can kill DLBCL cells, demonstrating that BCL6 is necessary for the survival of DLBCL cells and could be a therapeutic target. In this study, we found that BCL6 protein levels were consistently upregulated in DLBCL tissues, whereas its mRNA levels varied randomly in tissues, suggesting that a post-transcriptional mechanism was involved in BCL6 regulation. We used bioinformatics analysis to search for miRNAs, which potentially target BCL6, and identified specific targeting sites for miR-10a in the 3'-untranslated region (3'-UTR) of BCL6. We further identified an inverse correlation between miR-10a levels and BCL6 protein levels, but not mRNA levels, in DLBCL tumor tissue samples. By overexpressing or knocking down miR-10a in DLBCL cells, we experimentally validated that miR-10a directly recognizes the 3'-UTR of the BCL6 transcript and regulated BCL6 expression. Furthermore, we demonstrated that negatively regulating BCL6 by miR-10a suppressed the proliferation and promoted apoptosis of DLBCL cells.
Questions about NgAgo
Shawn Burgess, Linzhao Cheng, Feng Gu, Junjiu Huang, Zhiwei Huang, Shuo Lin, Jinsong Li, Wei Li, Wei Qin, Yujie Sun, Zhou Songyang, Wensheng Wei, Qiang Wu, Haoyi Wang, Xiaoqun Wang, Jing-Wei Xiong, Jianzhong Xi, Hui Yang, Bin Zhou, Bo Zhang
2016, 7(12): 913-915. doi: 10.1007/s13238-016-0343-9
MD simulation of high-resolution X-ray structures reveals post-translational modification dependent conformational changes in HSF-DNA interaction
Han Feng, Sheng Wang, Ling Guo, Avinash S. Punekar, Rudolf Ladenstein, Da-Cheng Wang, Wei Liu
2016, 7(12): 916-920. doi: 10.1007/s13238-016-0331-0