2016 Vol. 7, No. 8

Research articles
Structural basis of Zika virus helicase in recognizing its substrates
Hongliang Tian, Xiaoyun Ji, Xiaoyun Yang, Zhongxin Zhang, Zuokun Lu, Kailin Yang, Cheng Chen, Qi Zhao, Heng Chi, Zhongyu Mu, Wei Xie, Zefang Wang, Huiqiang Lou, Haitao Yang, Zihe Rao
2016, 7(8): 562-570. doi: 10.1007/s13238-016-0293-2
The recent explosive outbreak of Zika virus (ZIKV) infection has been reported in South and Central America and the Caribbean. Neonatal microcephaly associated with ZIKV infection has already caused a public health emergency of international concern. No specific vaccines or drugs are currently available to treat ZIKV infection. The ZIKV helicase, which plays a pivotal role in viral RNA replication, is an attractive target for therapy. We determined the crystal structures of ZIKV helicase-ATP-Mn2+ and ZIKV helicase-RNA. This is the first structure of any flavivirus helicase bound to ATP. Comparisons with related flavivirus helicases have shown that although the critical P-loop in the active site has variable conformations among different species, it adopts an identical mode to recognize ATP/Mn2+. The structure of ZIKV helicase-RNA has revealed that upon RNA binding, rotations of the motor domains can cause significant conformational changes. Strikingly, although ZIKV and dengue virus (DENV) apo-helicases share conserved residues for RNA binding, their different manners of motor domain rotations result in distinct individual modes for RNA recognition. It suggests that flavivirus helicases could have evolved a conserved engine to convert chemical energy from nucleoside triphosphate to mechanical energy for RNA unwinding, but different motor domain rotations result in variable RNA recognition modes to adapt to individual viral replication.
Ursolic acid synergistically enhances the therapeutic effects of oxaliplatin in colorectal cancer
Jianzhen Shan, Yanyan Xuan, Qi Zhang, Chunpeng Zhu, Zhen Liu, Suzhan Zhang
2016, 7(8): 571-585. doi: 10.1007/s13238-016-0295-0
Oxaliplatin is a key drug in chemotherapy of colorectal cancer (CRC). However, its efficacy is unsatisfied due to drug resistance of cancer cells. In this study, we tested whether a natural agent, ursolic acid, was able to enhance the efficacy of oxaliplatin for CRC. Four CRC cell lines including SW480, SW620, LoVo, and RKO were used as in vitro models, and a SW620 xenograft mouse model was used in further in vivo study. We found that ursolic acid inhibited proliferation and induced apoptosis of all four cells and enhanced the cytotoxicity of oxaliplatin. This effect was associated with down-regulation of Bcl-xL, Bcl-2, survivin, activation of caspase-3, 8, 9, and inhibition of KRAS expression and BRAF, MEK1/2, ERK1/2, p-38, JNK, AKT, IKKα, IκBα, and p65 phosphorylation of the MAPK, PI3K/AKT, and NF-κB signaling pathways. The two agents also showed synergistic effects against tumor growth in vivo. In addition, ursolic acid restored liver function and body weight of the mice treated with oxaliplatin. Thus, we concluded that ursolic acid could enhance the therapeutic effects of oxaliplatin against CRC both in vitro and in vivo, which offers an effective strategy to minimize the burden of oxaliplatin-induced adverse events and provides the groundwork for a new clinical strategy to treat CRC.
Structural characterization of coatomer in its cytosolic state
Shengliu Wang, Yujia Zhai, Xiaoyun Pang, Tongxin Niu, Yue-He Ding, Meng-Qiu Dong, Victor W. Hsu, Zhe Sun, Fei Sun
2016, 7(8): 586-600. doi: 10.1007/s13238-016-0296-z
Studies on coat protein I (COPI) have contributed to a basic understanding of how coat proteins generate vesicles to initiate intracellular transport. The core component of the COPI complex is coatomer, which is a multimeric complex that needs to be recruited from the cytosol to membrane in order to function in membrane bending and cargo sorting. Previous structural studies on the clathrin adaptors have found that membrane recruitment induces a large conformational change in promoting their role in cargo sorting. Here, pursuing negative-stain electron microscopy coupled with singleparticle analyses, and also performing CXMS (chemical cross-linking coupled with mass spectrometry) for validation, we have reconstructed the structure of coatomer in its soluble form. When compared to the previously elucidated structure of coatomer in its membrane-bound form we do not observe a large conformational change. Thus, the result uncovers a key difference between how COPI versus clathrin coats are regulated by membrane recruitment.
Activation of proHGF by St14 induces mouse embryonic stem cell differentiation
Xiaoshuang Yan, Yan Xue, Yiye Zhou, Yan Cheng, Shang Yin, Qingwen Ma, Fanyi Zeng
2016, 7(8): 601-605. doi: 10.1007/s13238-016-0282-5
The carboxypeptidase D homolog silver regulates memory formation via insulin pathway in Drosophila
Binyan Lu, Yi Zhao, Jie Zhao, Xiaoyang Yao, Yichun Shuai, Weiwei Ma, Yi Zhong
2016, 7(8): 606-610. doi: 10.1007/s13238-016-0291-4
Ribavirin is effective against drug-resistant H7N9 influenza virus infections
Yuhai Bi, Gary Wong, Yingxia Liu, Lei Liu, George F. Gao, Yi Shi
2016, 7(8): 611-614. doi: 10.1007/s13238-016-0287-0
Identification of endoplasmic reticulum-shaping proteins in Plasmodium parasites
Sha Sun, Li Lv, Zhi Yao, Purnima Bhanot, Junjie Hu, Qian Wang
2016, 7(8): 615-620. doi: 10.1007/s13238-016-0290-5
Dr. Jia-Xiang Shen: a pioneer of the Chinese pharmaceutical industry
Xianghai Guo, Baozhi Han
2016, 7(8): 545-547. doi: 10.1007/s13238-016-0294-1
Regulation of TAZ in cancer
Xin Zhou, Qun-Ying Lei
2016, 7(8): 548-561. doi: 10.1007/s13238-016-0288-z
TAZ, a transcriptional coactivator with PDZ-binding motif, is encoded by WWTR1 gene (WW domain containing transcription regulator 1). TAZ is tightly regulated in the hippo pathway-dependent and -independent manner in response to a wide range of extracellular and intrinsic signals, including cell density, cell polarity, F-actin related mechanical stress, ligands of G protein-coupled receptors (GPCRs), cellular energy status, hypoxia and osmotic stress. Besides its role in normal tissue development, TAZ plays critical roles in cell proliferation, differentiation, apoptosis, migration, invasion, epithelial-mesenchymal transition (EMT), and stemness in multiple human cancers. We discuss here the regulators and regulation of TAZ. We also highlight the tumorigenic roles of TAZ and its potential therapeutic impact in human cancers.