The Yes-associated protein (YAP) transcriptional coactivator is a key regulator of organ size and a candidate human oncogene inhibited by the Hippo tumor suppressor pathway. The TEAD family of transcription factors binds directly to and mediates YAP-induced gene expression. Here we report the three-dimensional structure of the YAP (residues 50-171)-TEAD1 (residues 194-411) complex, in which YAP wraps around the globular structure of TEAD1 and forms extensive interactions via three highly conserved interfaces. Interface 3, including YAP residues 86-100, is most critical for complex formation. Our study reveals the biochemical nature of the YAP-TEAD interaction, and provides a basis for pharmacological intervention of YAP-TEAD hyperactivation in human diseases. The Yes-associated protein (YAP) is a transcriptional coactivator (Yagi et al. 1999). YAP knockout in mice causes embryonic lethality (Morin-Kensicki et al. 2006), indicating its critical role in development. In contrast, transgenic expression of YAP dramatically increases mouse liver size in a reversible fashion (Camargo et al. 2007;Dong et al. 2007), suggesting a key role of YAP in organ size regulation. Consistent with its growth-promoting function, yap genomic amplification and elevated protein levels have been observed in several human cancers (Overholtzer et al. 2006;Zender et al. 2006;Dong et al. 2007;Zhao et al. 2007;Steinhardt et al. 2008). Furthermore, expression of active YAP potently induces transformation in both NIH3T3 and MCF10A cells (Overholtzer et al. 2006;Zhao et al. 2009), and liver-specific transgenic expression of YAP causes tumor formation in vivo (Camargo et al. 2007;Dong et al. 2007). These observations support the function of YAP as a human oncogene.As a transcriptional coactivator, YAP needs to bind transcription factors to stimulate gene expression. Reported YAP target transcription factors include TEAD, p73, Runx2, and the ErbB4 cytoplasmic domain (Yagi et al. 1999;Strano et al. 2001;Vassilev et al. 2001;Komuro et al. 2003). However, only TEAD has been demonstrated to be important for the growth-promoting function of YAP Zhao et al. 2008). In humans, the TEAD family has four highly homologous proteins sharing a conserved DNA-binding TEA domain. YAP and TEAD1 bind to a common set of promoters in MCF10A cells (Zhao et al. 2008). Knockdown of TEAD aborts expression of the majority of YAP-inducible genes and largely attenuates YAP-induced overgrowth, epithelial-mesenchymal transition (EMT), and oncogenic transformation (Zhao et al. 2008). Furthermore, the phenotype of TEAD1/TEAD2 double-knockout mice resembles YAP knockout mice . Notably, the role of the YAP and TEAD complex in growth promotion is implicated in Sveinsson's chorioretinal atrophy caused by the TEAD1 Y406H mutation, which abolishes its interaction with and activation by YAP (Kitagawa 2007;Zhao et al. 2008). Consistently, Scalloped (Sd), the Drosophila homolog of TEAD, directly mediates Yorkie (Yki)-induced gene expression and overgrowth phenotypes (Zhao et al. 2007;Gou...

Background Hepatocellular carcinoma (HCC) is one of the most common malignant tumors of the digestive system and has high morbidity and mortality rates. It is essential to search new biomarkers to improve the accuracy of early HCC diagnosis. Therefore, we evaluated the diagnostic value of prothrombin induced by vitamin K deficiency or antagonist- II (PIVKA-II) as a potential biomarker that complements α-fetoprotein (AFP) in HCC by detecting the serum PIVKA-II levels. Methods Serum PIVKA-II levels were compared in 168 HCC patients, 150 benign liver disease patients and 153 healthy controls to investigate the PIVKA-II potential to be a HCC biomarker. Receiver operating characteristic curve (ROC) analysis was used to evaluate the value of PIVKA-II in the diagnosis of HCC and its complementary role of AFP. The correlation between serum PIVKA-II levels and clinicopathological characteristics was analyzed to study the value of PIVKA-II in assessing HCC progression and prognosis. Finally, the ability of PIVKA-II in assessing the surgical treatment effects of HCC was studied by comparing the pre- and post-operative serum PIVKA-II levels in 89 HCC patients. Results Serum PIVKA-II levels in HCC patients were significantly higher than that in patients with benign liver disease and healthy controls. The PIVKA-II performance in the diagnosing HCC as an individual biomarker was remarkable. The combined detection of PIVKA-II and AFP improved the diagnostic efficiency of HCC. PIVKA-II retained significant diagnosis capabilities for AFP-negative HCC patients. Significant correlations were found between PIVKA-II expression levels and some clinicopathological characteristics, including tumor size, tumor stage, tumor metastasis, differentiation degree and complications. PIVKA-II expression obviously decreased after surgical resection. Conclusions PIVKA-II is a promising serum biomarker for the HCC diagnosis that can be used as a supplement for AFP. The combined diagnosis of the two markers greatly improved the diagnostic efficiency of HCC. The PIVKA-II levels in HCC patients were widely associated with clinicopathological characteristics representing tumor cell dissemination and/or poor prognosis. PIVKA-II can be used to evaluate the curative effects of HCC resection.

Nosiheptide-resistance methyltransferase (NHR) of Streptomyces actuosus is a class IV methyltransferase of the SpoU family and methylates 23S rRNA at nucleotide adenosine corresponding to A1067 in Escherichia coli. Such methylation is essential for resistance against nosiheptide, a sulfur peptide antibiotic, which is produced by the nosiheptide-producing strain, S. actuosus. Here, we report the crystal structures of NHR and NHR in complex with SAM (S-adenosyl-l-methionine) at 2.0 and 2.1 A resolution, respectively. NHR forms a functional homodimer, and dimerization is required for methyltransferase activity. The monomeric NHR is comprised of the N-terminal RNA binding domain (NTD) and the C-terminal catalytic domain (CTD). Overall, the structure of NHR suggests that the methyltransferase activity is achieved by "reading" the RNA substrate with NTD and "adding" methyl group using CTD. Comprehensive mutagenesis and methyltransferase activity assays reveal critical regions for SAM binding in CTD and loops (L1 and L3) essential for RNA recognition in NTD. Finally, the catalytic mechanism and structural model that NHR recognizes 23S rRNA is proposed based on the structural and biochemical analyses. Thus, our systematic structural studies reveal the substrate recognition and modification by the nosiheptide-resistance methyltransferase.

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Tung tree (Vernicia fordii) is an economically important tree widely cultivated for industrial oil production in China. To better understand the molecular basis of tung tree chloroplasts, we sequenced and characterized its genome using PacBio RS II sequencing platforms. The chloroplast genome was sequenced with 161,528 bp in length, composed with one pair of inverted repeats (IRs) of 26,819 bp, which were separated by one small single copy (SSC; 18,758 bp) and one large single copy (LSC; 89,132 bp). The genome contains 114 genes, coding for 81 protein, four ribosomal RNAs and 29 transfer RNAs. An expansion with integration of an additional rps19 gene in the IR regions was identified. Compared to the chloroplast genome of Jatropha curcas, a species from the same family, the tung tree chloroplast genome is distinct with 85 single nucleotide polymorphisms (SNPs) and 82 indels. Phylogenetic analysis suggests that V. fordii is a sister species with J. curcas within the Eurosids I. The nucleotide sequence provides vital molecular information for understanding the biology of this important oil tree.

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the damage caused by cold injury. The results also showed that V. fordii seedlings are more resistant to low temperatures than V. montana seedlings.