Tsinghua Peking Joint Center for Life science

Beijing, China

Tsinghua Peking Joint Center for Life science

Beijing, China
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Bae N.,University of Texas M. D. Anderson Cancer Center | Viviano M.,University of Salerno | Su X.,Tsinghua University | Su X.,Tsinghua Peking Joint Center for Life science | And 15 more authors.
Nature Chemical Biology | Year: 2017

The discovery of inhibitors of methyl- and acetyl-binding domains has provided evidence for the 'druggability' of epigenetic effector molecules. The small-molecule probe UNC1215 prevents methyl-dependent protein-protein interactions by engaging the aromatic cage of MBT domains and, with lower affinity, Tudor domains. Using a library of tagged UNC1215 analogs, we screened a protein-domain microarray of human methyllysine effector molecules to rapidly detect compounds with new binding profiles with either increased or decreased specificity. Using this approach, we identified a compound (EML405) that acquired a novel interaction with the Tudor-domain-containing protein Spindlin1 (SPIN1). Structural studies facilitated the rational synthesis of SPIN1 inhibitors with increased selectivity (EML631-633), which engage SPIN1 in cells, block its ability to 'read' H3K4me3 marks and inhibit its transcriptional-coactivator activity. Protein microarrays can thus be used as a platform to 'target-hop' and identify small molecules that bind and compete with domain-motif interactions. © Nature America, Inc., part of Springer Nature. All rights reserved.

Liu X.,Tsinghua University | Liu X.,Tsinghua Peking Joint Center for Life science | Li M.,Tsinghua University | Li M.,Tsinghua Peking Joint Center for Life science | And 4 more authors.
Nature | Year: 2017

Chromatin remodellers are helicase-like, ATP-dependent enzymes that alter chromatin structure and nucleosome positions to allow regulatory proteins access to DNA. Here we report the cryo-electron microscopy structure of chromatin remodeller Switch/sucrose non-fermentable (SWI2/SNF2) from Saccharomyces cerevisiae bound to the nucleosome. The structure shows that the two core domains of Snf2 are realigned upon nucleosome binding, suggesting activation of the enzyme. The core domains contact each other through two induced Brace helices, which are crucial for coupling ATP hydrolysis to chromatin remodelling. Snf2 binds to the phosphate backbones of one DNA gyre of the nucleosome mainly through its helicase motifs within the major domain cleft, suggesting a conserved mechanism of substrate engagement across different remodellers. Snf2 contacts the second DNA gyre via a positively charged surface, providing a mechanism to anchor the remodeller at a fixed position of the nucleosome. Snf2 locally deforms nucleosomal DNA at the site of binding, priming the substrate for the remodelling reaction. Together, these findings provide mechanistic insights into chromatin remodelling. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

Zhang M.,CAS Institute of Botany | Zhang M.,University of Chinese Academy of Sciences | Zhang R.,CAS Institute of Botany | Zhang R.,University of Chinese Academy of Sciences | And 5 more authors.
Journal of Experimental Botany | Year: 2016

The actin cytoskeleton is increasingly recognized as a major regulator of pollen tube growth. Actin filaments have distinct distribution patterns and dynamic properties within different regions of the pollen tube. Apical actin filaments are highly dynamic and crucial for pollen tube growth. However, how apical actin filaments are generated and properly constructed remains an open question. Here we showed that Arabidopsis fimbrin5 (FIM5) decorates filamentous structures throughout the entire tube but is apically concentrated. Apical actin structures are disorganized to different degrees in the pollen tubes of fim5 loss-of-function mutants. Further observations suggest that apical actin structures are not constructed properly because apical actin filaments cannot be maintained at the cortex of fim5 pollen tubes. Actin filaments appeared to be more curved in fim5 pollen tubes and this was confirmed by measurements showing that the convolutedness and the rate of change of convolutedness of actin filaments was significantly increased in fim5 pollen tubes. This suggests that the rigidity of the actin filaments may be compromised in fim5 pollen tubes. Further, the apical cell wall composition is altered, implying that tip-directed vesicle trafficking events are impaired in fim5 pollen tubes. Thus, we found that FIM5 decorates apical actin filaments and regulates their organization in order to drive polarized pollen tube growth. © 2016 The Author 2016.

Liu X.,China Agricultural University | Liu X.,CAS Institute of Botany | Qu X.,Tsinghua University | Qu X.,Tsinghua Peking Joint Center for Life science | And 9 more authors.
Molecular Plant | Year: 2015

Pollen tube growth is an essential step during flowering plant reproduction, whose growth depends on a population of dynamic apical actin filaments. Apical actin filaments were thought to be involved in the regulation of vesicle fusion and targeting in the pollen tube. However, the molecular mechanisms that regulate the construction of apical actin structures in the pollen tube remain largely unclear. Here, we identify profilin as an important player in the regulation of actin polymerization at the apical membrane in the pollen tube. Downregulation of profilin decreased the amount of filamentous actin and induced disorganization of apical actin filaments, and reduced tip-directed vesicle transport and accumulation in the pollen tube. Direct visualization of actin dynamics revealed that the elongation of actin filaments originating at the apical membrane decreased in profilin mutant pollen tubes. Mutant profilin that is defective in binding poly-L-proline only partially rescues the actin polymerization defect in profilin mutant pollen tubes, although it fully rescues the actin turnover phenotype. We propose that profilin controls the construction of actin structures at the pollen tube tip, presumably by favoring formin-mediated actin polymerization at the apical membrane. This study identifies profilin as an important player in the regulation of apical actin polymerization, presumably by favoring formin-mediated actin assembly at the apical membrane, which may represent a universal actin polymerization pathway underlying rapid polarized pollen tube growth. © 2015 The Author.

Huang W.,Tsinghua Peking Joint Center for Life science | Huang W.,Center for Structural Biology | Choi W.,Tsinghua Peking Joint Center for Life science | Choi W.,Center for Structural Biology | And 22 more authors.
Cell Research | Year: 2012

The Beclin 1 gene is a haplo-insufficient tumor suppressor and plays an essential role in autophagy. However, the molecular mechanism by which Beclin 1 functions remains largely unknown. Here we report the crystal structure of the evolutionarily conserved domain (ECD) of Beclin 1 at 1.6 Å resolution. Beclin 1 ECD exhibits a previously unreported fold, with three structural repeats arranged symmetrically around a central axis. Beclin 1 ECD defines a novel class of membrane-binding domain, with a strong preference for lipid membrane enriched with cardiolipin. The tip of a surface loop in Beclin 1 ECD, comprising three aromatic amino acids, acts as a hydrophobic finger to associate with lipid membrane, consequently resulting in the deformation of membrane and liposomes. Mutation of these aromatic residues rendered Beclin 1 unable to stably associate with lipid membrane in vitro and unable to fully rescue autophagy in Beclin 1-knockdown cells in vivo. These observations form an important framework for deciphering the biological functions of Beclin 1. © 2012 IBCB, SIBS, CAS All rights reserved.

Liu J.,Princeton University | Liu J.,Eastman Chemical Company | Liu C.,Tsinghua University | He W.,Tsinghua University | He W.,Tsinghua Peking Joint Center for Life science
Current Organic Chemistry | Year: 2013

In this review, major categories of molecular fluorophores were summarized with emphasis on their synthetic strategies and chemical transformations. Recent advancement in small-molecule fluorophores as novel molecular probes in living cells was also discussed. © 2013 Bentham Science Publishers.

Zhang Q.,Tsinghua Peking Joint Center for Life science | Cai S.,Tsinghua University | Li L.,Tsinghua University | Chen Y.,Tsinghua Peking Joint Center for Life science | And 6 more authors.
ACS Catalysis | Year: 2013

Ag nanoparticle-catalyzed aerobic oxidation of benzyl alcohols in basic DMSO gave efficient formation of styryl ethers, featuring single carbon transfer and Cî - C and C-O bond formation. A deuterium labeling experiment established that DMSO was the carbon source. Further experiments showed the reaction proceeded through a styryl sulfoxide intermediate originating from basic DMSO and transient benzaldehyde. Control reactions in the absence of the Ag NPs or air indicated that oxidation of the styryl sulfoxide was required for the final C-O bond formation. This work demonstrated that metal nanoparticles could be applied to tandem heterogeneous catalysis in organic chemistry. © 2013 American Chemical Society.

Chang H.-Y.,National Taiwan University | Liao C.-Y.,National Taiwan University | Su G.-C.,National Taiwan University | Lin S.-W.,Academia Sinica, Taiwan | And 3 more authors.
Journal of Biological Chemistry | Year: 2015

DMC1 and RAD51 are conserved recombinases that catalyze homologous recombination. DMC1 and RAD51 share similar properties in DNA binding, DNA-stimulated ATP hydrolysis, and catalysis of homologous DNA strand exchange. A large body of evidence indicates that attenuation of ATP hydrolysis leads to stabilization of the RAD51-ssDNA presynaptic filament and enhancement of DNA strand exchange. However, the functional relationship of ATPase activity, presynaptic filament stability, and DMC1-mediated homologous DNA strand exchange has remained largely unexplored. To address this important question, we have constructed several mutant variants of human DMC1 and characterized them biochemically to gain mechanistic insights. Two mutations, K132R and D223N, that change key residues in the Walker A and B nucleotide-binding motifs ablate ATP binding and render DMC1 inactive. On the other hand, the nucleotide-binding cap D317K mutant binds ATP normally but shows significantly attenuated ATPase activity and, accordingly, forms a highly stable presynaptic filament. Surprisingly, unlike RAD51, presynaptic filament stabilization achieved via ATP hydrolysis attenuation does not lead to any enhancement of DMC1-catalyzed homologous DNA pairing and strand exchange. This conclusion is further supported by examining wild-type DMC1 with non-hydrolyzable ATP analogues. Thus, our results reveal an important mechanistic difference between RAD51 and DMC1. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Xiao Z.,Tsinghua University | Xiao Z.,Tsinghua Peking Joint Center for Life science | Zou Q.,Tsinghua University | Liu Y.,Tsinghua University | And 3 more authors.
Nature Communications | Year: 2016

The closely regulated process of mRNA translation is crucial for precise control of protein abundance and quality. Ribosome profiling, a combination of ribosome foot-printing and RNA deep sequencing, has been used in a large variety of studies to quantify genome-wide mRNA translation. Here, we developed Xtail, an analysis pipeline tailored for ribosome profiling data that comprehensively and accurately identifies differentially translated genes in pairwise comparisons. Applied on simulated and real datasets, Xtail exhibits high sensitivity with minimal false-positive rates, outperforming existing methods in the accuracy of quantifying differential translations. With published ribosome profiling datasets, Xtail does not only reveal differentially translated genes that make biological sense, but also uncovers new events of differential translation in human cancer cells on mTOR signalling perturbation and in human primary macrophages on interferon gamma (IFN-I 3) treatment. This demonstrates the value of Xtail in providing novel insights into the molecular mechanisms that involve translational dysregulations.

PubMed | Tsinghua University, CAS Shanghai Institutes for Biological Sciences, Tsinghua Peking Joint Center for Life science and Sloan Kettering Cancer Center
Type: Journal Article | Journal: Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

Aberrant cleavage of amyloid precursor protein (APP) by -secretase contributes to the development of Alzheimers disease. More than 200 disease-derived mutations have been identified in presenilin (the catalytic subunit of -secretase), making modulation of -secretase activity a potentially attractive therapeutic opportunity. Unfortunately, the technical challenges in dealing with intact -secretase have hindered discovery of modulators and demand a convenient substitute approach. Here we report that, similar to -secretase, the archaeal presenilin homolog PSH faithfully processes the substrate APP C99 into A42, A40, and A38. The molar ratio of the cleavage products A42 over A40 by PSH is nearly identical to that by -secretase. The proteolytic activity of PSH is specifically suppressed by presenilin-specific inhibitors. Known modulators of -secretase also modulate PSH similarly in terms of the A42/A40 ratio. Structural analysis reveals association of a known -secretase inhibitor with PSH between its two catalytic aspartate residues. These findings identify PSH as a surrogate protease for the screening of agents that may regulate the protease activity and the cleavage preference of -secretase.

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