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Li, Yang

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Li, Yang
Author's Publications: search.filters.isAuthorOfPublication.9e000f8a-fc75-444c-8ccd-16711e3185fe

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    CLIC, a tool for expanding biological pathways based on co-expression across thousands of datasets
    (Public Library of Science, 2017) Li, Yang; Jourdain, Alexis A.; Calvo, Sarah; Liu, Jun; Mootha, Vamsi
    In recent years, there has been a huge rise in the number of publicly available transcriptional profiling datasets. These massive compendia comprise billions of measurements and provide a special opportunity to predict the function of unstudied genes based on co-expression to well-studied pathways. Such analyses can be very challenging, however, since biological pathways are modular and may exhibit co-expression only in specific contexts. To overcome these challenges we introduce CLIC, CLustering by Inferred Co-expression. CLIC accepts as input a pathway consisting of two or more genes. It then uses a Bayesian partition model to simultaneously partition the input gene set into coherent co-expressed modules (CEMs), while assigning the posterior probability for each dataset in support of each CEM. CLIC then expands each CEM by scanning the transcriptome for additional co-expressed genes, quantified by an integrated log-likelihood ratio (LLR) score weighted for each dataset. As a byproduct, CLIC automatically learns the conditions (datasets) within which a CEM is operative. We implemented CLIC using a compendium of 1774 mouse microarray datasets (28628 microarrays) or 1887 human microarray datasets (45158 microarrays). CLIC analysis reveals that of 910 canonical biological pathways, 30% consist of strongly co-expressed gene modules for which new members are predicted. For example, CLIC predicts a functional connection between protein C7orf55 (FMC1) and the mitochondrial ATP synthase complex that we have experimentally validated. CLIC is freely available at www.gene-clic.org. We anticipate that CLIC will be valuable both for revealing new components of biological pathways as well as the conditions in which they are active.
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    Molecular basis of caspase-1 polymerization and its inhibition by a novel capping mechanism
    (2016) Lu, Alvin; Li, Yang; Schmidt, Florian I.; Yin, Qian; Chen, Shuobing; Fu, Tian-Min; Tong, Alexander B.; Ploegh, Hidde L.; Mao, Youdong; Wu, Hao
    Inflammasomes are cytosolic caspase-1 activation complexes that sense intrinsic and extrinsic danger signals to trigger inflammatory responses and pyroptotic cell death. Homotypic interactions by Pyrin domains (PYD) and caspase recruitment domains (CARD) in inflammasome component proteins mediate oligomerization into filamentous assemblies. Several cytosolic proteins consisting of only the interaction domains exert inhibitory effects on inflammasome assembly. In this study, we determined the structure of human caspase-1CARD filament by cryo-electron microscopy and investigated the biophysical properties of two caspase-1-like CARD-only proteins, human inhibitor of CARD (INCA or CARD17) and ICEBERG (or CARD18). Our results reveal the surprising finding that INCA caps caspase-1 filament, thereby exerting potent inhibition with low nanomolar Ki on caspase-1CARD polymerization in vitro and inflammasome activation in cells. While caspase-1CARD uses six complementary surfaces of three types for filament assembly, INCA is defective in two of the six interfaces to terminate caspase-1 filament.
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    SFX analysis of non-biological polycrystalline samples
    (International Union of Crystallography, 2015) Zhang, Tao; Jin, Shifeng; Gu, Yuanxin; He, Yao; Li, Ming; Li, Yang; Fan, Haifu
    Serial femtosecond crystallography (SFX) is capable of collecting three-dimensional single-crystal diffraction data using polycrystalline samples. This may dramatically enhance the power of X-ray powder diffraction. In this paper a test has been performed using simulated diffraction patterns. The test sample is a mixture of two zeolites with crystal grain sizes from 100 to 300 nm. X-ray diffraction snapshots by SFX were simulated and processed using the program suite CrystFEL. Identification according to the primitive unit-cell volume determined from individual snapshots was able to separate the whole set of snapshots into two subsets, which correspond to the two zeolites in the sample. Monte Carlo integration in CrystFEL was then applied to them separately. This led to two sets of three-dimensional single-crystal diffraction intensities, based on which crystal structures of the two zeolites were solved easily by direct methods implemented in the program SHELXD.
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    Plasticity in PYD assembly revealed by cryo-EM structure of the PYD filament of AIM2
    (2015) Lu, Alvin Z.; Li, Yang; Yin, Qian; Ruan, Jianbin; Yu, Xiong; Egelman, Edward; Wu, Hao
    Absent in melanoma 2 (AIM2) is an essential cytosolic double-stranded DNA receptor that assembles with the adaptor, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and caspase-1 to form the AIM2 inflammasome, which leads to proteolytic maturation of cytokines and pyroptotic cell death. AIM2 contains an N-terminal Pyrin domain (PYD) that interacts with ASC through PYD/PYD interactions and nucleates ASCPYD filament formation. To elucidate the molecular basis of AIM2-induced ASCPYD polymerization, we generated AIM2PYD filaments fused to green fluorescent protein (GFP) and determined its cryo-electron microscopic (cryo-EM) structure. The map showed distinct definition of helices, allowing fitting of the crystal structure. Surprisingly, the GFP-AIM2PYD filament is a 1-start helix with helical parameters distinct from those of the 3-start ASCPYD filament. However, despite the apparent symmetry difference, helical net and detailed interface analyses reveal minimal changes in subunit packing. GFP-AIM2PYD nucleated ASCPYD filament formation in comparable efficiency as untagged AIM2PYD, suggesting assembly plasticity in both AIM2PYD and ASCPYD. The DNA-binding domain of AIM2 is able to form AIM2/DNA filaments, within which the AIM2PYD is brought into proximity to template ASCPYD filament assembly. Because ASC is able to interact with many PYD-containing receptors for the formation of inflammasomes, the observed structural plasticity may be critically important for this versatility in the PYD/PYD interactions.