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IEEE International Workshop on Genomic Signal Processing and Statistics (GENSIPS)

作者： Yanxun Xu Xiaofeng Zheng Yuan Yuan Marcos R Estecio Jean-Pierre Issa Yuan Ji Shoudan Liang Department of Statistics Rice University Houston TX USA Department of Bioinformatics and Computational Biology University of Texas M.D. Anderson Cancer Center Houston TX USA Graduate Program in Structural and Computational Biology and Molecular Biophysics Baylor College of Medicine Houston TX USA Department of Biochemistry and Molecular Biology University of Texas M.D. Anderson Cancer Center Houston TX USA Fels Institute for Cancer Research and Molecular Biology Temple University Philadelphia PA USA CCRI NorthShore University HealthSystem Chicago IL USA

ISBN: (纸本)9781467352345

A single-nucleotide polymorphism (SNP) is a single base change in the DNA sequence and is the most common polymorphism. Since some SNPs have a major influence on disease susceptibility, detecting SNPs plays an important role in biomedical research. To take fully advantage of the next-generation sequencing (NGS) technology and detect SNP more effectively, we propose a Bayesian approach that computes a posterior probability of hidden nucleotide variations at each covered genomic position. The position with higher posterior probability of hidden nucleotide variation has a higher chance to be a SNP. We apply the proposed method to detect SNPs in two cell lines: the prostate cancer cell line PC3 and the embryonic stem cell line H1. A comparison between our results with dbSNP database shows a high ratio of overlap (≥95 %). The positions that are called only under our model but not in dbSNP may serve as candidates for new SNPs.

关键词： comparison candidates generation Single nucleotide polymorphism sequence number protection a posteriori probability DNA Sequence Bayesian inference Disease Susceptibility Analyses, Sequence

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Amyloid formation in heterogenous environments:Glycosoaminoglycans can induce amyloid formation by non-amyloidogenic proteins and interfere with amyloid inhibitors

Amyloid formation in heterogenous environments:Glycosoaminog...

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The 3rd Asia Pacific Protein Association Conference in Conjunction with the 3rd Symposium of the Chinese Protein Society

作者： Hui Wang Fanling Meng Daniel P.Raleigh Department of Chemistry State University of New York at Stony Brook Graduate Program in Biochemistry and Structural Biology Graduate Program in BiophysicsState University of New York at Stony Brook

Amyloid formation,the aggregation of normally soluble proteins into partially orderedβ-rich structures,is a characteristic component of many human *** formation takes place in a heterogenous environment in vivo with the potential for interactions with membranes and with components of the extracellular matrix.A range of strategies have been applied to the problem of developing inhibitors of amyloid formation,however,the majority of in vitro assays of amyloid formation and amyloid

关键词： Amyloid formation in heterogenous environments:Glycosoaminoglycans can induce amyloid formation by non-amyloidogenic proteins and interfere with amyloid inhibitors

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Probing the folding of mini-protein Beta3s by two-dimensional infrared spectroscopy;simulation study

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PMC Biophysics 2010年第1期3卷 1-16页

作者： Marai, Christopher N.J. Mukamel, Shaul Wang, Jin Graduate Program in Biochemistry and Structural Biology State University of New York at Stony Brook New York 11794-3400 United States Department of Chemistry University of California Irvine CA 92697-2025 United States Department of Chemistry State University of New York at Stony Brook New York 11794-3400 United States Department of Physics State University of New York at Stony Brook New York 11794-3400 United States

We propose to use infrared coherent two-dimensional correlation spectroscopy (2DCS) to characterize the folding mechanism of the mini-protein Beta3s. In this study Beta3s was folded by molecular dynamics (MD) simulation and intermediate conformational ensembles were identified. The one and two-dimensional correlation spectrum was calculated for the intermediate and native states of the mini-protein. A direct structure-spectra relationship was determined by analysis of conformational properties and specific residue contributions. We identified the structural origin of diagonal and off-diagonal peaks in the 2DCS spectra for the native and intermediate conformational ensembles in the folding mechanism. This work supports the implementation of computational techniques in conjunction with experimental 2DCS to study the folding mechanism of proteins. In addition to exploring the folding mechanism the work presented here can be applied in combination with experiment to refine and validate current molecular dynamics force fields. © 2010 Marai et al.

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structural insights into TDP-43 in nucleic-acid binding and domain interactions

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Nucleic Acids Research 2009年第6期37卷 1799-1808页

作者： Kuo, Pan-Hsien Doudeva, Lyudmila G. Wang, Yi-Ting Shen, Che-Kun James Yuan, Hanna S. Institute of Bioinformatics and Structural Biology National Tsing Hua University Taipei Taiwan Institute of Molecular Biology National Taiwan University Taipei Taiwan Taiwan International Graduate Program Chemical Biology and Molecular Biophysics National Taiwan University Taipei Taiwan Graduate Institute of Biochemistry and Molecular Biology National Taiwan University Taipei Taiwan

TDP-43 is a pathogenic protein: its normal function in binding to UG-rich RNA is related to cystic fibrosis, and inclusion of its C-terminal fragments in brain cells is directly linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Here we report the 1.65 Å crystal structure of the C-terminal RRM2 domain of TDP-43 in complex with a single-stranded DNA. We show that TDP-43 is a dimeric protein with two RRM domains, both involved in DNA and RNA binding. The crystal structure reveals the basis of TDP-43's TG/ UG preference in nucleic acids binding. It also reveals that RRM2 domain has an atypical RRM-fold with an additional β-strand involved in making protein-protein interactions. This self association of RRM2 domains produced thermal-stable RRM2 assemblies with a melting point greater than 85°C as monitored by circular dichroism at physiological conditions. These studies thus characterize the recognition between TDP-43 and nucleic acids and the mode of RRM2 self association, and provide molecular models for understanding the role of TDP-43 in cystic fibrosis and the neurodegenerative diseases related to TDP-43 proteinopathy. © 2009 The Author(s).

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Redesign of high-affinity nonspecific nucleases with altered sequence preference

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Journal of the American Chemical Society 2009年第47期131卷 17345-17353页

作者： Wang, Yi-Ting Wright, Jon D. Doudeva, Lyudmila G. Jhang, Hua-Ci Lim, Carmay Yuan, Hanna S. Institute of Molecular Biology Academia Sinica Taipei Taiwan Institute of Biomedical Sciences Academia Sinica Taipei Taiwan Institute of Chemical Biology and Molecular Biophysics Taiwan International Graduate Program Academia Sinica Taipei Taiwan Institute of Bioinformatics and Structural Biology Department of Chemistry National Tsing Hua University HsinChu Taiwan Institute of Biochemistry and Molecular Biology National Taiwan University Taipei Taiwan

It is of crucial importance to elucidate the underlying principles that govern the binding affinity and selectivity between proteins and DNA. Here we use the nuclease domain of Colicin E7 (nColE7) as a model system to generate redesigned nucleases with improved DNA-binding affinities. ColE7 is a bacterial toxin, bearing a nonspecific endonuclease domain with a preference for hydrolyzing DNA phosphodiester bonds at the 3O-side after thymine and adenine;i.e., it prefers Thy and Ade at the -1 site. Using systematic computational screening, six nColE7 mutants were predicted to bind DNA with high affinity. Five of the redesigned single-point mutants were constructed and purified, and four mutants had a 3- to 5-fold higher DNA binding affinity than wild-type nColE7 as measured by fluorescence kinetic assays. Moreover, three of the designed mutants, D493N, D493Q, and D493R, digested DNA with an increased preference for guanine at +3 sites compared to the wild-type enzyme, as shown by DNA footprint assays. X-ray structure determination of the ColE7 mutant D493Q-DNA complex in conjunction with structural and free energy decomposition analyses provides a physical basis for the improved protein-DNA interactions: Replacing D493 at the protein-DNA interface with an amino acid residue that can maintain the native hydrogen bonds removes the unfavorable electrostatic repulsion between the negatively charged carboxylate and DNA phosphate groups. These results show that computational screening combined with biochemical, structural, and free energy analyses provide a useful means for generating redesigned nucleases with a higher DNA-binding affinity and altered sequence preferences in DNA cleavage. © 2009 American Chemical Society.

关键词： DNA

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structural insights into TDP-43, a new player in neurodegenerative diseases

Structural insights into TDP-43, a new player in neurodegene...

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亚洲晶体学联合大会

作者： Pan-Hsien Kuo Lyudmila G.Doudeva Che-Kun James Shen Hanna S.Yuan Institute of Bioinformatics and Structural Biology National Tsing Hua University Institute of Molecular Biology Academia Sinica Taiwan International Graduate Program Chemical Biology and Molecular BiophysicsAcademia Sinica Graduate Institute of Biochemistry and Molecular Biology National Taiwan University

关键词： TDP RNA domain structural insights into TDP-43 a new player in neurodegenerative diseases

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Dual functions of an exosome component protein Rrp46/CRN-5 in RNA degradation and DNA fragmentation

Dual functions of an exosome component protein Rrp46/CRN-5 i...

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亚洲晶体学联合大会

作者： Yu-Yuan Hsiao Lyudmila G.Doudeva Hanna S.Yuan Institute of Molecular Biology Academia Sinica Institute of Bioinformatics and Structural Biology National Tsing Hua University Graduate Institute of Biochemistry and Molecular Biology National Taiwan University Taiwan Institute of Chemical Biology and Molecular Biophysics Taiwan International Graduate ProgramAcademia Sinica

Rrp46 is one of the RNase PH family proteins, first identified as a component protein of the eukaryotic exosome, a protein complex involved in RNA turnover, surveillance and processing. The Rrp46 homolog, CRN-5, was s... 详细信息

关键词： DNase Dual functions of an exosome component protein Rrp46/CRN-5 in RNA degradation and DNA fragmentation DNA exosome RNA

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structural basis of inhibition specificities of 3C and 3C-like proteases by zinc-coordinating and peptidomimetic compounds

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Journal of Biological Chemistry 2009年第12期284卷 7646-7655页

作者： Lee, Cheng-Chung Kuo, Chih-Jung Ko, Tzu-Ping Hsu, Min-Feng Tsui, Yao-Chen Chang, Shih-Cheng Yang, Syaulan Chen, Shu-Jen Chen, Hua-Chien Hsu, Ming-Chu Shih, Shin-Ru Liang, Po-Huang Wang, Andrew H.-J. Structural Biology Program Institute of Biochemistry and Molecular Biology National Yang-Ming University Taipei 11221 Taiwan Institute of Biological Chemistry Academia Sinica Taipei 11529 Taiwan National Core Facility of High-Throughput Protein Crystallography Academia Sinica Taipei 11529 Taiwan Taiwan International Graduate Program Academia Sinica Taipei 11529 Taiwan Institute of Biochemical Sciences National Taiwan University Taipei 10617 Taiwan Department of Medical Biotechnology and Laboratory Science Chang Gung University Tao-Yuan 333 Taiwan Clinical Virology Laboratory Department of Clinical Pathology Chang Gung Memorial Hospital Tao-Yuan 333 Taiwan TaiGen Biotechnology Taipei 114 Taiwan

Human coxsackievirus (CV) belongs to the picornavirus family, which consists of over 200 medically relevant viruses. In picornavirus, a chymotrypsin-like protease (3Cpro) is required for viral replication by processing the polyproteins, and thus it is regarded as an antiviral drug target. A 3C-like protease (3CLpro) also exists in human coronaviruses (CoV) such as 229E and the one causing severe acute respiratory syndrome (SARS). To combat SARS, we previously had developed peptidomimetic and zinc-coordinating inhibitors of 3CLpro. As shown in the present study, some of these compounds were also found to be active against 3Cpro of CV strain B3 (CVB3). Several crystal structures of 3Cpro from CVB3 and 3CLpro from CoV-229E and SARS-CoV in complex with the inhibitors were solved. The zinc-coordinating inhibitor is tetrahedrally coordinated to the His40-Cys147 catalytic dyad of CVB3 3Cpro. The presence of specific binding pockets for the residues of peptidomimetic inhibitors explains the binding specificity. Our results provide a structural basis for inhibitor optimization and development of potential drugs for antiviral therapies. © 2009 by The American Society for biochemistry and Molecular biology, Inc.

关键词： Zinc compounds

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ϕ-Value Analysis for Ultrafast Folding Proteins by NMR Relaxation Dispersion

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Journal of the American Chemical Society 2009年第2期132卷 450-451页

作者： Jae-Hyun Cho Nichole O’Connell Daniel P. Raleigh Arthur G. Palmer, III Department of Biochemistry and Molecular Biophysics Columbia University 630 West 168th Street New York New York 10032 and Department of Chemistry and Graduate Program in Biochemistry and Structural Biology State University of New York at Stony Brook Stony Brook New York 11794

Proteins that fold rapidly, on the (sub-) microsecond time scale, offer the prospect of direct comparison between experimental data and molecular dynamics simulations. However, experimental studies for such proteins frequently are hindered because folding rates are too fast to measure using conventional stopped-flow methods. To overcome this impediment, NMR spin relaxation dispersion experiments are used to quantify mutational effects on kinetics (ΔΔG°), stability (ΔΔG°), and ϕ-values (ΔΔG†/ΔΔG°) for proteins exhibiting chemical exchange line broadening that is fast on the NMR chemical shift time scale. The accuracy of ϕ-value analysis is enhanced because mutational effects on denatured or intermediate states can be detected through changes in line broadening. The transition and intermediate states of the villin headpiece domain, HP67, are characterized in varying solvent conditions to validate the method.

关键词： Kinetic parameters Genetics Colloids Quantum mechanics Nuclear magnetic resonance spectroscopy

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Glycans on influenza hemagglutinin affect receptor binding and immune response

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Proceedings of the National Academy of Sciences of the United States of America 2009年第43期106卷 18137-18142页

作者： Wang, Cheng-Chi Chen, Juine-Ruey Tseng, Yung-Chieh Hsu, Che-Hsiung Hung, Yu-Fu Chen, Shih-Wei Chen, Chin-Mei Khoo, Kay-Hooi Cheng, Ting-Jen Cheng, Yih-Shyun E. Jan, Jia-Tsrong Wu, Chung-Yi Ma, Che Wong, Chi-Huey Genomics Research Center Taipei 115 Taiwan Institute of Biochemical Sciences National Taiwan University Taipei 106 Taiwan Institute of Biochemistry and Molecular Biology National Yang-Ming University Taipei 112 Taiwan Chemical Biology and Molecular Biophysics Taiwan International Graduate Program Taipei 115 Taiwan Institute of Bioinformatics and Structural Biology National Tsing Hua University Hsinchu 300 Taiwan Institute of Biological Chemistry Academia Sinica Taipei 115 Taiwan

Recent cases of avian influenza H5N1 and the swine-origin 2009 H1N1 have caused a great concern that a global disaster like the 1918 influenza pandemic may occur again. Viral transmission begins with a critical interaction between hemagglutinin (HA) glycoprotein, which is on the viral coat of influenza, and sialic acid (SA) containing glycans, which are on the host cell surface. To elucidate the role of HA glycosylation in this important interaction, various defined HA glycoforms were prepared, and their binding affinity and specificity were studied by using a synthetic SA microarray. Truncation of the N-glycan structures on HA increased SA binding affinities while decreasing specificity toward disparate SA ligands. The contribution of each monosaccharide and sulfate group within SA ligand structures to HA binding energy was quantitatively dissected. It was found that the sulfate group adds nearly 100-fold (2.04 kcal/mol) in binding energy to fully glycosylated HA, and so does the biantennary glycan to the monoglycosylated HA glycoform. Antibodies raised against HA protein bearing only a single N-linked GlcNAc at each glycosylation site showed better binding affinity and neutralization activity against influenza subtypes than the fully glycosylated HAs elicited. Thus, removal of structurally nonessential glycans on viral surface glycoproteins may be a very effective and general approach for vaccine design against influenza and other human viruses.

关键词： Flu vaccine Glycan binding Glycosylation

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