Evolutionary Analysis and Comparative Genomics of Protein Superfamilies

蛋白质超家族的进化分析和比较基因组学

• 批准号: 8558127
• 负责人: Aravind Iyer
• 金额: $ 130.15万
• 依托单位: NATIONAL LIBRARY OF MEDICINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8558127
• 关键词: ATP phosphohydrolase; Adenosine Diphosphate Ribose; Adopted; Algae; Animals; Area; Bacteria; Bacterial Proteins; Bacterial Toxins; Biological; Biological Process; Biology; C-terminal; Caenorhabditis; Catalytic Domain; Cells; Chromatin; Classification; Comb animal structure; Comparative Genomic Analysis; Complex; Computing Methodologies; Consult; Contractor; DNA; DNA Binding; DNA Binding Domain; DNA Repair; DNA Restriction Enzymes; DNA glycosylase; DNA-Directed RNA Polymerase; Data; Deaminase; Demography; Drosophila genus; Elements; Enzymatic Biochemistry; Epigenetic Process; Eukaryota; Evolution; Functional RNA; Future; General Transcription Factors; Genes; Genetic Transcription; Genome; Gram-Positive Bacteria; Helix-Turn-Helix Motifs; Histone H3; Homologous Gene; Human; ISWI; Journals; Life; Light; Lysine; Manuscripts; Mediating; Mediator of activation protein; Messenger RNA; Metabolism; Methods; Microscopic; Modification; Molecular; Monograph; Mutation; Myeloid Leukemia; N-terminal; Nucleic Acids; Nucleotide Deaminases; Nucleotides; Opitz syndrome; Orthologous Gene; PHD Finger; Pathologic Mutagenesis; Pathway interactions; Peer Review; Peptide Hydrolases; Plant Proteins; Play; Polycomb; Portraits; Postdoctoral Fellow; Property; Proteins; Proteome; Publications; Publishing; RNA; RNA Interference; RNA-Directed RNA Polymerase; Recruitment Activity; Research; Research Project Grants; Role; SWI2/SNF2; Science; Scientist; Sequence Analysis; Sigma Factor; Signal Transduction; Staging; Structure; System; Taxonomy; Tertiary Protein Structure; Toxin; Transcription Factor TFIIB; Transcriptional Regulation; Transfer RNA; Virus; Winged Helix; Work; Yeasts; base; chromatin protein; comparative genomics; developmental disease; extracellular; genome sequencing; interest; link protein; novel; pathogen; plant fungi; programs; protein complex; protein structure function; sensor; sex; transcription factor; trend

Dr. Aravind has an ongoing interest in using computational methods to decipher various aspects of protein structure, function and evolution. During 2012, Dr. Aravind demonstrated exceptional progress and effective planning and execution of several major research projects along these lines. These research projects cover the areas of molecular enzymology, signal transduction and transcriptional regulation mechanisms using computational methods. His group comprising of 1 staff scientist, 3 post-doctoral fellows and one contractor has over 10 publications in peer-reviewed publications in top scientific journals. He also published a comprehensive monograph on signal sensor domains in bacteria, which is recognized as a major work in this field. In this period, Dr. Aravind was also consulted to serve as a referee for several manuscripts submitted to the journals Science, Cell, Genome Research, JMB and Nucleic Acids Research, Genome Biology. He was an invited to speaker at three venues in course of the year. Some highlights of Dr. Aravinds 2012 research program include the following: Dr Aravind and his team provided a portrait of the bacterial transcription apparatus in light of the data emerging from structural studies, sequence analysis and comparative genomics to bring out important but underappreciated features. They described the key structural highlights and evolutionary implications emerging from comparison of the cellular RNA polymerase subunits with the RNA-dependent RNA polymerase involved in RNAi in eukaryotes and their homologs from newly identified bacterial selfish elements. They described some previously unnoticed domains and the possible evolutionary stages leading to the RNA polymerases of extant life forms. They then presented the case for the ancient orthology of the basal transcription factors, the sigma factor and TFIIB, in the bacterial and the archaeo-eukaryotic lineages. They also presented a synopsis of the structural and architectural taxonomy of specific transcription factors and their genome-scale demography. In this context, they presented certain notable deviations from the otherwise invariant proteome-wide trends in transcription factor distribution and used it to predict the presence of an unusual lineage-specifically expanded signaling system in certain firmicutes like Paenibacillus. They then discussed the intersection between functional properties of transcription factors and the organization of transcriptional networks. Finally, they presented some of the interesting evolutionary conundrums posed by the newly gained understanding of the bacterial transcription apparatus and potential areas for future explorations. Human ASXL proteins, orthologs of Drosophila Additional Sex combs, have been implicated in conjunction with TET2 as a major target for mutations and translocations leading to a wide range of myeloid leukemias, related myelodysplastic conditions (ASXL1 and ASXL2) and the Bohring-Opitz syndrome, a developmental disorder (ASXL1). Using sensitive sequence and structure comparison methods, Dr Aravind and his team showed that most animal ASXL proteins contain a novel N-terminal domain that is also found in several other eukaryotic chromatin proteins, diverse restriction endonucleases and DNA glycosylases, the RNA polymerase delta subunit of Gram-positive bacteria and certain bacterial proteins that combine features of the RNA polymerase α-subunit and sigma factors. This domain adopts the winged helix-turn-helix fold and is predicted to bind DNA. Based on its domain architectural contexts, they presented evidence that this domain might play an important role, both in eukaryotes and bacteria, in the recruitment of diverse effector activities, including the Polycomb repressive complexes, to DNA, depending on the state of epigenetic modifications such as 5-methylcytosine and its oxidized derivatives. In other eukaryotic chromatin proteins, this predicted DNA-binding domain is fused to a region with three conserved motifs that are also found in diverse eukaryotic chromatin proteins, such as the animal BAZ/WAL proteins, plant HB1 and MBD9, yeast Itc1p and Ioc3, RSF1, CECR2 and NURF1. Based on the crystal structure of Ioc3, they established that these motifs in conjunction with the DDT motif constitute a structural determinant that is central to nucleosomal repositioning by the ISWI clade of SWI2/SNF2 ATPases. they also showed that the central domain of the ASXL proteins (ASXH domain) is conserved outside of animals in fungi and plants, where it is combined with other domains, suggesting that it might be an ancient module mediating interactions between chromatin-linked protein complexes and transcription factors via its conserved LXLL motif. They presented evidence that the C-terminal PHD finger of ASXL protein has certain peculiar structural modifications that might allow it to recognize internal modified lysines other than those from the N terminus of histone H3, making it the mediator of previously unexpected interactions in chromatin. The deaminase-like fold includes, in addition to nucleic acid/nucleotide deaminases, several catalytic domains such as the JAB domain, and others involved in nucleotide and ADP-ribose metabolism. Using sensitive sequence and structural comparison methods, Dr. Aravind and his team developed a comprehensive natural classification of the deaminase-like fold and show that its ancestral version was likely to operate on nucleotides or nucleic acids. Consequently, they presented evidence that a specific group of JAB domains are likely to possess a DNA repair function, distinct from the previously known deubiquitinating peptidase activity. They also identified numerous previously unknown clades of nucleic acid deaminases. Using inference based on contextual information, they suggested that most of these clades are toxin domains of two distinct classes of bacterial toxin systems, namely polymorphic toxins implicated in bacterial interstrain competition and those that target distantly related cells. Genome context information suggests that these toxins might be delivered via diverse secretory systems, such as Type V, Type VI, PVC and a novel PrsW-like intramembrane peptidase-dependent mechanism. They proposed that certain deaminase toxins might be deployed by diverse extracellular and intracellular pathogens as also endosymbionts as effectors targeting nucleic acids of host cells. Their analysis suggested that these toxin deaminases have been acquired by eukaryotes on several independent occasions and recruited as organellar or nucleo-cytoplasmic RNA modifiers, operating on tRNAs, mRNAs and short non-coding RNAs, and also as mutators of hyper-variable genes, viruses and selfish elements. This scenario potentially explains the origin of mutagenic AID/APOBEC-like deaminases, including novel versions from Caenorhabditis, Nematostella and diverse algae and a large class of fast-evolving fungal deaminases. These observations greatly expand the distribution of possible unidentified mutagenic processes catalyzed by nucleic acid deaminases.

Aravind 博士一直对使用计算方法破译蛋白质结构、功能和进化的各个方面感兴趣。 2012 年期间，Aravind 博士在几个重大研究项目中取得了非凡的进展以及有效的规划和执行。这些研究项目涵盖使用计算方法的分子酶学、信号转导和转录调控机制领域。他的团队由 1 名科学家、3 名博士后研究员和 1 名承包商组成，在顶级科学期刊的同行评审出版物上发表了 10 多篇论文。他还出版了一本关于细菌信号传感器领域的综合专着，被认为是该领域的重要著作。在此期间，Aravind博士还受邀担任投稿至《Science》、《Cell》、《Genome Research》、《JMB》和《Nucleic Acids Research》、《Genome Biology》等期刊的多篇稿件的审稿人。 年内，他受邀在三个场馆发表演讲。 Aravinds 博士 2012 年研究计划的一些亮点包括： Aravind 博士和他的团队根据结构研究、序列分析和比较基因组学中出现的数据提供了细菌转录装置的肖像，以揭示重要但未被充分认识的特征。他们描述了细胞 RNA 聚合酶亚基与参与真核生物 RNAi 的 RNA 依赖性 RNA 聚合酶及其来自新鉴定的细菌自私元件的同源物的比较中出现的关键结构亮点和进化意义。他们描述了一些以前未被注意到的结构域以及导致现存生命形式的RNA聚合酶的可能的进化阶段。然后，他们提出了细菌和古真核细胞谱系中基础转录因子、西格玛因子和 TFIIB 的古代直系同源的案例。他们还概述了特定转录因子的结构和体系结构分类学及其基因组规模的人口统计学。在这种情况下，他们提出了转录因子分布中与其他不变的蛋白质组范围趋势的某些显着偏差，并用它来预测某些厚壁菌门（如类芽孢杆菌）中是否存在不寻常的谱系特异性扩展信号系统。然后他们讨论了转录因子的功能特性和转录网络的组织之间的交叉点。最后，他们提出了一些有趣的进化难题，这些难题是由对细菌转录装置的新了解和未来探索的潜在领域所提出的。 人类 ASXL 蛋白是果蝇附加性梳的直系同源物，与 TET2 一起作为突变和易位的主要靶点，导致多种骨髓性白血病、相关骨髓增生异常性疾病（ASXL1 和 ASXL2）以及 Bohring-Opitz 综合征（一种发育障碍）（ASXL1）。 Aravind 博士和他的团队使用灵敏的序列和结构比较方法表明，大多数动物 ASXL 蛋白都含有一个新的 N 末端结构域，该结构域也存在于其他几种真核染色质蛋白、多种限制性内切酶和 DNA 糖基化酶、革兰氏阳性细菌的 RNA 聚合酶 δ 亚基以及结合了 RNA 聚合酶特征的某些细菌蛋白中。 α-亚基和西格玛因子。该结构域采用翼状螺旋-转角-螺旋折叠，预计可结合 DNA。基于其结构域结构背景，他们提出了证据，表明该结构域可能在真核生物和细菌中发挥重要作用，在向 DNA 招募多种效应子活性（包括 Polycomb 抑制复合物）方面发挥着重要作用，具体取决于表观遗传修饰（如 5-甲基胞嘧啶及其氧化衍生物）的状态。在其他真核染色质蛋白中，这种预测的 DNA 结合结构域融合到具有三个保守基序的区域，这些基序也存在于多种真核染色质蛋白中，例如动物 BAZ/WAL 蛋白、植物 HB1 和 MBD9、酵母 Itc1p 和 Ioc3、RSF1、CEC​​R2 和 NURF1。基于 Ioc3 的晶体结构，他们确定这些基序与 DDT 基序一起构成了结构决定簇，该结构决定簇对于 SWI2/SNF2 ATP 酶的 ISWI 分支进行核小体重新定位至关重要。他们还表明，ASXL 蛋白的中心结构域（ASXH 结构域）在动物体外的真菌和植物中是保守的，它与其他结构域结合，表明它可能是一个古老的模块，通过其保守的 LXLL 基序介导染色质连接蛋白复合物和转录因子之间的相互作用。他们提出的证据表明，ASXL 蛋白的 C 端 PHD 指具有某些特殊的结构修饰，可能使其能够识别组蛋白 H3 N 端以外的内部修饰赖氨酸，从而使其成为染色质中先前意想不到的相互作用的介体。 除了核酸/核苷酸脱氨酶之外，脱氨酶样折叠还包括几个催化结构域，例如JAB结构域，以及参与核苷酸和ADP-核糖代谢的其他结构域。 Aravind 博士和他的团队利用灵敏的序列和结构比较方法，开发了一种脱氨酶样折叠的全面自然分类，并表明其祖先版本可能对核苷酸或核酸起作用。因此，他们提出的证据表明，一组特定的 JAB 结构域可能具有 DNA 修复功能，与之前已知的去泛素化肽酶活性不同。他们还鉴定了许多以前未知的核酸脱氨酶进化枝。利用基于上下文信息的推论，他们认为这些进化枝中的大多数是两类不同细菌毒素系统的毒素域，即涉及细菌株间竞争的多态性毒素和针对远亲细胞的毒素。基因组背景信息表明，这些毒素可能通过不同的分泌系统传递，例如 V 型、VI 型、PVC 和一种新型的类似 PrsW 的膜内肽酶依赖性机制。他们提出，某些脱氨酶毒素可能被多种细胞外和细胞内病原体以及内共生体利用，作为靶向宿主细胞核酸的效应物。他们的分析表明，这些毒素脱氨酶已在多个独立的场合被真核生物获得，并被招募为细胞器或核细胞质 RNA 修饰剂，作用于 tRNA、mRNA 和短非编码 RNA，也作为高变基因、病毒和自私元素的突变体。这种情况可能解释了诱变 AID/APOBEC 类脱氨酶的起源，包括来自秀丽隐杆线虫、线虫和多种藻类的新版本以及一大类快速进化的真菌脱氨酶。这些观察结果极大地扩展了由核酸脱氨酶催化的可能的未识别诱变过程的分布。