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: 7594479
• 负责人: Aravind Iyer
• 金额: $ 30.01万
• 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/7594479
• 关键词: Active Sites; Activities of Daily Living; Adhesions; Amino Acid Sequence; Animals; Apicomplexa; Architecture; Ascomycota; Bacterial Adhesins; Beds; Binding; Biochemical; Biological; Biological Process; Biology; Cell membrane; Cells; Chromatin; Class; Classification; Code; Comparative Genomic Analysis; Complement; Complex; Cytoskeleton; DNA Binding Domain; Data; Development; Developmental Process; EGF gene; Elements; Entamoeba; Eukaryota; Eukaryotic Cell; Evolution; Family; Fever; Fingers; Gene Expression; Genes; Genetic Polymorphism; Genetic Transcription; Glutamate-Ammonia Ligase; Immune; Immune response; Individual; Invaded; Iron; Lateral; Ligands; Link; Lipids; Macromolecular Complexes; Membrane Proteins; Metabolism; Metals; Microscopic; Natural History; Nucleic Acids; Organelles; Organism; Parasites; Pathogenesis; Pathway interactions; Pattern; Peptide Sequence Determination; Phase; Phosphoribosyl-AMP cyclohydrolase; Phosphoric Monoester Hydrolases; Plants; Plasmodium; Play; Post-Translational Protein Processing; Prokaryotic Cells; Protein Export Pathway; Protein Family; Proteins; RNA; Range; Recording of previous events; Recruitment Activity; Role; Saccharomyces cerevisiae; Signal Transduction; Structure; Sulfur; Surface; System; Tertiary Protein Structure; Theileria; Time; Transposase; Ubiquitin; Variant; Yeasts; Zinc Fingers; base; beta pleated sheet; fasciclin; fungus; genome sequencing; glycosylation; grasp; leukocyte proliferation; macromolecular assembly; member; molybdenum cofactor; novel; parasitism; pressure; reconstruction; response; rhoptry; ribosomal protein L25; scaffold; transcription factor

1) Natural history and classification of the beta-grasp fold domains. The beta-grasp fold (beta-GF), prototyped by ubiquitin (UB), has been recruited for a strikingly diverse range of biochemical functions. These functions include providing a scaffold for different enzymatic active sites (e.g. NUDIX phosphohydrolases) and iron-sulfur clusters, RNA-soluble-ligand and co-factor-binding, sulfur transfer, adaptor functions in signaling, assembly of macromolecular complexes and post-translational protein modification. To understand the basis for the functional versatility of this small fold we undertook a comprehensive sequence-structure analysis of the fold and developed a natural classification for its members. As a result we were able to define the core distinguishing features of the fold and numerous elaborations, including several previously unrecognized variants. Systematic analysis of all known interactions of the fold showed that its manifold functional abilities arise primarily from the prominent beta-sheet, which provides an exposed surface for diverse interactions or additionally, by forming open barrel-like structures. We show that in the beta-GF both enzymatic activities and the binding of diverse co-factors (e.g. molybdopterin) have independently evolved on at least three occasions each, and iron-sulfur-cluster-binding on at least two independent occasions. Our analysis identified multiple previously unknown large monophyletic assemblages within the beta-GF, including one which unifies versions found in the fasciclin-1 superfamily, the ribosomal protein L25, the phosphoribosyl AMP cyclohydrolase (HisI) and glutamine synthetase. We also uncovered several new groups of beta-GF domains including a domain found in bacterial flagellar and fimbrial assembly components, and 5 new UB-like domains in the eukaryotes. Evolutionary reconstruction indicates that the beta-GF had differentiated into at least 7 distinct lineages by the time of the last universal common ancestor of all extant organisms, encompassing much of the structural diversity observed in extant versions of the fold. The earliest beta-GF members were probably involved in RNA metabolism and subsequently radiated into various functional niches. Most of the structural diversification occurred in the prokaryotes, whereas the eukaryotic phase was mainly marked by a specific expansion of the ubiquitin-like beta-GF members. The eukaryotic UB superfamily diversified into at least 67 distinct families, of which at least 19-20 families were already present in the eukaryotic common ancestor, including several protein and one lipid conjugated forms. Another key aspect of the eukaryotic phase of evolution of the beta-GF was the dramatic increase in domain architectural complexity of proteins related to the expansion of UB-like domains in numerous adaptor roles. 2) The natural history of the WRKY-GCM1 zinc fingers and the relationship between transcription factors and transposons. WRKY and GCM1 are metal chelating DNA-binding domains (DBD) which share a four stranded fold. Using sensitive sequence searches, we show that this WRKY-GCM1 fold is also shared by the FLYWCH Zn-finger domain and the DBDs of two classes of Mutator-like element (MULE) transposases. We present evidence that they share a stabilizing core, which suggests a possible origin from a BED finger-like intermediate that was in turn ultimately derived from a C2H2 Zn-finger domain. Through a systematic study of the phyletic pattern, we show that this WRKY-GCM1 superfamily is a widespread eukaryote-specific group of transcription factors (TFs). We identified several new members across diverse eukaryotic lineages, including potential TFs in animals, fungi and Entamoeba. By integrating sequence, structure, gene expression and transcriptional network data, we present evidence that at least two major global regulators belonging to this superfamily in Saccharomyces cerevisiae (Rcs1p and Aft2p) have evolved from transposons, and attained the status of transcription regulatory hubs in recent course of ascomycete yeast evolution. In plants, we show that the lineage-specific expansion of WRKY-GCM1 domain proteins acquired functional diversity mainly through expression divergence rather than by protein sequence divergence. We also use the WRKY-GCM1 superfamily as an example to illustrate the importance of transposons in the emergence of new TFs in different lineages. 3) Apicomplexan transcription factors. Apicomplexa have developed distinctive adaptations for invading and surviving within animal cells. Here a synthetic overview of the diversity and evolutionary history of cell membrane-associated, -secreted, and -exported proteins related to apicomplexan parasitism is presented. A notable feature in this regard was the early acquisition of adhesion protein domains and glycosylation systems through lateral transfer from animals. These were utilized in multiple contexts, including invasion of host cells and parasite-specific developmental processes. Apicomplexans possess a specialized version of the ancestral alveolate extrusion machinery, the rhoptries and micronemes, which are deployed in invasion and delivery of proteins into host cells. Each apicomplexan lineage has evolved a unique spectrum of extruded proteins that modify host molecules in diverse ways. Hematozoans, in particular, appear to have evolved novel systems for export of proteins into the host organelles and cell membrane during intracellular development. These exported proteins are an important aspect of the pathogenesis of Plasmodium and Theileria, being involved in response to fever and in leukocyte proliferation respectively. The complement of apicomplexan surface proteins has primarily diversified via massive lineage-specific expansions of certain protein families, which are often coded by subtelomeric gene arrays. Many of these families have been found to be central to immune evasion. Domain shuffling and accretion have resulted in adhesins with new domain architectures. In terms of individual genes, constant selective pressures from the host immune response has resulted in extensive protein polymorphisms and gene losses. Apicomplexans have also evolved complex regulatory mechanisms controlling expression and maturation of surface proteins at the chromatin, transcriptional, posttranscriptional, and posttranslational levels. Evolutionary reconstruction suggests that the ancestral apicomplexan had thrombospondin and EGF domain adhesins, which were linked to the parasite cytoskeleton, and played a central role in invasion through formation of the moving junction. It also suggests that the ancestral parasite had O-linked glycosylation of surface proteins which was partially or entirely lost in hematozoan lineages.

1）β-grasp折叠域的自然历史和分类。 β-抓握折叠 (beta-GF) 以泛素 (UB) 为原型，已被招募来实现极其多样化的生化功能。这些功能包括为不同的酶活性位点（例如 NUDIX 磷酸水解酶）和铁硫簇、RNA 可溶性配体和辅因子结合、硫转移、信号传导中的接头功能、大分子复合物的组装和翻译后提供支架。蛋白质修饰。为了了解这个小折叠功能多样性的基础，我们对折叠进行了全面的序列结构分析，并为其成员开发了一个自然分类。因此，我们能够定义折叠的核心区别特征和大量的阐述，包括几个以前未识别的变体。对折叠所有已知相互作用的系统分析表明，其多种功能能力主要来自突出的β-折叠，它为不同的相互作用提供了暴露的表面，或者另外通过形成开放的桶状结构。我们表明，在 β-GF 中，酶活性和不同辅助因子（例如钼蝶呤）的结合至少在三次独立进化，并且铁硫簇结合至少在两次独立进化。我们的分析鉴定了 β-GF 内多个先前未知的大型单系组合，其中包括在 fasciclin-1 超家族、核糖体蛋白 L25、磷酸核糖 AMP 环水解酶 (HisI) 和谷氨酰胺合成酶中发现的统一版本。我们还发现了几组新的 β-GF 结构域，包括在细菌鞭毛和菌毛组装成分中发现的结构域，以及真核生物中的 5 个新的 UB 样结构域。进化重建表明，到所有现存生物体的最后一个通用共同祖先出现时，β-GF 已分化为至少 7 个不同的谱系，涵盖了在现存的折叠版本中观察到的大部分结构多样性。最早的 β-GF 成员可能参与 RNA 代谢，并随后辐射到各种功能领域。大多数结构多样化发生在原核生物中，而真核阶段主要以泛素样β-GF成员的特异性扩增为标志。真核UB超家族分化为至少67个不同的家族，其中至少19-20个家族已经存在于真核共同祖先中，包括几种蛋白质和一种脂质缀合形式。 β-GF 真核进化阶段的另一个关键方面是与许多接头角色中 UB 样结构域的扩展相关的蛋白质结构域复杂性的急剧增加。 2）WRKY-GCM1锌指的自然历史以及转录因子和转座子之间的关系。 WRKY 和 GCM1 是金属螯合 DNA 结合结构域 (DBD)，它们共享四链折叠。通过灵敏的序列搜索，我们发现 FLYWCH 锌指结构域和两类类突变元件 (MULE) 转座酶的 DBD 也共享这种 WRKY-GCM1 折叠。我们提供的证据表明它们共享一个稳定核心，这表明可能起源于 BED 指状中间体，而该中间体最终又衍生自 C2H2 锌指结构域。通过对系统发育模式的系统研究，我们表明 WRKY-GCM1 超家族是广泛存在的真核生物特异性转录因子 (TF) 组。我们在不同的真核生物谱系中鉴定了几个新成员，包括动物、真菌和内阿米巴中的潜在转录因子。通过整合序列、结构、基因表达和转录网络数据，我们提供了证据表明，酿酒酵母中至少有两个属于该超家族的主要全局调控因子（Rcs1p和Aft2p）是从转座子进化而来的，并在最近获得了转录调控中心的地位。子囊菌酵母的进化过程。在植物中，我们发现 WRKY-GCM1 结构域蛋白的谱系特异性扩展主要通过表达差异而不是蛋白质序列差异获得功能多样性。我们还以WRKY-GCM1超家族为例来说明转座子在不同谱系中新转录因子出现中的重要性。 3) 顶复体转录因子。 顶复门已经发展出独特的适应能力来入侵动物细胞并在其中生存。这里对与顶端复门寄生相关的细胞膜相关、分泌和输出蛋白质的多样性和进化历史进行了综合概述。这方面的一个显着特征是通过动物横向转移早期获得粘附蛋白结构域和糖基化系统。这些被用于多种情况，包括宿主细胞的入侵和寄生虫特异性的发育过程。顶复门拥有一种特殊版本的祖先肺泡挤出机制，即棒状体和微线体，它们用于入侵和将蛋白质递送到宿主细胞中。每个顶端复合体谱系都进化出了一系列独特的挤压蛋白质，它们以不同的方式修饰宿主分子。尤其是血液动物，似乎已经进化出了在细胞内发育过程中将蛋白质输出到宿主细胞器和细胞膜中的新系统。这些输出的蛋白质是疟原虫和泰勒虫发病机制的一个重要方面，分别参与发烧反应和白细胞增殖。顶端复合体表面蛋白的补充主要通过某些蛋白质家族的大规模谱系特异性扩展而多样化，这些蛋白质家族通常由亚端粒基因阵列编码。其中许多家族被发现是免疫逃避的核心。域改组和增生导致粘附素具有新的域结构。就个体基因而言，来自宿主免疫反应的持续选择压力导致了广泛的蛋白质多态性和基因丢失。顶复门还进化出了复杂的调节机制，在染色质、转录、转录后和翻译后水平上控制表面蛋白的表达和成熟。进化重建表明，祖先的顶端复合体具有血小板反应蛋白和EGF结构域粘附素，它们与寄生虫细胞骨架相连，并通过形成移动连接在入侵中发挥核心作用。它还表明，祖先寄生虫具有表面蛋白的O-连接糖基化，而这种糖基化在血液动物谱系中部分或完全丢失。