TP Atlas: integration and dissemination of advances in Targeted Proteins Research Program (TPRP)—structural biology project phase II in Japan
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The Targeted Proteins Research Program (TPRP) promoted by the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan is the phase II of structural biology project (2007–2011) following the Protein 3000 Project (2002–2006) in Japan. While the phase I Protein 3000 Project put partial emphasis on the construction and maintenance of pipelines for structural analyses, the TPRP is dedicated to revealing the structures and functions of the targeted proteins that have great importance in both basic research and industrial applications. To pursue this objective, 35 Targeted Proteins (TP) Projects selected in the three areas of fundamental biology, medicine and pharmacology, and food and environment are tightly collaborated with 10 Advanced Technology (AT) Projects in the four fields of protein production, structural analyses, chemical library and screening, and information platform. Here, the outlines and achievements of the 35 TP Projects are summarized in the system named TP Atlas. Progress in the diversified areas is described in the modules of Graphical Summary, General Summary, Tabular Summary, and Structure Gallery of the TP Atlas in the standard and unified format. Advances in TP Projects owing to novel technologies stemmed from AT Projects and collaborative research among TP Projects are illustrated as a hallmark of the Program. The TP Atlas can be accessed at http://net.genes.nig.ac.jp/tpatlas/index_e.html.
KeywordsStructural biology National project Research dissemination Targeted Proteins Research Program Protein 3000 Project
Structural biology that seeks to describe the 3-dimensional structures of proteins in correlation with their functions not only serves as the basis for life science research, but also plays a vital role in industrial applications as exemplified in drug developments. Several structural biology projects such as Protein Structure Initiative (http://www.sbkb.org/) and Structural Genomics Consortium (http://www.thesgc.org/about/) are pursuing structures of proteins on a genome wide scale in USA and Europe. In Japan, “National Project on Protein Structural and Functional Analyses” (2002–2006, commonly called “Protein 3000 Project”) funded by the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan contributed to achieve advances in structural biology and to establish the three dedicated centers for structural biology at SPring-8 (http://www.spring8.or.jp/en/), Photon Factory (http://pfwww.kek.jp/index.html), and RIKEN (RIKEN NMR Facility(http://www.ynmr.riken.jp/en/home.html)).
Targeted Proteins Research Program (TPRP, http://www.tanpaku.org/e_index.php) promoted by MEXT, the phase II of structural biology project following the Protein 3000 Project (2002–2006) in Japan, started in 2007 with the five-year plan. By fully utilizing the knowledge and pipelines obtained in the Protein 3000 Project, the Program aims to reveal the structures and functions of the targeted proteins that have great importance in both basic research and industrial applications. To pursue this objective, 35 Targeted Proteins (TP) Projects selected in the three areas of fundamental biology, medicine and pharmacology, and food and environment are tightly collaborated with 10 Advanced Technology (AT) Projects in the four fields of protein production, structural analyses, chemical library and screening, and information platform. Collaboration, especially collaboration between structural analyses and functional analyses, is the key feature of the Program, since both the structural analyses of the selected target proteins guided by the functional information and the functional analyses based on the solved structures have been found to be mutually effective.
In the area of fundamental biology, researchers are embarking on 13 projects to elucidate a variety of biological systems and functions such as proteasome, autophagy and vesicular trafficking through the structural and functional analyses of key proteins involved. In the area of medicine and pharmacology, 10 projects are tackling target proteins and enzymes implicated in diverse diseases from metabolic syndromes to neglected diseases. In the area of food and environment, 12 projects are characterizing important proteins in bacteria, plants, insects, and rodents, which could lead to such beneficial products as antibiotics, modified enzymes and stress-tolerant crops.
Here, the information platform team in the AT Projects summarizes the outlines and achievements of the 35 TP Projects in the system named TP Atlas as part of the dissemination of TPRP. Progress in the diversified areas is described in the modules of Graphical Summary, General Summary, Tabular Summary, and Structure Gallery of the TP Atlas in the standard and unified format. Advances in TP Projects owing to novel technologies stemmed from AT Projects and collaborative research among TP Projects are illustrated as a hallmark of the Program. The TP Atlas can be accessed at http://net.genes.nig.ac.jp/tpatlas/index_e.html.
Outline of TP Atlas
The Graphical Summary for the TP Project of Keap1-Nrf stress sensor  was shown in Figure S1, while its entire TP Atlas was shown in Fig. 1 (http://net.genes.nig.ac.jp/networkDB/Ctrl?CI=FBB1&lang=en). The antioxidant response is important for the amelioration of oxidative stress. Nrf2-Keap1 system plays a significant physiological role in combating oxidative stress, thereby activating the body’s own protective response. Keap1 is an oxidative stress sensor protein and Nrf2 (Nfe2l2) is a master regulator of the antioxidant response. Under normal or unstressed conditions, Keap1 suppresses Nrf2 in the cytoplasm. Oxidative stress disrupts the suppression by Keap1, resulting in a build-up of Nrf2. Unbound Nrf2 is then able to translocate into the nucleus, where it will induce many cytoprotective genes including antioxidative enzymes and detoxication enzymes. This series of the cascade was drawn in the Graphical Summary (Figure S1) with 7 distinct molecules and 10 different processes. The meaning of each process icon can be referred by clicking the legend in the upper right of the graph (supplementary material, Figure S2). Each pathway graph can be zoomed in four steps.
As exemplified in the Figs. 1 and 2 (see also supplementary materials, Figures S1 and S3), a variety of intracellular and extracellular biological processes in the all 35 TP Projects ranging from signal transduction pathways to enzymatic reactions pathways were delineated in the unified format with such components as cell, entity and process of Cell Illustrator software. Since the Graphical Summary is described in the format of CSML (Cell System Markup Languages) (http://www.csml.org/), it can be downloaded as a CSML file for further editing and processing with Cell Illustrator.
TP Structural Gallery and P3000 Structure Gallery
Protein 3000 Structure Gallery (http://mdbpr4.genes.nig.ac.jp/p3k/index.html.en) is a comprehensive collection of structural data produced from “Protein 3000 Project” (2002–2006) (the preceding project of TPRP) funded by MEXT. The Information Platform team of TPRP produces and maintains the site since one of its missions is to disseminate information on TPRP and its related activities.
The outlines and achievements of 35 TP Projects in TPRP were summarized in the system TP Atlas as part of the dissemination of the National Program in Japan. Dissemination is a critical aspect of the mission of large national or international research projects. The post-audit committee of the “Protein 3000 Project” (2002–2006) (the preceding project of TPRP) pointed out the poor sharing and distribution of the Project output. One of the 6 main conclusions of the assessment panel of the Protein Structure Initiative in USA was the poor dissemination of the results (http://www.nigms.nih.gov/News/Reports/PSIAssessmentPanel2007.htm). TP Atlas is a part of efforts in response to the above-mentioned criticism and recommendation. Our emphasis has been put on how the progress in diversified areas could be summarized in the standard and unified format to enable intuitive appreciation for the broad scientific community.
Research advances in the diversified areas are uniformly depicted in the TP Atlas by utilizing both graphical and tabular formats. Figures (Graphical Summary) and plain sentences (Outline) at the entrance of the TP Atlas enable intuitive appreciation of each TP Project without any detailed knowledge of the subject. Cell Illustrator software is particularly suitable for the drawing of the Graphical Summary, since it provides with various icons to delineate diversified “unit processes” in cells. Since graphs in Cell Illustrator are described in the format of CSML (Cell System Markup Languages) (http://www.csml.org/) based on XML, users can download CSML files for further editing and processing.
Noteworthy advances in AT Projects are beamline developments for future synchrotron radiation protein crystallography including a new micro-beam beamline [6, 7, 8, 9] and the construction of public chemical library in Japan for open innovation in drug discovery (http://www.ocdd.u-tokyo.ac.jp/index_e.html). Among more than 350 structures solved in TPRP, worthy of special mention are successful structural analyses of membrane proteins [10, 11, 12, 13, 14, 15, 16], protein complex assemblies [17, 18, 19, 20, 21], proteins implicated in various diseases [22, 23, 24], and plant hormone receptors [25, 26, 27].
A typical example of collaborative research among TP Projects is the joint research led by Keiji Tanaka (Fundamental Biology A2: proteasome, TP Atlas: http://net.genes.nig.ac.jp/networkDB/Ctrl?CI=FBA2&lang=en) and Masayuki Yamamoto (Fundamental Biology B1: Keap1-Nrf2 sensor, TP Atlas: http://net.genes.nig.ac.jp/networkDB/Ctrl?CI=FBB1&lang=en). The joint team identified a novel regulatory mechanism by the selective autophagy substrate p62 of the transcription factor Nrf2 through inactivation of Keap1  (see Fig. 3). Advances in TP Projects owing to novel technologies stemmed from AT Projects have been remarkable as a hallmark of the Program. The TARGET tag technology developed by Junichi Takagi et al. [29, 30] in AT Projects (Fig. 7) has been the driving force for the successful structural analyses of two important proteins implicated in various diseases; namely, Semaphorin-Plexin Complex (Medicine and Pharmacology B4: semaphorins & their receptors, TP Atlas: http://net.genes.nig.ac.jp/networkDB/Ctrl?CI=MPB4&lang=en)  (see Fig. 6) and Autotaxin (Medicine and Pharmacology B3: ENPP family proteins, TP Atlas: http://net.genes.nig.ac.jp/networkDB/Ctrl?CI=MPB3&lang=en) . The structural information on Autotaxin has paved the way for the development of new inhibitors .
We thank Koji Suzuki of Hitachi Solutions, Ltd. and Hidemi Nishimura of Holonics, Ltd for their technical assistance. This work was supported by the Targeted Proteins Research Program (TPRP) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan.
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