Grand Project of Protein Research, 5th of September 2002
-Three thousand kinds of proteins in 5 years-
We have already introduced research on the structure and the function of intracellular carrier proteins several times. Genetic information recorded to human genes producing proteins have almost been clarified in the Human Genome Project under international cooperation. The next important step is to find out about the structure and the function of proteins made from the genetic information. For this, the elucidation of vital phenomenon will advance and it will become possible to find effective means of treating diseases. In the U.S.A. or Europe, national projects of protein research have started following the Human Genome Project. In Japan, the national project "Protein 3000 Project", in which KEK is participating, was launched this summer. Today, we will introduce KEK's plan.

Protein 3000 Project
The purpose of this project is to analyze the structure and function of 3000 or more kinds of proteins for 5 years. It is thought that the analysis of about 10,000 kinds of proteins is necessary to learn the basic structure and function of proteins. This project aims to analyze more than a third of the requirement, to obtain the rights by patenting, and to develop the drugs through making full use of genetic information (genome medicine).

The organizations at the core for the project are Riken Institute of Physical and Chemical Research (Riken), High Energy Accelerator Research Organization (KEK, PF), Hokkaido University, The University of Tokyo, Yokohama City University, Kyoto University, Osaka University, as shown in Figure 1.

There are 2 programs that pursue the analysis. One is the comprehensive structural and functional analysis of the basic structure of 2500 or more kinds of proteins using a large scale and rapid method proceeded by RIKEN as the leader. The other consists of individual programs to handle a total 500 kinds of proteins through the structural and functional analysis according to 7 themes, focusing on the variety of the structure and function of protein, with other institutes as leaders. Here, we will explain the structural and functional analysis of protein, one of the individual programs, performed by Professor Soichi Wakatsuki's group in the Institute of Materials Structure Science that has KEK as the leader. The researchers state that the most noteworthy themes in this project are the intracellular transportation and posttranslational modification (Figure 2). Both are vital roles that proteins play to maintain our living activity.

What is intracellular transportation?
As described before, proteins that are essential for maintaining the life activities within the cells of which our bodies are comprised, are transported to cell membranes or a destination outside cells through the organelles in cells. Substances as a transport signal are put on the protein and transported as cargo for accurate transportation to the destination. There are many hereditary diseases caused by the lack of normal structure or function of the protein that regulates such transportation. Accurate supply of protein to necessary places in the body is indispensable for life activities. Thus, understanding the function of carrier protein is crucial research in aspects of both basic biology and medicine.

What is post-translational modification?
Some people might be unfamiliar with this specific term. Proteins are made from genetic information recorded in genes and the production of specific protein from the information starts from reading out the sequence of amino acids, which is the material of protein. The process by which an amino acid sequence is read out from genetic information recorded to the gene, and protein is created, is called translation. An expression marked on gene information is translated and is changed into an expression written in amino acid. Proteins are created after this translation but it is not sufficient. Post-translational protein is still immature so that it prepares accessories for the job to become full-fledged and start to act (Figure 3). This process is called modification. Modification means decoration or restriction. Modification of protein indicates that protein is equipped with the material and tools to play a limited role. The protein of KEK's research, which is the structural and functional analysis of protein on the theme of post-translational modification, is equipped with sugar chains. Sugar chains are substances that sugar, such as glucose or fructose, links together to form a chain. Sugar chains on the surface of proteins confer important roles, such as the "label," which indicates the type of protein, "connector," which joints proteins to each other, and "sign," which helps to distinguish the type of cell, on proteins. Since most proteins exert their functions when they are equipped with sugar chains, the elucidation of the structure and the function of the sugar chains bound to protein are critical themes in protein research.

KEK's role
Proteins equipped with sugar chains also closely relate to intracellular protein transport. The analysis that both research fields are mutually complemented is expected to develop rapidly in these research fields. As introduced before, the synchrotron radiation facility in KEK has shown great activity in performing the X-ray structural analysis of protein. We plan to use this facility for the program "Protein 3000 Project" and the researchers who jointly use this facility will also participate in this program (Figures 1 and 4). We will continue to introduce this program targeted to carry out the structural and functional analysis of 70 kinds of proteins in the next 5 years, according to the results that will be obtained.

Figure 1-1
Protein 3000 Project is the national project that aims to promote research such as the structural and functional analysis of approximately 3000 or more kinds of proteins and patenting the results obtained in the 5 years from FY 2000. The project is generally divided into the comprehensive analysis program (by RIKEN) and the individual analysis program (by institutes such as universities). The former will carry out the structural and functional analysis of 2500 kinds of proteins and the latter 500 kinds.

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Figure 1-2
Organizations that participate Protein 3000 Project
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Figure 2
Among the individual programs, the Structural Biology Group of KEK, PF was selected as the core institute for the research themes such as the posttranslational modification and transport. The group will perform the structural and functional analysis of proteins involved in these research themes, collaborating with other research institutes.
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Figure 3
Proteins after translations from genes are still immature and need various modifications such as the glycosylation before they obtain their finished form. Moreover, in the process, proteins need to be transported to various intracellular organelles or outside the cells by intracellular transport. Thus, posttranslational modification and intracellular are closely related to each other.
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Figure 4
This is an example of technology development by the Structural Biology Group of KEK, PF as a leader aiming at high utilization and convenience of the researchers who jointly use the facility.
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