2010 | Press Release
Clarification of the molecular shape of oxidative stress sensors in the body - Toward prevention and treatment of lifestyle-related diseases by understanding the biological defense mechanism -
A research group led by Professor Masayuki Yamamoto, Senior Assistant Professor Hirofumi Kurokawa at Tohoku University Graduate School of Medicine, and Researcher and Group Leader Chikara Sato at Neuroscience Research Institute, National Institute of ADVANCED INDSUTRIAL SCIENCE AND TECHNOLOGY (AIST) has clarified that Keap1, a sensor molecule of oxidative stresses, is in a cherry-like shape with two spheres. The research results are expected to help understanding the biological defense mechanism at the molecular level, and to help developing a new prevention and treatment strategies for cancer and lifestyle-related diseases.
The achievement published online before print in Proceeding of the National Academy of Science of the USA. The paper’s title is “Keap1 is a forked-stem dimer structure with two large spheres enclosing the intervening, double glycine repeat, and C-terminal domains”.
Our body is consistently exposed to oxidative stresses that have gathered attention as pathogenesis of diseases such as cancer, arteriosclerosis and diabetes. Under oxidative stresses, molecular sensor Keap1 activates transcription factor Nrf2. Nrf2 induces the expression of many genes which encodes biological defense enzymes including antioxidant and detoxification enzymes to protect the body. The past research results show that some types of food abundantly contain components that promote Keap1 to activate Nrf2.
A clarification of the Keap1 molecule shape, or its three-dimensional structure, is a key issue to advance understanding the precise biological defense mechanism and to establish the basis of drug discovery.
In this study, the research group has clarified a shape of Keap1 protein in mice by single particle analysis consisting of an electron microscopy and Information Science and Technology. The results show that two keap1 molecules combine to form a dimer structure with two spheres in a cherry-like shape. Under non-stressed condition, these Keap1 spheres bind Nrf2 at the two points to reduce its abundance in the nucleus and to suppress the biological defense enzyme expression induced by Nrf2. When Keap1 senses oxidative stresses, one of spheres unbinds Nrf2 to increase its abundance, and to lead to the inductive enzyme expression. The process is called “Hinge-Latch” mechanism because it is just like to unbar a door to open. The research results provide molecular basis by clarifying the Keap1 shape, which is important to explain the regulation mechanism in which Keap1 responds to oxidative stresses to stabilize Nrf2.
Many lung cancer cases have recently been reported in which mutated KEAP1 gene causes spheres not to bind Nrf2, or a number of mutated Nrf2 can not bind Keap1. Overaccumulation of Nrf2 in cancer cells strengthen the defensive capacity of cancer to proliferate in either case. This led to the evidence that the Keap1 function relates to a pathogenic mechanism of lung cancer. The research aims to promote an analysis of a molecular mechanism of oxidative stress sensors by clarifying the Keap1 shape, and to develop understanding the relation between Keap1 function failure and diseases.
The research has been conducted with the aid of Targeted Proteins Research Program (TPRP), Grant-in-Aid for Creative Scientific Research, Grant-in-Aid for Scientific Research on Priority Areas, New Energy and Industrial Technology Development Organization (NEDO), and Grant-in-Aid for Scientific Research (B).
Professor Masayuki Yamamoto
Tohoku University Graduate School of Medicine
Associate Professor Fuji Nagami
Public Relations Office at Tohoku University Graduate School of Medicine