In the living organism, a protein molecule folds into its three-dimensional structure that is encoded in its sequence. Since the function of a protein is closely linked to its structure, experimental determination of the protein structure is a matter of high importance. The amyloid fibrils are protein aggregates that are formed by normally soluble proteins. The fibril formation can accompany diseases include Alzheimer's disease and familial amyloid polyneuropathies. Structural studies have revealed that the fibrils are composed of beta-sheet structure in a characteristic cross-beta conformation. We are trying to develop a detailed structural understanding of the formation of amyloid fibrils by transthyretin and to identify the potential targets for disease treatment. In addition to X-ray crystallography, we are using nuclear magnetic resonance (NMR) spectroscopy, neutron crystallography, protein engineering, biophysical methods to characterize the structure and function of proteins.
The aim of our study is to understand the structure and function of proteins which are fundamentally important in disease onset and progression. Under some conditions, proteins fail to fold correctly, or to remain correctly folded, and this failure can result in a wide range of diseases. One group of diseases, known as amyloidosis, which includes familial amyloid polyneuropathy and spinocerebellar ataxia, involves the deposition of misfolded proteins in a variety of organs such as liver, heart and brain. Amyloid fibrils have been the target of increasing attention because of their central role in several human pathologies, including Alzheimer's disease and transthyretin-related amyloidosis. Our research interests also center on the structural bases for the formation of amyloid fibrils by transthyretin using a combination of neutron crystallography, X-ray crystallography and biochemical methods. In particular, neutron protein crystallography is an experimental method of directly locating H atoms that are essential in enzymatic function and molecular recognition. Targets for these studies include important proteins in the treatment of amyloidosis, osteoporosis and other disease states.
Mineyuki Mizuguchi, Ph.D., Professor Takayuki Obita, Ph.D., Associate Professor Takeshi Yokoyama, Ph.D., Assistant Professor Y. Nabeshima, Ph.D., Research assistant K. Fujii, Graduate Student A. Nakada, Graduate Student H. Asai, Undergraduate Student Y. Takayama, Undergraduate Student S. Nishimata, Undergraduate Student N. Matsuzawa, Undergraduate Student A. Miyake, Undergraduate Student M. Suzuki, Undergraduate Student Y. Takai, Undergraduate Student M. Matsushita, Undergraduate Student T. Yamashita, Undergraduate Student K. Taguchi, Undergraduate Student I. Ikemura, Undergraduate Student R. Otsu, Undergraduate Student R. Sato, Undergraduate Student T. Mizuno, Undergraduate Student
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Mail to M.M.: mineyuki@pha.u-toyama.ac.jp Tel to M.M.: +81-76-434-7595 Fax to the Lab.: +81-76-434-5061
