SEMINAR

Exploring the early stages of protein association in the formation of amyloid fibrils

Abstract
Amyloid fibrils are protein aggregates associated with numerous human amyloidoses and neurodegenerative diseases [1]. Their formation is typically described by a nucleation-dependent aggregation mechanism, in which the nucleation acts as a rate-limiting step of the overall reaction. The nucleation is therefore considered as one of the most crucial phases that dictate the onset of such diseases and exploring its molecular mechanisms is very important for therapeutic advances as well as fundamental understanding of the capability of proteins to form amyloid structures [2].

In this talk, I will present our recent progress on the investigation of early association events of protein molecules during the nucleation process. By using insulin and its derived peptide fragment, we have found that early aggregated species transiently accumulated preceding the formation of amyloid fibrils [3]. From a time-resolved small angle X-ray scattering measurement, we have revealed a rold-like structural property of the early aggregates (MS submitted). After the formation of the early aggregates, they appeared to further coalesce to form larger assemblies, and then be followed by subsequent transconformation towards mature amyloid fibrils. On the basis of these observations, a possible mechanism describing how the amyloidogenic nuclei generate will be discussed.

References:
[1] C.M. Dobson. (2003) Protein folding and misfolding. Nature 426, 884-890.
[2] F. Bemporad and F. Chiti. (2012) Protein misfolded oligomers: experimental approaches, mechanism of formation, and structure-toxicity relationships. Chem. Biol. 19, 315-327.
[3] E. Chatani et al. (2014) Stepwise organization of the β-structure identifies key regions essential for the propagation and cytotoxicity of insulin amyloid fibrils. J Biol Chem 289, 10399-10410.

BIOGRAPHY

2011-present: Associate Professor, Graduate School of Science, Kobe University
2008-2011: Assistant Professor, College of Pharmaceutical Science, Ritsumeikan University
2003-2008: Postdoctoral Fellow, Institute for Protein Research, Osaka University
2002-2003: Assistant Research Staff, Faculty of Agriculture, Kyoto University
2002: PhD, Department of Applied Life Sciences, Graduate School of Agriculture, Kyoto University

Research Fields and Interests:
My research has principally focused on physicochemical properties of protein molecules and my current interest is protein aggregation including amyloid fibril formation. Insulin protein has been mainly used as a model protein for understanding the detailed molecular mechanisms of amyloid fibril formation and recently we are trying to investigate the nucleation event occurring in the early stage of the fibrillation pathway. My research interest expands to every process associated with clustering or assembling, with a goal for the future of comprehensive understanding of protein self-organization.

Selected Publications:

Chatani, E., Tsuchisaka, Y., Masuda, Y. and Tsenkova, R. (2014) Water molecular system dynamics associated with amyloidogenic nucleation as revealed by real time near infrared spectroscopy and aquaphotomics. PLOS One 9, e101997. [PMID: 25013915]

Chatani, E., Imamura, H., Yamamoto, N. and Kato, M. (2014) Stepwise organization of the β-structure identifies key regions essential for the propagation and cytotoxicity of insulin amyloid fibrils. J. Biol. Chem. 289, 10399-10410. [PMID: 24569992]

Chatani, E., Yagi, H., Naiki, H. and Goto, Y. (2012) Polymorphism of β2-microglobulin amyloid fibrils manifested by ultrasonication-enhanced fibril formation in trifluoroethanol. J. Biol. Chem. 287, 22827-22837. [PMID: 22566695]

Konuma, T.†, Chatani, E.†, Yagi, M., Sakurai, K., Ikegami,　T., Naiki, H. and Goto, Y. (†equally contributed) (2011) Kinetic intermediates of β2-microglobulin fibril elongation probed by pulse-labeling H/D exchange combined with NMR analysis, J. Mol. Biol. 405, 851-862. [PMID: 21108949]

Chatani, E., Lee, Y.-H., Yagi, H., Yoshimura, Y., Naiki, H. and Goto, Y. (2009) Ultrasonication-dependent production and breakdown lead to minimum-sized amyloid fibrils. Proc. Natl. Acad. Sci. USA 106, 11119-11124. [PMID: 19564620]