A02-1：Understanding a network of metallochaperones regulating intracellular copper dynamics
Yoshiaki Furukawa
(Department of Chemistry, Keio University)
Lab website/ Facebook
Biometals in our body are well known to be regulated so as to make them homeostatic in their qualities as well as quantities. Indeed, disruption of such homeostasis in biometals can be observed in various human diseases. In particular, neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease are characterized by abnormal accumulation/deficiency of biometals in central nervous system; therefore, understanding mechanisms of the homeostatic control of biometals will help to develop cures for the diseases. In my project, I will try to reveal an intracellular network regulating copper dynamics.
Whole-body copper content in adults is only around 80 mg, but it is an essential trace element for our lives. Most of copper ions in our body are bound to proteins and function as active sites for electron transport, enzymatic reactions, and so on. Given its high redox activity, however, a copper ion can exert quite high toxicity by producing reactive oxygen species from molecular oxygens. Indeed, mutations in a copper exporter ATP7B lead to abnormal accumulation of copper ions and cause Wilson disease presenting liver dysfunction and neurological/psychological symptoms.
To understand homeostatic control of copper ions in cells, I will try to reveal a protein-protein interaction network by noting “copper chaperones” responsible for intracellular transport of copper ions.
Major publications
E. Tokuda, I. Anzai, T. Nomura, K. Toichi, M. Watanabe, S. Ohara, S. Watanabe, K. Yamanaka, Y. Morisaki, H. Misawa, and *Y. Furukawa
“Immunochemical characterization on pathological oligomers of mutant Cu/Zn-superoxide dismutase in amyotrophic lateral sclerosis”
Molecular Neurodegeneration, 2017, 12, 2
doi: 10.1186/s13024-016-0145-9
K. Toichi, K. Yamanaka, and *Y. Furukawa
“Disulfide scrambling describes the oligomer formation of SOD1 proteins in the familial form of ALS”
The Journal of Biological Chemistry, 2013, 288, 4970-4980
doi: 10.1074/jbc.M112.414235
*Y. Furukawa, K. Kaneko, K. Yamanaka, T. V. O’Halloran, and *N. Nukina
“Complete loss of post-translational modifications triggers fibrillar aggregation of SOD1 in the familial form of amyotrophic lateral sclerosis”
The Journal of Biological Chemistry, 2008, 283, 24167-24176
doi: 10.1074/jbc.M802083200
Y. Furukawa, R. Fu, H.-X. Deng, T. Siddique, and *T. V. O’Halloran
“Disulfide cross-linked protein represents a significant fraction of ALS-associated Cu,Zn-superoxide dismutase aggregates in spinal cords of model mice”
Proceedings of the National Academy of Sciences, USA, 2006, 103, 7148-7153
doi: 10.1073/pnas.0602048103
Y. Furukawa, A. S. Torres, and *T. V. O’Halloran
“Oxygen induced maturation of SOD1: A key role for disulfide formation by the copper chaperone CCS”
EMBO Journal, 2004, 23, 2872-2881
doi: 10.1038/sj.emboj.7600276