| Project/Area Number |
14037256
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Kumamoto University |
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Principal Investigator |
OGURA Teru Kumamoto University, Institute of Molecular Embryology and Genetics, Professor (00158825)
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| Co-Investigator(Kenkyū-buntansha) |
YAMANAKA Kunitoshi Kumamto University, Institute of Molecular Embryology and Genetics, Associate Professor (90212290)
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| Project Period (FY) |
2002 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥138,400,000 (Direct Cost: ¥138,400,000)
Fiscal Year 2006: ¥24,600,000 (Direct Cost: ¥24,600,000)
Fiscal Year 2005: ¥24,600,000 (Direct Cost: ¥24,600,000)
Fiscal Year 2004: ¥26,100,000 (Direct Cost: ¥26,100,000)
Fiscal Year 2003: ¥26,100,000 (Direct Cost: ¥26,100,000)
Fiscal Year 2002: ¥37,000,000 (Direct Cost: ¥37,000,000)
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| Keywords | AAA protein / chaperone / ATP-dependent protease / ATPase / C.elegans / genetic diseases / protein aggregation / microtubule / トランスロケーション / アンフォールディング / 転写制御 / 大腸菌 / シャペロン / ミトコンドリア / 遺伝性痙性対麻痺 / ポリグルタミン病 |
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| Research Abstract |
Molecular mechanisms of common activities of AAA chaperones such as ATP hydrolysis and translocation of substrate proteins have been studied. We have proposed an intersubunit catalysis mechanism of ATP hydrolysis by AAA ATPases and a threading model for substrate translocation, and obtained supporting evidence for these models. Mutagenesis of conserved residues at the pore of the hexameric ATPase ring of an AAA protease, FtsH, indicated that the conserved aromatic residue is suggested to act for substrate binding and translocation. It was found that FtsH can initiate proteolysis of flavodoxin by translocating an internal loop to the protease chamber in an ATP dependent manner. We have also found that degradation of unfolded polypeptides by some chimeras of FtsH and its C.eleganshomologs do not require ATP hydrolysis. Firm evidence for the intersubunit catalysis mechanism of ATP hydrolysis by AAA ATPases has been obtained using mutants of the C.elegans fidgetin homolog, FIGL-1. We have also studied cellular functions of some AAA proteins in C.elegaas, which are homologous to causative factors of human genetic diseases. It was found that p97, which is related to inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia, plays important roles in switching from spermatogenesis to oogenesis and progression of meiosis I as well as ERAD. We have observed that overexpression of p97 in C.elegans partially suppresses polyglutamine aggregate formation in vivo and that purified p97 suppresses aggregate formation of huntingtin fragments in an ATP-independent manner in vitro. We have shown spatiotemporally differential expression pattern of six UBX adaptor proteins of p97 in C.elegans. We showed that overexpression of SPAS-1, the C.elegans homolog of spastin related to hereditary spastic paraplegia, caused disassembly of microtubule network, indicating that SPAS-1 is involved in microtubule dynamics.
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