New role of Parkin as a E3 in the causal mechanism of Parkinson's disease
| Project/Area Number |
25860721
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Neurology
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| Research Institution | Keio University |
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Principal Investigator |
KUJURO Yuki 慶應義塾大学, 医学部, 講師 (非常勤) (60398625)
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| Project Period (FY) |
2013-04-01 – 2015-03-31
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| Project Status |
Completed (Fiscal Year 2014)
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| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2013: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
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| Keywords | Parkin / パーキンソン病 / Ｐａｒｋｉｎ / チオエステル中間体 / E3 |
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| Outline of Final Research Achievements |
Parkin is categorized as RING-IBR-RING (RBR) type E3 and cooperates with PINK1in clearance of damaged mitochondira. Here we show that similar to the ubiquitin-cascading reaction of HECT type E3s, Parkin also forms ubiquitin-ester adduct at the position of conserved cysteine (Cys431). Ubiquitin-ester formation is observed when mitochondrial membrane potential is decreased, and this intermediate formation is essential for substrate ubiquitylation. Knockout of PINK1 and expression of pathogenic PINK1 mutants blocked the ubiquitin-ester formation, suggesting that PINK1 is essential for this step. Moreover, disease-relevant mutations of Parkin inhibit the ubiquitin-ester linkage formation. Importantly, Ala mutation at Parkin Ser65, a PINK1-mediated phosphorylation site abolishes ubiquitin-ester formation, whereas phosphorylation-mimic Ser-to-Asp/Glu change at the site partially enabled Parkin to form ubiquitin-ester intermediate irrespective of Parkin phosphorylation.
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Report
(3 results)
Research Products
(4 results)
