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| Type |
Poster Presentation |
| Area |
Physical Chemistry |
| Room No. |
Event Hall |
| Time |
4월 20일 (금요일) 11:00~12:30 |
| Code |
PHYS.P-247 |
| Subject |
Specific Binding of Cholesterol to the Amyloid Precursor Protein depends on the Lipid Membrane Microdomain |
| Authors |
Tony Myungkeun Cho, Seokmin Shin1,*
Dept. of Chem, Seoul National University, Korea
1Division of Chemistry, Seoul National University, Korea
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| Abstract |
Alzheimer’s disease is the most common neurodegenerative disease in humans, yet the molecular mechanism of the formation of Aβ monomer, which is thought to be the hallmark of Alzheimer’s disease, from Amyloid-precursor protein (APP) has not been elucidated. In recent NMR measurements, the binding of cholesterol to C99, the 99-residue fragment of APP, was found to play a crucial role in the production of Aβ42. According to in vitro studies of the γ-secretase, the production of Aβ also required phosphatidylcholine (PC) and lipid rafts. Molecular dynamics simulations was employed to investigate the effect of the decreasing helicity of C99 on the binding mechanisms of cholesterol to C99 in various lipid microdomains. The helicity of C99 was sampled with biasing force to extend the sampling conformation. As the orientation of C99 in the phase separated lipid raft is lopsided and allows for favorable cholesterol binding, we expect that the loosened helicity inhibits cholesterol binding by distorting the binding motif and the conformation within the raft that may lead to more excluded volume. The resulting difficulty in recruiting the γ-secretase to the lipid raft may reduce Aβ42 production. This study provides insight into the driving forces of C99 cleavage and molecular mechanism of amyloidogenic pathway of Aβ.
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| E-mail |
mktonycho@snu.ac.kr |
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121st General Meeting of the KCS