کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5913747 | 1162701 | 2015 | 10 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Molecular dynamics simulation study reveals potential substrate entry path into γ-secretase/presenilin-1
دانلود مقاله + سفارش ترجمه
دانلود مقاله ISI انگلیسی
رایگان برای ایرانیان
کلمات کلیدی
PoPCRMSFRMSDNTFAPPPS1CTFPresenilin-1γ-Secretase1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine - 1-پالمیتویل-2-اولئویل-اس-گلیسرو-3-فسفاتانولامین1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine - 1-پالمیتویل-2-اولئویل-اسن-گلیسرو-3-فسفوشولینPCA - PCApresenilin 1 - Presenilin 1FEL - UPAlzheimer’s disease - بیماری آلزایمرPrincipal components analysis - تجزیه و تحلیل اجزای اصلیtransmembrane domain - دامنه فرابنفشMolecular dynamics simulation - شبیه سازی دینامیک مولکولیC-terminal fragment - قطعه C ترمینالN-terminal fragment - قطعه N-terminalprincipal component - مولفه های اصلیroot mean square deviation - میانگین انحراف مربع ریشهroot mean square fluctuation - نوسان میانگین مربع ریشهPOPE - پاپMembrane protein - پروتئین غشائیamyloid precursor protein - پروتئین پیش ماده آمیلوئیfree energy landscape - چشم انداز انرژی آزاد
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شناسی مولکولی
پیش نمایش صفحه اول مقاله
![عکس صفحه اول مقاله: Molecular dynamics simulation study reveals potential substrate entry path into γ-secretase/presenilin-1 Molecular dynamics simulation study reveals potential substrate entry path into γ-secretase/presenilin-1](/preview/png/5913747.png)
چکیده انگلیسی
Presenilin 1 (PS1) is the catalytic unit of γ-secretase which cleaves more than one hundred substrates. Among them, amyloid precursor protein (APP) and Notch are notable for their pivotal role in the pathogenesis of Alzheimer's disease (AD) and certain types of cancer. The hydrolysis process occurring inside the hydrophobic lipid bilayer remains unclear. With the aim to understand the mechanism of intramembrane proteolysis by γ-secretase, we constructed a homology model of human PS1 and performed molecular dynamics simulation in explicit membrane phospholipids with different components. During the simulation, TM9 was found to exhibit a high level of flexibility that involved in “gate-open” movement of TM2 and TM6, and thus partially exposed the catalytic residues. The highly conserved PALP motif acts as an anchor to mediate the conformation changes of TM6 induced by TM9. Moreover, direct interactions were observed between 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE) and the active site of γ-secretase, indicating that the lipid molecules have the potential to modulate γ-secretase by contacting with the catalytic residues, i.e., ASP 257 and ASP 385 of PS1. The intermediate states indicate a potential substrate penetration pathway through the interface of TM2 and TM6, which may be induced by changes of TM9. To our knowledge, this is the first molecular simulation study that reveals dynamic behavior of the human PS1 structure in the lipid bilayer and provides insight into the substrate entry path for subsequent intramembrane hydrolysis, which is critical information required for new strategy development of γ-secretase modulators to alleviate devastating AD.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Structural Biology - Volume 191, Issue 2, August 2015, Pages 120-129
Journal: Journal of Structural Biology - Volume 191, Issue 2, August 2015, Pages 120-129
نویسندگان
Ren Kong, Shan Chang, Weiming Xia, Stephen T.C. Wong,