کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1981701 | 1539420 | 2014 | 14 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Changed membrane integration and catalytic site conformation are two mechanisms behind the increased Aβ42/Aβ40 ratio by presenilin 1 familial Alzheimer-linked mutations
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کلمات کلیدی
APPγ-SecretaseTMDCTFLEPAICDMGDMSDCRMAβGVPGCBNTFamyloid β-peptide - β-پپتید آمیلوئیدEndo H - اندو هendoglycosidase H - اندوگلیکوزیداز HFAD - بدBis-tris - بیس-تریسAlzheimer disease - بیماری آلزایمرAmyloid precursor protein intracellular domain - دامنه داخل سلولی پروتئین پیش ماده آمیلوئیدTransmembrane domains - دامنه های ترانزیستورProtein structure - ساختار پروتئینendoplasmic reticulum - شبکه آندوپلاسمی Familial AD - فامیل ADC-terminal fragment - قطعه C ترمینالN-terminal fragment - قطعه N-terminalwild type - نوع وحشیPresenilin - پرنسیلینamyloid precursor protein - پروتئین پیش ماده آمیلوئیamyloid-β peptide - پپتید آمیلیید بLeader peptidase - پپتیداز LeaderCHAPSO - چپسوMeso Scale Discovery - کشف مقیاس Mesomembrane integration - یکپارچه سازی غشاء
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
The enzyme complex γ-secretase generates amyloid β-peptide (Aβ), a 37-43-residue peptide associated with Alzheimer disease (AD). Mutations in presenilin 1 (PS1), the catalytical subunit of γ-secretase, result in familial AD (FAD). A unifying theme among FAD mutations is an alteration in the ratio Aβ species produced (the Aβ42/Aβ40 ratio), but the molecular mechanisms responsible remain elusive. In this report we have studied the impact of several different PS1 FAD mutations on the integration of selected PS1 transmembrane domains and on PS1 active site conformation, and whether any effects translate to a particular amyloid precursor protein (APP) processing phenotype. Most mutations studied caused an increase in the Aβ42/Aβ40 ratio, but via different mechanisms. The mutations that caused a particular large increase in the Aβ42/Aβ40 ratio did also display an impaired APP intracellular domain (AICD) formation and a lower total Aβ production. Interestingly, seven mutations close to the catalytic site caused a severely impaired integration of proximal transmembrane/hydrophobic sequences into the membrane. This structural defect did not correlate to a particular APP processing phenotype. Six selected FAD mutations, all of which exhibited different APP processing profiles and impact on PS1 transmembrane domain integration, were found to display an altered active site conformation. Combined, our data suggest that FAD mutations affect the PS1 structure and active site differently, resulting in several complex APP processing phenotypes, where the most aggressive mutations in terms of increased Aβ42/Aβ40 ratio are associated with a decrease in total γ-secretase activity.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: FEBS Open Bio - Volume 4, 2014, Pages 393-406
Journal: FEBS Open Bio - Volume 4, 2014, Pages 393-406
نویسندگان
Johanna Wanngren, Patricia Lara, Karin Ãjemalm, Silvia Maioli, Nasim Moradi, Lu Chen, Lars O. Tjernberg, Johan Lundkvist, IngMarie Nilsson, Helena Karlström,