Gamma secretase(GS)is an intramembranous enzyme that acts on the amyloid precursor protein and Notch inside lipid membranes.The enzyme is responsible for amyloid-𝛽propagation,one of the well-known causes of Al...Gamma secretase(GS)is an intramembranous enzyme that acts on the amyloid precursor protein and Notch inside lipid membranes.The enzyme is responsible for amyloid-𝛽propagation,one of the well-known causes of Alzheimer’s disease.However,the effects of lipids on GS activity and structural dynamics are unknown.Therefore,in this study,we performed coarse-grained molecular dynamics simulations to probe the effects of five individual lipids on GS.These lipids included 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine(POPE),1-palmitoyl2-oleoyl-sn-glycero-3-phosphocholine(POPC),1,2-dipalmitoyl-sn-phosphatidylcholine(DOPC),2-dimyristoyl-snglycero-3-phosphocholine(DMPC),and 1,2-dilauroyl-sn-glycero-3-phosphocholine(DLPC).These lipids are structurally characterized by different heads(i.e.,NH_(3)[PE]for POPE vs.NC_(3)[PC]for POPC),number of double bonds(one for POPC vs.two for DOPC),and alkyl tail chain lengths(16:1/18:1 for DOPC vs.14:0/14:0 for DMPC vs.12:0/12:0 for DLPC).This indicates distinct microenvironments and adjustable structural elements for catalytic function when GS is embedded.Our results revealed that the presence of more unsaturated bonds in DOPC than in POPC resulted in greater GS stability.Moreover,lipids with short alkyl tail chains or with PC heads instead of PE heads had improved mobility of the sixth transmembrane helix of GS,which is responsible for the considerable active site flexibility and presenilin 1 subunit plasticity.The length of the DMPC alkyl tail chain was between that of DOPC and DLPC because the up-down and cross-correlation motions of GS in DMPC was the lowest among the three lipids,and GS mobility in DMPC was the lowest among all five lipids.This may be because the alkyl tail chain length(i.e.,3.8 nm thickness of the DMPC bilayer)was suitable for GS embedding,thereby restraining more GS motions than that of the long(DOPC)or short lipids(DLPC).Collectively,these results indicated that GS activity can be modulated through changes in conformational fluctuations,structural perturba展开更多
目的探讨Nicastrin(NCSTN)基因启动子区多态性与散发阿尔茨海默病(sporadic Alzheimer s dis-ease,SAD)发病的关系及其机制。方法用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)和直接测序的方法对中国北方汉族359例SAD患者和331名正...目的探讨Nicastrin(NCSTN)基因启动子区多态性与散发阿尔茨海默病(sporadic Alzheimer s dis-ease,SAD)发病的关系及其机制。方法用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)和直接测序的方法对中国北方汉族359例SAD患者和331名正常对照者NCSTN基因启动子区单核苷酸多态性位点(SNP)进行筛查,基因分型后,进行病例对照-相关分析。构建三种不同基因型启动子质粒,通过双荧光报告基因系统检测不同启动子质粒的转录活性。结果①中国北方人群中的NCSTN基因启动子区ATG上游2245 bp范围内存在3个SNP:-1216C/A(rs2147471),-796T/G(rs10752637)和-436C/T(rs1324738);②-1216C/A和-796T/G的基因型频率在各自的SAD组和正常对照组中的分布差异有统计学意义;③三种启动子质粒的转录活性差异无统计。结论NCSTN启动子区SNP:-796T/G和-1216C/A,与SAD的发病具有相关性,但未发现这两个位点具有病理学功能。展开更多
基金supported by Shandong Provincial Natural Science Foundation of China(ZR2022MB073).
文摘Gamma secretase(GS)is an intramembranous enzyme that acts on the amyloid precursor protein and Notch inside lipid membranes.The enzyme is responsible for amyloid-𝛽propagation,one of the well-known causes of Alzheimer’s disease.However,the effects of lipids on GS activity and structural dynamics are unknown.Therefore,in this study,we performed coarse-grained molecular dynamics simulations to probe the effects of five individual lipids on GS.These lipids included 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine(POPE),1-palmitoyl2-oleoyl-sn-glycero-3-phosphocholine(POPC),1,2-dipalmitoyl-sn-phosphatidylcholine(DOPC),2-dimyristoyl-snglycero-3-phosphocholine(DMPC),and 1,2-dilauroyl-sn-glycero-3-phosphocholine(DLPC).These lipids are structurally characterized by different heads(i.e.,NH_(3)[PE]for POPE vs.NC_(3)[PC]for POPC),number of double bonds(one for POPC vs.two for DOPC),and alkyl tail chain lengths(16:1/18:1 for DOPC vs.14:0/14:0 for DMPC vs.12:0/12:0 for DLPC).This indicates distinct microenvironments and adjustable structural elements for catalytic function when GS is embedded.Our results revealed that the presence of more unsaturated bonds in DOPC than in POPC resulted in greater GS stability.Moreover,lipids with short alkyl tail chains or with PC heads instead of PE heads had improved mobility of the sixth transmembrane helix of GS,which is responsible for the considerable active site flexibility and presenilin 1 subunit plasticity.The length of the DMPC alkyl tail chain was between that of DOPC and DLPC because the up-down and cross-correlation motions of GS in DMPC was the lowest among the three lipids,and GS mobility in DMPC was the lowest among all five lipids.This may be because the alkyl tail chain length(i.e.,3.8 nm thickness of the DMPC bilayer)was suitable for GS embedding,thereby restraining more GS motions than that of the long(DOPC)or short lipids(DLPC).Collectively,these results indicated that GS activity can be modulated through changes in conformational fluctuations,structural perturba
基金supported by grants from National Basic Research program of China (2004CB518601)The National Natural Science Foundation of China (30400226,30730052,30630062)~~
文摘目的探讨Nicastrin(NCSTN)基因启动子区多态性与散发阿尔茨海默病(sporadic Alzheimer s dis-ease,SAD)发病的关系及其机制。方法用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)和直接测序的方法对中国北方汉族359例SAD患者和331名正常对照者NCSTN基因启动子区单核苷酸多态性位点(SNP)进行筛查,基因分型后,进行病例对照-相关分析。构建三种不同基因型启动子质粒,通过双荧光报告基因系统检测不同启动子质粒的转录活性。结果①中国北方人群中的NCSTN基因启动子区ATG上游2245 bp范围内存在3个SNP:-1216C/A(rs2147471),-796T/G(rs10752637)和-436C/T(rs1324738);②-1216C/A和-796T/G的基因型频率在各自的SAD组和正常对照组中的分布差异有统计学意义;③三种启动子质粒的转录活性差异无统计。结论NCSTN启动子区SNP:-796T/G和-1216C/A,与SAD的发病具有相关性,但未发现这两个位点具有病理学功能。
