Presenilin-1 affects trafficking and processing of betaAPP and is targeted in a complex with nicastrin to the plasma membrane.
Presenilin-1 affects trafficking and processing of betaAPP and is targeted in a complex with nicastrin to the plasma membrane.
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DOI：
10.1083/jcb.200201123
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发表时间：
2002-08-05
期刊：
影响因子：
--
通讯作者：
Haass C
中科院分区：
文献类型：
--
作者：
Kaether C;Lammich S;Edbauer D;Ertl M;Rietdorf J;Capell A;Steiner H;Haass C
β-淀粉样肽（Aβ）是由β-和γ-分泌酶连续裂解产生的。γ-分泌酶的膜内裂解主要依赖于早老素（PS1和PS2）的活性。虽然有证据表明PS是具有γ-分泌酶活性的乙酰化蛋白酶，但其亚细胞定位是否与Aβ产生的细胞位点重叠仍存在争议。我们现在证明，具有生物活性的GFP标记的PS1以及内源性PS1被靶向到活细胞的质膜（PM）。在到达PM的途中，PS1与γ-分泌酶复合物的重要组分nicastrin（Nct）结合。该复合物通过分泌途径靶向，其中PS1结合的Nct变得对糖苷内切酶H具有抗性。此外，表面生物素化的Nct可以与PS1抗体共免疫沉淀，表明该复合物位于具有γ-分泌酶活性的细胞位点。通过诱变一个关键的天冬氨酸残基或通过γ-分泌酶抑制剂使PS1或PS2功能失活，导致β-淀粉样前体蛋白的延迟再内化及其在细胞表面的积累。我们的数据表明，PS作为具有生物活性的复合物与Nct通过分泌途径靶向细胞表面，并表明PS在γ-分泌酶加工和运输中具有双重功能。
Amyloid β-peptide (Aβ) is generated by the consecutive cleavages of β- and γ-secretase. The intramembraneous γ-secretase cleavage critically depends on the activity of presenilins (PS1 and PS2). Although there is evidence that PSs are aspartyl proteases with γ-secretase activity, it remains controversial whether their subcellular localization overlaps with the cellular sites of Aβ production. We now demonstrate that biologically active GFP-tagged PS1 as well as endogenous PS1 are targeted to the plasma membrane (PM) of living cells. On the way to the PM, PS1 binds to nicastrin (Nct), an essential component of the γ-secretase complex. This complex is targeted through the secretory pathway where PS1-bound Nct becomes endoglycosidase H resistant. Moreover, surface-biotinylated Nct can be coimmunoprecipitated with PS1 antibodies, demonstrating that this complex is located to cellular sites with γ-secretase activity. Inactivating PS1 or PS2 function by mutagenesis of one of the critical aspartate residues or by γ-secretase inhibitors results in delayed reinternalization of the β-amyloid precursor protein and its accumulation at the cell surface. Our data suggest that PS is targeted as a biologically active complex with Nct through the secretory pathway to the cell surface and suggest a dual function of PS in γ-secretase processing and in trafficking.
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DOI：
10.1083/jcb.200104045
发表时间：
2001-08-20
期刊：
The Journal of cell biology
影响因子：
--
作者：
Cupers P;Bentahir M;Craessaerts K;Orlans I;Vanderstichele H;Saftig P;De Strooper B;Annaert W
通讯作者：
Annaert W
影响因子：
21.3
作者：
Herreman, A;Serneels, L;De Strooper, B
通讯作者：
De Strooper, B
影响因子：
4.8
作者：
Leem, JY;Vijayan, S;Thinakaran, G
通讯作者：
Thinakaran, G
影响因子：
11.8
作者：
López-Schier, H;St Johnston, D
通讯作者：
St Johnston, D
影响因子：
4.8
作者：
Kimberly, WT;Xia, WM;Selkoe, DJ
通讯作者：
Selkoe, DJ