Presenilin 1 regulates pharmacologically distinct γ-secretase activities -: Implications for the role of presenilin in γ-secretase cleavage
Presenilin 1 regulates pharmacologically distinct γ-secretase activities -: Implications for the role of presenilin in γ-secretase cleavage
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DOI：
10.1074/jbc.m002812200
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发表时间：
2000-08-25
影响因子：
4.8
通讯作者：
Golde, TE
中科院分区：
文献类型：
--
作者：
Murphy, MP;Uljon, SN;Golde, TE
早老素(PSS)是阿尔茨海默病的潜在治疗靶点，因为它们在调节产生淀粉样β蛋白(Aβ)的伽玛分泌酶裂解中起作用，目前尚不清楚PSS如何调节伽玛分泌酶的裂解，但有证据表明，PSS既可以是伽玛分泌酶裂解的基本辅助因子，也可以是间接影响伽马分泌酶裂解的细胞内运输的调节者。使用抑制Aβ产生的早老素1(PS1)突变体和被药理上不同的伽马分泌酶切割的淀粉样蛋白前体的跨膜结构域突变体，我们证明PS1调节多种药理上不同的伽马分泌酶活性以及诱导的α分泌酶活性。PS1很可能间接地调节这些活动(如在贩卖或伴侣角色中)，因为这些数据表明，对于PS1来说，它必须具有多个活性位点或以各种催化活性形式存在，这些催化活性形式被我们研究的突变同等程度地改变。
Presenilins (PSs) are polytopic membrane proteins that have been implicated as potential therapeutic targets in Alzheimer's disease because of their role in regulating the gamma-secretase cleavage that generates the amyloid beta protein (A beta), It is not clear how PSs regulate gamma-secretase cleavage, but there is evidence that PSs could be either essential cofactors in the gamma-secretase cleavage, gamma-secretase themselves, or regulators of intracellular trafficking that indirectly influence gamma-secretase cleavage. Using presenilin 1 (PS1) mutants that inhibit A beta production in conjunction with transmembrane domain mutants of the amyloid protein precursor that are cleaved by pharmacologically distinct gamma-secretases, we show that PS1 regulates multiple pharmacologically distinct gamma-secretase activities as well as inducible alpha-secretase activity. It is likely that PS1 acts indirectly to regulate these activities (as in a trafficking or chaperone role), because these data indicate that for PS1 to be gamma-secretase it must either have multiple active sites or exist in a variety of catalytically active forms that are altered to an equivalent extent by the mutations we have studied.