A conserved mechanism for steroid receptor translocation to the plasma membrane
A conserved mechanism for steroid receptor translocation to the plasma membrane
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DOI：
10.1074/jbc.m611877200
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发表时间：
2007-08-03
影响因子：
4.8
通讯作者：
Levin, Ellis R.
中科院分区：
文献类型：
--
作者：
Pedram, Ali;Razandi, Mahnaz;Levin, Ellis R.
已经提出多种类固醇受体（SR）定位于质膜。已经描述了雌激素受体α（ER α）膜转位的一些结构元件，但与其他类固醇受体相关的机制完全未知。在这里，我们确定了一个高度保守的9个氨基酸基序的配体结合域（E域）的人/小鼠ER α和ER β，孕酮受体A和B，和雄激素受体。相对于半胱氨酸，-2位的苯丙氨酸或酪氨酸、0位的半胱氨酸和+5/6位的疏水性异亮氨酸/亮氨酸或亮氨酸/亮氨酸组合的突变显著降低了膜定位、MAP和PI 3-激酶活化、胸苷掺入DNA和细胞活力，这些都是由特异性SR配体刺激的。定位序列介导的棕榈酰化的每个SR，这有利于小窝蛋白-1协会，随后的膜定位，和类固醇信号。因此，E结构域内的棕榈酰化是经典性类固醇受体的膜转位和功能的关键修饰。
Multiple steroid receptors (SR) have been proposed to localize to the plasma membrane. Some structural elements for membrane translocation of the estrogen receptor alpha( ER alpha) have been described, but the mechanisms relevant to other steroid receptors are entirely unknown. Here, we identify a highly conserved 9 amino acid motif in the ligand binding domains (E domains) of human/mouse ER alpha and ER beta, progesterone receptors A and B, and the androgen receptor. Mutation of the phenylalanine or tyrosine at position -2, cysteine at position 0, and hydrophobic isoleucine/leucine or leucine/leucine combinations at positions +5/6, relative to cysteine, significantly reduced membrane localization, MAP and PI 3-kinase activation, thymidine incorporation into DNA, and cell viability, stimulated by specific SR ligands. The localization sequence mediated palmitoylation of each SR, which facilitated caveolin-1 association, subsequent membrane localization, and steroid signaling. Palmitoylation within the E domain is therefore a crucial modification for membrane translocation and function of classical sex steroid receptors.