Phosphorylation of the PTEN tail acts as an inhibitory switch by preventing its recruitment into a protein complex
Phosphorylation of the PTEN tail acts as an inhibitory switch by preventing its recruitment into a protein complex
复制标题
DOI：
10.1074/jbc.c100556200
复制
发表时间：
2001-12-28
影响因子：
4.8
通讯作者：
Sellers, WR
中科院分区：
文献类型：
--
作者：
Vazquez, F;Grossman, SR;Sellers, WR
PTEN是一种肿瘤抑制蛋白，其功能在很大程度上是通过去磷酸化脂质第二信使磷脂酰肌醇3,4,5-三磷酸，并通过这样做来拮抗磷酸肌醇3-激酶的作用。PTEN结构域包括一个n端磷酸酶结构域、一个脂质结合C2结构域和一个含有PDZ结合序列的50个氨基酸的c端尾部。我们之前发现PTEN尾部的磷酸化负性调节PTEN活性。我们现在发现磷酸化的PTEN以单体“封闭”构象存在，并且对含有PDZ结构域的蛋白质具有低亲和力。相反，当未磷酸化时，PTEN处于“开放”构象，被招募到高分子量复合物（PTEN相关复合物）中，并与含有pdz的蛋白质（如MAGI-2）强烈相互作用。因此，与野生型PTEN相比，磷酸化缺陷突变型PTEN与MAGI-2强烈合作，阻断Akt的激活。这些结果表明，PTEN尾部的磷酸化引起构象变化，导致PDZ结合域的屏蔽。因此，PTEN结合PDZ结构域蛋白的能力显著降低。这些数据表明，PTEN尾部的磷酸化通过控制PTEN进入PTEN相关复合物的募集来抑制PTEN的活性。
PTEN is a tumor suppressor protein that functions, in large part, by dephosphorylating the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate and by doing so antagonizing the action of phosphoinositide 3-kinase. PTEN structural domains include an N-terminal phosphatase domain, a lipid-binding C2 domain, and a 50-amino acid C-terminal tail that contains a PDZ binding sequence. We showed previously that phosphorylation of the PTEN tail negatively regulates PTEN activity. We now show that phosphorylated PTEN exists in a monomeric "closed" conformation and has low affinity for PDZ domain-containing proteins. Conversely, when unphosphorylated, PTEN is in an "open" conformation, is recruited into a high molecular weight complex (PTEN-associated complex), and strongly interacts with PDZ-containing proteins such as MAGI-2. As a consequence, when compared with wild-type PTEN, the phosphorylation-deficient mutant form of PTEN strongly cooperates with MAGI-2 to block Akt activation. These results indicate that phosphorylation of the PTEN tail causes a conformational change that results in the masking of the PDZ binding domain. Consequently, the ability of PTEN to bind to PDZ domain-containing proteins is reduced dramatically. These data suggest that phosphorylation of the PTEN tail suppresses the activity of PTEN by controlling the recruitment of PTEN into the PTEN-associated complex.