Conformational stability and catalytic activity of PTEN variants linked to cancers and autism spectrum disorders.
Conformational stability and catalytic activity of PTEN variants linked to cancers and autism spectrum disorders.
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DOI：
10.1021/acs.biochem.5b00028
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发表时间：
2015-02-24
期刊：
影响因子：
2.9
通讯作者：
Raines, Ronald T.
中科院分区：
文献类型：
--
作者：
Johnston, Sean B.;Raines, Ronald T.
磷酸肌醇是在哺乳动物细胞中起关键调节作用的膜组分。催化磷酸肌醇PIP 3去磷酸化的酶PTEN在大多数散发性肿瘤中受损。PTEN基因的突变也与自闭症谱系障碍和其他形式的发育迟缓有关。在此，人PTEN显示在生理条件下处于解折叠的尖端。与自闭症谱系上的体细胞癌症和病症相关的人类PTEN的变体显示出其构象稳定性、催化活性或两者都受损。那些仅与自闭症相关的变异比与癌症相关的变异具有更高的活性。PTEN-L是一种分泌的反式活性同种型，具有比野生型酶更高的构象稳定性。这些数据表明，PTEN是一种脆弱的酶，在细胞代谢中起着至关重要的作用，并表明PTEN-L是一个关键的催化活性库。
Phosphoinositides are membrane components that play critical regulatory roles in mammalian cells. The enzyme PTEN, which catalyzes the dephosphorylation of the phosphoinositide PIP3, is damaged in most sporadic tumors. Mutations in the PTEN gene have also been linked to autism spectrum disorders and other forms of delayed development. Here, human PTEN is shown to be on the cusp of unfolding under physiological conditions. Variants of human PTEN linked to somatic cancers and disorders on the autism spectrum are shown to be impaired in their conformational stability, catalytic activity, or both. Those variants linked only to autism have higher activity than those linked to cancers. PTEN-L, which is a secreted trans-active isoform, has greater conformational stability than does the wild-type enzyme. These data indicate that PTEN is a fragile enzyme cast in a crucial role in cellular metabolism, and suggest that PTEN-L is a repository for a critical catalytic activity.
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