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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Identification of myotubularin as the lipid phosphatase catalytic subunit associated with the 3-phosphatase adapter protein, 3-PAP.
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Identification of myotubularin as the lipid phosphatase catalytic subunit associated with the 3-phosphatase adapter protein, 3-PAP.

机译：鉴定肌管蛋白是与3-磷酸酶衔接蛋白3-PAP相关的脂质磷酸酶催化亚基。

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摘要

Myotubularin is a dual-specific phosphatase that dephosphorylates phosphatidylinositol 3-phosphate and phosphatidylinositol (3,5)-bisphosphate. Mutations in myotubularin result in the human disease X-linked myotubular myopathy, characterized by persistence of muscle fibers that retain an immature phenotype. We have previously reported the identification of the 3-phosphatase adapter protein (3-PAP), a catalytically inactive member of the myotubularin gene family, which coprecipitates lipid phosphatidylinositol 3-phosphate-3-phosphatase activity from lysates of human platelets. We have now identified myotubularin as the catalytically active 3-phosphatase subunit interacting with 3-PAP. A 65-kDa polypeptide, coprecipitating with endogenous 3-PAP, was purified from SDS/PAGE, subjected to trypsin digestion, and analyzed by collision-induced dissociation tandem MS. Three peptides derived from human myotubularin were identified. Association between 3-PAP and myotubularin was confirmed by reciprocal coimmunoprecipitation of both endogenous and recombinant proteins expressed in K562 cells. Recombinant myotubularin localized to the plasma membrane, causing extensive filopodia formation. However, coexpression of 3-PAP with myotubularin led to attenuation of the plasma membrane phenotype, associated with myotubularin relocalization to the cytosol. Collectively these studies indicate 3-PAP functions as an "adapter" for myotubularin, regulating myotubularin intracellular location and thereby altering the phenotype resulting from myotubularin overexpression.
机译：肌微管蛋白是一种双特异性磷酸酶，可将磷脂酰肌醇3-磷酸和磷脂酰肌醇（3,5）-双磷酸去磷酸化。肌管蛋白突变会导致人类疾病X连锁型肌管肌病，其特征是保留未成熟表型的肌纤维持续存在。我们以前曾报道过鉴定3-磷酸酶衔接蛋白（3-PAP），它是肌管蛋白基因家族的一种催化失活成员，它可以从人血小板的裂解物中共沉淀脂质磷脂酰肌醇3-磷酸-3-磷酸酶的活性。现在我们已经确定了肌微管蛋白是与3-PAP相互作用的催化活性3-磷酸酶亚基。从SDS / PAGE纯化与内源性3-PAP共沉淀的65 kDa多肽，进行胰蛋白酶消化，并通过碰撞诱导解离串联MS进行分析。鉴定了三种源自人肌管蛋白的肽。通过相互共免疫沉淀在K562细胞中表达的内源性蛋白质和重组蛋白，证实了3-PAP和肌微管蛋白之间的关联。重组肌管蛋白定位于质膜，引起大量丝状伪足的形成。然而，3-PAP与肌微管蛋白的共表达导致质膜表型的减弱，与肌微管蛋白重新定位到细胞质有关。这些研究共同表明3-PAP充当肌管蛋白的“适配器”，调节肌管蛋白在细胞内的位置，从而改变由肌管蛋白过表达引起的表型。

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