Regulation of MTMR2 by the inactive phosphatase MTMR13

描述（由申请人提供）：肌管蛋白相关蛋白2（MTMR 2）是一种磷脂磷酸酶，对PI（3）P和PI（3，5）P2的3个位置具有特异性。MTMR 2中的功能缺失突变导致脱髓鞘性周围神经病Charcot-Maire-Tooth病4 B型（CMT-4 B），这是一种以局灶性折叠髓鞘为特征的严重衰弱性遗传性病症。第二个肌管蛋白家族成员MTMR 13（也称为SET结构域结合因子2 [SBF 2]）的隐性突变也会导致CMT-4 B。MTMR 13是微管蛋白肌醇脂质磷酸酶家族的无催化活性成员。我们实验室的最新数据表明，MTMR 2也与密切相关的蛋白MTMR 5（也称为SBF 1）结合并受其调节。MTMR 5与MTMR 13具有59%的同一性，具有相同的结构域组成，并且也是无活性的磷酸酶。然而，MTMR 5不太可能参与CMT-4 B。我们建议研究MTMR 2的脂质磷酸酶活性是如何调节的。具体地，将检查MTMR 13对MTMR 2功能的影响。最初的实验将涉及研究MTMR 2和MTMR 13蛋白是否物理相互作用。将在体外和细胞生物学实验中分析MTMR 13缔合对MTMR 2的催化活性的影响。还将研究MTMR 2-MTMR 13相互作用对两种蛋白质的细胞定位的影响。最后，提出实验来鉴定与MTMR 13和MTMR 2相关的其他蛋白质。

DESCRIPTION (provided by applicant): Myotubularin related protein 2 (MTMR2) is a phospho-lipid phosphatase specific for the 3 positions of PI(3)P and Pl(3,5)P2. Loss of function mutations in MTMR2 cause the demyelinating peripheral neuropathy Charcot-Maire-Tooth disease type 4B (CMT-4B), a severely debilitating, hereditary condition characterized by focally folded myelin sheaths. Recessive mutations in a second myotubularin family member, MTMR13 (also called SET domain binding factor 2 [SBF2]) also cause CMT-4B. MTMR13 is a catalytically inactive member of the myotubularin inositol lipid phosphatase family. Recent data from our laboratory indicate that MTMR2 also binds to and is regulated by the closely related protein MTMR5 (also called SBF1). MTMR5 is 59% identical to MTMR13, has an identical domain composition, and is also an inactive phosphatase. However, MTMR5 is unlikely to be involved in CMT-4B. We propose to investigate how the lipid phosphatase activity of MTMR2 is regulated. Specifically, the effect of MTMR13 on MTMR2 function will be examined. Initial experiments will involve investigating whether the MTMR2 and MTMR13 proteins physically interact. The effect of MTMR13 association on the catalytic activity of MTMR2 will be analyzed both in vitro and in cell biological experiments. The effect of MTMR2-MTMR13 interactions on the cellular localization of both proteins will also be investigated. Finally, experiments are proposed to identify additional proteins that associate with MTMR13 and MTMR2.