THE PROTEIN-DEFICIENT IN LOWE SYNDROME IS A PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 5-PHOSPHATASE
THE PROTEIN-DEFICIENT IN LOWE SYNDROME IS A PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 5-PHOSPHATASE
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DOI：
10.1073/pnas.92.11.4853
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发表时间：
1995-05-23
影响因子：
11.1
通讯作者：
MAJERUS, PW
中科院分区：
文献类型：
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作者：
ZHANG, XL;JEFFERSON, AB;MAJERUS, PW
Lowe综合征，也称为眼脑肾综合征，是由X染色体编码的OCRL基因突变引起的，OCRL蛋白与肌醇多磷酸5-磷酸酶II具有51%的相同性（5-磷酸酶II），表明OCRL可能是一种类似的酶，我们设计了编码与血小板5-磷酸酶同源的氨基酸的OCRL cDNA的构建体，用于在杆状病毒感染的Sf 9昆虫细胞中表达，该cDNA编码OCRL蛋白的aa 264-968。该重组蛋白也催化血小板型5-磷酸酶II的反应，因此OCRL将1，4，5-三磷酸肌醇转化为1，4-二磷酸肌醇，并将1，3，4，5-四磷酸肌醇转化为1，3，4-三磷酸肌醇。最重要的是，该酶将磷脂酰肌醇4，5-二磷酸转化为磷脂酰肌醇4-磷酸。OCRL催化这三个反应的相对能力不同于5-磷酸酶II和来自血小板的另一种5-磷酸酶同工酶5-磷酸酶I。重组OCRL蛋白水解磷脂底物的能力比5-磷酸酶II好10至30倍，而5-磷酸酶I根本不裂解脂质。我们还表明OCRL作为磷脂酰肌醇4，这些结果表明，OCRL主要是一种脂质磷酸酶，可以控制关键代谢产物磷脂酰肌醇4，5-二磷酸的细胞水平。这种酶的缺乏显然引起Lowe综合征的多变表现。
Lowe syndrome, also known as oculocerebrorenal syndrome, is caused by mutations in the X chromosome encoded OCRL gene, The OCRL protein is 51% identical to inositol polyphosphate 5-phosphatase II (5-phosphatase II) from human platelets over a span of 744 aa, suggesting that OCRL may be a similar enzyme, We engineered a construct of the OCRL cDNA that encodes amino acids homologous to the platelet 5-phosphatase for expression in baculovirus-infected Sf9 insect cells, This cDNA encodes aa 264-968 of the OCRL protein. The recombinant protein was found to catalyze the reactions also carried out by platelet 5-phosphatase II, Thus OCRL converts inositol 1,4,5-trisphosphate to inositol 1,4-bisphosphate, and it converts inositol 1,3,4,5-tetrakisphosphate to inositol 1,3,4-trisphosphate. Most important, the enzyme converts phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 4-phosphate. The relative ability of OCRL to catalyze the three reactions is different from that of 5-phosphatase II and from that of another 5 phosphatase isoenzyme from platelets, 5-phosphatase I, The recombinant OCRL protein hydrolyzes the phospholipid substrate 10 to 30-fold better than 5-phosphatase II, and 5-phosphatase I does not cleave the lipid at all, We also show that OCRL functions as a phosphatidylinositol 4,5-bisphosphate 5-phosphatase in OCRL-expressing Sf9 cells, These results suggest that OCRL is mainly a lipid phosphatase that may control cellular levels of a critical metabolite, phosphatidylinositol 4,5-bisphosphate. Deficiency of this enzyme apparently causes the protean manifestations of Lowe syndrome.