Insights into Lysosomal PI(3,5)P(2) Homeostasis from a Structural-Biochemical Analysis of the PIKfyve Lipid Kinase Complex.
Insights into Lysosomal PI(3,5)P(2) Homeostasis from a Structural-Biochemical Analysis of the PIKfyve Lipid Kinase Complex.
复制标题
DOI：
10.1016/j.molcel.2020.10.003
复制
发表时间：
2020-11-19
期刊：
影响因子：
16
通讯作者：
Reinisch KM
中科院分区：
文献类型：
--
作者：
Lees JA;Li P;Kumar N;Weisman LS;Reinisch KM
仅由PIKfyve脂质激酶复合物产生的磷酸肌醇PI（3，5）P2是溶酶体生物学的关键。在这里，我们探讨PI（3，5）P2水平在细胞内的调节。我们发现PIKfyve复合物包含5个拷贝的支架蛋白Vac14，和一个拷贝的脂质激酶PIKfyve，从PI3P产生PI（3，5）P2，和脂质磷酸酶图4，逆转反应。图4在三元复合物中作为脂质磷酸酶是有活性的，而复合物内的PIKfyve由于空间限制而不能接近膜掺入的磷酸肌醇。我们进一步发现，PIKfyve和Fig4的磷酸肌醇导向活性都受到复合物内蛋白质导向活性的调节。PIKfyve自身磷酸化抑制其脂质激酶活性并刺激图4脂质磷酸酶活性。此外，图4也是作用于PIKfyve以刺激其脂质激酶活性的蛋白磷酸酶，解释了为什么催化活性图4是PIKfyve在体内产生最大PI（3，5）P2所必需的。
The phosphoinositide PI(3,5)P2, generated exclusively by the PIKfyve lipid kinase complex, is key for lysosomal biology. Here we explore how PI(3,5)P2 levels within cells are regulated. We find the PIKfyve complex comprises 5 copies of the scaffolding protein Vac14, and one copy each of the lipid kinase PIKfyve, generating PI(3,5)P2 from PI3P, and the lipid phosphatase Fig4, reversing the reaction. Fig4 is active as a lipid phosphatase in the ternary complex, whereas PIKfyve within the complex cannot access membrane-incorporated phosphoinositides due to steric constraints. We find further that the phosphoinositide-directed activities of both PIKfyve and Fig4 are regulated by protein-directed activities within the complex. PIKfyve autophosphorylation represses its lipid kinase activity and stimulates Fig4 lipid phosphatase activity. Further, Fig4 is also a protein phosphatase acting on PIKfyve to stimulate its lipid kinase activity, explaining why catalytically active Fig4 is required for maximal PI(3,5)P2 production by PIKfyve in vivo.
登录
查看更多内容
DOI：
10.1073/pnas.1722517115
发表时间：
2018-05-01
影响因子：
11.1
作者：
Malia PC;Numrich J;Nishimura T;González Montoro A;Stefan CJ;Ungermann C
通讯作者：
Ungermann C
影响因子：
48
作者：
Zheng SQ;Palovcak E;Armache JP;Verba KA;Cheng Y;Agard DA
通讯作者：
Agard DA
影响因子：
2.9
作者：
Taylor, GS;Dixon, JE
通讯作者：
Dixon, JE
影响因子：
2.9
作者：
Sbrissa, D;Ikonomov, OC;Shisheva, A
通讯作者：
Shisheva, A
影响因子：
3.8
作者：
Nelson EA;Dyall J;Hoenen T;Barnes AB;Zhou H;Liang JY;Michelotti J;Dewey WH;DeWald LE;Bennett RS;Morris PJ;Guha R;Klumpp-Thomas C;McKnight C;Chen YC;Xu X;Wang A;Hughes E;Martin S;Thomas C;Jahrling PB;Hensley LE;Olinger GG Jr;White JM
通讯作者：
White JM