Publisher Correction: Crystal structure of a lipin/Pah phosphatidic acid phosphatase.
Publisher Correction: Crystal structure of a lipin/Pah phosphatidic acid phosphatase.
复制标题
出版商更正：脂质/Pah 磷脂酸磷酸酶的晶体结构。
DOI：
10.1038/s41467-020-15509-0
复制
发表时间：
2020
影响因子：
16.6
通讯作者：
Airola,MichaelV
中科院分区：
文献类型：
--
作者：
Khayyo,ValerieI;Hoffmann,ReeceM;Wang,Huan;Bell,JustinA;Burke,JohnE;Reue,Karen;Airola,MichaelV
脂质/PAH磷脂酸磷酸酶(PAPs)产生二酰甘油来调节甘油三酯的合成和细胞信号转导。失活突变会导致横纹肌溶解、自体炎症性疾病和异常脂肪储存。疾病突变聚集在人类保守的N-Lip和C-Lip区域，这两个区域被500个残基隔开。为了了解N-Lip和C-Lip如何结合形成PAP功能，我们测定了直接融合N-Lip和C-Lip的四膜虫嗜热四膜虫Pah2(TtPah2)的晶体结构。TtPah2采用双域结构，其中N-Lip与部分C-Lip结合形成免疫球蛋白样结构域，其余C-Lip形成类HAD催化结构域。小鼠Lipin-2的N-Lip C-Lip融合具有催化活性，这表明哺乳动物Lipins的功能与TtPah2具有相同的结构域结构。HDX-MS鉴定了膜结合所必需的N-末端两亲性螺旋。疾病突变会破坏催化作用或破坏蛋白质折叠的稳定性。这说明了脂类/Pah PAP功能、膜结合和脂类相关病理的机制。
Lipin/Pah phosphatidic acid phosphatases (PAPs) generate diacylglycerol to regulate triglyceride synthesis and cellular signaling. Inactivating mutations cause rhabdomyolysis, autoinflammatory disease, and aberrant fat storage. Disease-mutations cluster within the conserved N-Lip and C-Lip regions that are separated by 500-residues in humans. To understand how the N-Lip and C-Lip combine for PAP function, we determined crystal structures ofTetrahymena thermophilaPah2 (TtPah2) that directly fuses the N-Lip and C-Lip.TtPah2 adopts a two-domain architecture where the N-Lip combines with part of the C-Lip to form an immunoglobulin-like domain and the remaining C-Lip forms a HAD-like catalytic domain. An N-Lip C-Lip fusion of mouse lipin-2 is catalytically active, which suggests mammalian lipins function with the same domain architecture asTtPah2. HDX-MS identifies an N-terminal amphipathic helix essential for membrane association. Disease-mutations disrupt catalysis or destabilize the protein fold. This illustrates mechanisms for lipin/Pah PAP function, membrane association, and lipin-related pathologies.