Structural and mechanistic insights into disease-associated endolysosomal exonucleases PLD3 and PLD4

被引:4
|
作者
Yuan, Meng [1 ]
Peng, Linghang [2 ]
Huang, Deli [2 ,4 ,5 ]
Gavin, Amanda [2 ]
Luan, Fangkun [2 ]
Tran, Jenny [2 ]
Feng, Ziqi [1 ]
Zhu, Xueyong [1 ]
Matteson, Jeanne [1 ]
Wilson, Ian A. [1 ,3 ]
Nemazee, David [2 ]
机构
[1] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA
[2] Scripps Res Inst, Dept Immunol & Microbiol, La Jolla, CA 92037 USA
[3] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA
[4] Zhejiang Univ, Life Sci Inst, Hangzhou 310058, Zhejiang, Peoples R China
[5] Zhejiang Univ, Innovat Ctr Cell Signaling Network, Hangzhou 310058, Zhejiang, Peoples R China
关键词
DOUBLE-STRANDED DNA; PHOSPHOLIPASE-D; CRYSTAL-STRUCTURE; ACID-PHOSPHATASE; GENE; ENZYME; VARIANTS;
D O I
10.1016/j.str.2024.02.019
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Endolysosomal exonucleases PLD3 and PLD4 (phospholipases D3 and D4) are associated with autoinflam- matory and autoimmune diseases. We report structures of these enzymes, and the molecular basis of their catalysis. The structures reveal an intra-chain dimer topology forming a basic active site at the interface. Like other PLD superfamily members, PLD3 and PLD4 carry HxKxxxxD/E motifs and participate in phospho- diester-bond cleavage. The enzymes digest ssDNA and ssRNA in a 5 0 -to -3 0 manner and are blocked by 5 0 -phosphorylation. We captured structures in apo, intermediate, and product states and revealed a "link- and-release"two-step catalysis. We also unexpectedly demonstrated phosphatase activity via a covalent 3-phosphohistidine intermediate. PLD4 contains an extra hydrophobic clamp that stabilizes substrate and could affect oligonucleotide substrate preference and product release. Biochemical and structural analysis of disease -associated mutants of PLD3/4 demonstrated reduced enzyme activity or thermostability and the possible basis for disease association. Furthermore, these findings provide insight into therapeutic design.
引用
收藏
页码:766 / 779.e7
页数:22
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