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Crystal Structure of Catalytic Domain of Human Phospholipase D1
Structural highlights
DiseasePLD1_HUMAN The disease is caused by mutations affecting the gene represented in this entry. FunctionPLD1_HUMAN Implicated as a critical step in numerous cellular pathways, including signal transduction, membrane trafficking, and the regulation of mitosis. May be involved in the regulation of perinuclear intravesicular membrane traffic (By similarity). Publication Abstract from PubMedThe signal transduction enzyme phospholipase D1 (PLD1) hydrolyzes phosphatidylcholine to generate the lipid second-messenger phosphatidic acid, which plays roles in disease processes such as thrombosis and cancer. PLD1 is directly and synergistically regulated by protein kinase C, Arf and Rho GTPases, and the membrane lipid phosphatidylinositol-4,5-bisphosphate (PIP2). Here, we present a 1.8 A-resolution crystal structure of the human PLD1 catalytic domain, which is characterized by a globular fold with a funnel-shaped hydrophobic cavity leading to the active site. Adjacent is a PIP2-binding polybasic pocket at the membrane interface that is essential for activity. The C terminus folds into and contributes part of the catalytic pocket, which harbors a phosphohistidine that mimics an intermediate stage of the catalytic cycle. Mapping of PLD1 mutations that disrupt RhoA activation identifies the RhoA-PLD1 binding interface. This structure sheds light on PLD1 regulation by lipid and protein effectors, enabling rationale inhibitor design for this well-studied therapeutic target. Crystal structure of human PLD1 provides insight into activation by PI(4,5)P2 and RhoA.,Bowling FZ, Salazar CM, Bell JA, Huq TS, Frohman MA, Airola MV Nat Chem Biol. 2020 Apr;16(4):400-407. doi: 10.1038/s41589-020-0499-8. Epub 2020 , Mar 16. PMID:32198492[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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