Crystal structure of Alzheimer's disease phospholipase D3 provides a molecular basis for understanding its normal and pathological functions
Kenta Ishiia b, Stefan J. Hermansa b, Maria Eleni Georgopouloua b c, Tracy L. Neroa, Nancy C. Hancocka b, Gabriela A. N. Crespia b, Michael A. Gormana, Jonathan H. Gooia b, Michael W. Parkera b✉
- aDepartment of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute University of Melbourne Parkville Australia
- bStructural Biology Laboratory St Vincent's Institute of Medical Research Fitzroy Australia
- cARC Centre for Cryo‐electron Microscopy of Membrane Proteins, Bio21 Molecular Science and Biotechnology Institute University of Melbourne Parkville Australia
- ✉Corresponding author
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Abstract
Human 5'-3' exonuclease PLD3, a member of the phospholipase D family of enzymes, has been validated as a therapeutic target for treating Alzheimer's disease. Here, we have determined the crystal structure of the luminal domain of the enzyme at 2.3 Å resolution, revealing a bilobal structure with a catalytic site located between the lobes. We then compared the structure with published crystal structures of other human PLD family members which revealed that a number of catalytic and lipid recognition residues, previously shown to be key for phospholipase activity, are not conserved or, are absent. This led us to test whether the enzyme is actually a phospholipase. We could not measure any phospholipase activity but the enzyme shows robust nuclease activity. Finally, we have mapped key single nucleotide polymorphisms onto the structure which reveals plausible reasons as to why they have an impact on Alzheimer's disease.
TL;DRThe crystal structure of the luminal domain of the phospholipase D enzyme is determined at 2.3 Å resolution, revealing a bilobal structure with a catalytic site located between the lobes and key single nucleotide polymorphisms are mapped onto the structure which reveals plausible reasons as to why they have an impact on Alzheimer's disease. (Semantic Scholar)