Journal article
Crystal structure of Alzheimer's disease phospholipase D3 provides a molecular basis for understanding its normal and pathological functions
K Ishii, SJ Hermans, ME Georgopoulou, TL Nero, NC Hancock, GAN Crespi, MA Gorman, JH Gooi, MW Parker
FEBS Journal | WILEY | Published : 2024
DOI: 10.1111/febs.17277
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 phos..
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Awarded by University of Melbourne
Funding Acknowledgements
Some of this research was conducted at the MX2 beamlines of the Australian Synchrotron, part of the Australian Nuclear Science and Technology Organization, and made use of the ACRF Detector at the MX2 beamline. This research made use of the ACRF Facility for Innovative Cancer Drug Discovery, Bio21 Molecular Science and Biotechnology Institute. We acknowledge the Bio21-WEHI crystallization facility, the Melbourne Protein Characterization Platform, and the Melbourne Mass Spectrometry and Proteomics Facility, at the Bio21 Molecular Science and Biotechnology Institute, for exceptional technical support. Funding from the Victorian State Government Operational Infrastructure Support Scheme is acknowledged. M.E.G. has a PhD scholarship funded through the ARC Industry Transformation Training Centre for Cryo-electron Microscopy of Membrane Proteins (IC200100052). M.W.P. is a National Health and Medical Research Council of Australia (NHMRC) Investigator Fellow (APP1194263). The NHMRC had no direct involvement in this work. Open access publishing facilitated by The University of Melbourne, as part of the Wiley - The University of Melbourne agreement via the Council of Australian University Librarians.