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Specificity of Loxosceles α clade phospholipase D enzymes for choline-containing lipids: role of a conserved aromatic cage

View ORCID ProfileEmmanuel E. Moutoussamy, View ORCID ProfileQaiser Waheed, View ORCID ProfileGreta J. Binford, View ORCID ProfileHanif M. Khan, View ORCID ProfileShane M. Moran, View ORCID ProfileAnna R. Eitel, Matthew H.J. Cordes, View ORCID ProfileNathalie Reuter
doi: https://doi.org/10.1101/2021.07.16.452673
Emmanuel E. Moutoussamy
1Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway
2Department of Biological Sciences, University of Bergen, Bergen, Norway
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Qaiser Waheed
1Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway
2Department of Biological Sciences, University of Bergen, Bergen, Norway
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Greta J. Binford
3Department of Biology, Lewis and Clark College, Portland, Oregon, United States
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Hanif M. Khan
1Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway
2Department of Biological Sciences, University of Bergen, Bergen, Norway
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Shane M. Moran
4Department of Chemistry and Biochemistry, University of Arizona, Arizona, United States
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Anna R. Eitel
4Department of Chemistry and Biochemistry, University of Arizona, Arizona, United States
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Matthew H.J. Cordes
4Department of Chemistry and Biochemistry, University of Arizona, Arizona, United States
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Nathalie Reuter
1Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway
5Department of Chemistry, University of Bergen, Bergen, Norway
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  • For correspondence: nathalie.reuter@uib.no
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ABSTRACT

Spider venom GDPD-like phospholipases D (SicTox) have been identified to be one of the major toxins in recluse spider venom. They are divided into two major clades: the α clade and the β clade. Most α clade toxins present high activity against lipids with choline head groups such as sphingomyelin, while activities in β clade toxins vary and include preference for substrates containing ethanolamine headgroups (Sicarius terrosus, St_βIB1). A structural comparison of available PLDs structures reveals a conserved aromatic cage in the α clade. To test the potential influence of the aromatic cage on membrane-lipid specificity we performed molecular-dynamics (MD) simulations of the binding of several PLDs onto lipid bilayers containing choline headgroups; two SicTox from the α clade, Loxosceles intermedia αIA1 (Li_αIA) and Loxosceles laeta αIII1 (Ll_αIII1), and one from the β clade, St_βIB1. The simulation results reveal that the aromatic cage captures a choline-headgroup and suggest that the cage plays a major role in lipid specificity. We also simulated an engineered St_βIB1, where we introduced the aromatic cage, and this led to binding with choline-containing lipids. Moreover, a multiple sequence alignment revealed the conservation of the aromatic cage among the α clade PLDs. Here, we confirmed the membrane binding site of α and β clade PLDs on choline and ethanolamine-containing bilayers, respectively. Furthermore, our results suggest a major role in choline lipid recognition of the aromatic cage of the α clade PLDs. The MD simulation results are supported by in vitro liposome binding assay experiments.

Competing Interest Statement

The authors have declared no competing interest.

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Posted July 18, 2021.
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Specificity of Loxosceles α clade phospholipase D enzymes for choline-containing lipids: role of a conserved aromatic cage
Emmanuel E. Moutoussamy, Qaiser Waheed, Greta J. Binford, Hanif M. Khan, Shane M. Moran, Anna R. Eitel, Matthew H.J. Cordes, Nathalie Reuter
bioRxiv 2021.07.16.452673; doi: https://doi.org/10.1101/2021.07.16.452673
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Specificity of Loxosceles α clade phospholipase D enzymes for choline-containing lipids: role of a conserved aromatic cage
Emmanuel E. Moutoussamy, Qaiser Waheed, Greta J. Binford, Hanif M. Khan, Shane M. Moran, Anna R. Eitel, Matthew H.J. Cordes, Nathalie Reuter
bioRxiv 2021.07.16.452673; doi: https://doi.org/10.1101/2021.07.16.452673

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