Nicotiana alata defensin chimeras reveal differences in the mechanism of fungal and tumor cell killing and an enhanced antifungal variant

Bleackley, Mark R., Payne, Jennifer A. E., Hayes, Brigitte M. E, Durek, Thomas, Craik, David J., Shafee, Thomas M. A., Poon, Ivan K. H., Hulett, Mark D., Van Der Weerden, Nicole L. and Anderson, Marilyn A. (2016) Nicotiana alata defensin chimeras reveal differences in the mechanism of fungal and tumor cell killing and an enhanced antifungal variant. Antimicrobial Agents and Chemotherapy, 60 10: 6302-6312. doi:10.1128/AAC.01479-16

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Author Bleackley, Mark R.
Payne, Jennifer A. E.
Hayes, Brigitte M. E
Durek, Thomas
Craik, David J.
Shafee, Thomas M. A.
Poon, Ivan K. H.
Hulett, Mark D.
Van Der Weerden, Nicole L.
Anderson, Marilyn A.
Title Nicotiana alata defensin chimeras reveal differences in the mechanism of fungal and tumor cell killing and an enhanced antifungal variant
Formatted title
Nicotiana alata defensin chimeras reveal differences in the mechanism of fungal and tumor cell killing and an enhanced antifungal variant
Journal name Antimicrobial Agents and Chemotherapy   Check publisher's open access policy
ISSN 1098-6596
0066-4804
Publication date 2016-10-01
Sub-type Article (original research)
DOI 10.1128/AAC.01479-16
Open Access Status File (Publisher version)
Volume 60
Issue 10
Start page 6302
End page 6312
Total pages 11
Place of publication Washington, DC, United States
Publisher American Society for Microbiology
Language eng
Formatted abstract
The plant defensin NaD1 is a potent antifungal molecule that also targets tumor cells with a high efficiency. We examined the features of NaD1 that contribute to these two activities by producing a series of chimeras with NaD2, a defensin that has relatively poor activity against fungi and no activity against tumor cells. All plant defensins have a common tertiary structure known as a cysteine-stabilized α-β motif which consists of an α helix and a triple-stranded β-sheet stabilized by four disulfide bonds. The chimeras were produced by replacing loops 1 to 7, the sequences between each of the conserved cysteine residues on NaD1, with the corresponding loops from NaD2. The loop 5 swap replaced the sequence motif (SKILRR) that mediates tight binding with phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and is essential for the potent cytotoxic effect of NaD1 on tumor cells. Consistent with previous reports, there was a strong correlation between PI(4,5)P2 binding and the tumor cell killing activity of all of the chimeras. However, this correlation did not extend to antifungal activity. Some of the loop swap chimeras were efficient antifungal molecules, even though they bound poorly to PI(4,5)P2, suggesting that additional mechanisms operate against fungal cells. Unexpectedly, the loop 1B swap chimera was 10 times more active than NaD1 against filamentous fungi. This led to the conclusion that defensin loops have evolved as modular components that combine to make antifungal molecules with variable mechanisms of action and that artificial combinations of loops can increase antifungal activity compared to that of the natural variants.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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