Zinc Binding by Histatin 5 Promotes Fungicidal Membrane Disruption in C. albicans and C. glabrata.
Zinc Binding by Histatin 5 Promotes Fungicidal Membrane Disruption in C. albicans and C. glabrata.
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DOI：
10.3390/jof6030124
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发表时间：
2020-07-31
期刊：
影响因子：
--
通讯作者：
Edgerton M
中科院分区：
文献类型：
--
作者：
Norris HL;Kumar R;Ong CY;Xu D;Edgerton M
组胺抑制素5（Hst 5）是一种由唾液分泌的抗菌肽，具有抗白色念珠菌的活性。Hst 5结合多种阳离子，包括二聚诱导锌（Zn 2+），尽管这种能力的功能还不完全清楚。Hst 5被C.白色念珠菌和作用于细胞内的目标，在无金属条件下，然而，锌2+是丰富的唾液，并可能在功能上影响Hst 5。我们假设，Zn 2+结合将通过二聚化诱导膜破坏孔。通过对Hst 5及其衍生物P113（Hst 5的AA 4-15）和Hst 5ΔMB（Hst 5的AA 1-3和15-19突变为Glu）的研究，我们发现Zn ~（2+）能显著提高Hst 5和P113对C.白色念珠菌和光滑念珠菌。细胞缔合测定确定Zn 2+不影响肽的初始表面结合，但由于活性肽摄取，Zn 2+确实降低了细胞缔合。用Zn 2+进行的ATP流出试验表明，Hst 5和P113使膜快速透化，并且Zn 2+亲和力与更高的膜破坏能力相关。高效液相色谱（HPLC）显示，Hst 5的较高相对Zn 2+亲和力可能促进二聚化。总之，这些结果表明，在Zn 2+存在下，肽组装成杀真菌孔结构，代表了一种新的作用机制，具有令人兴奋的潜力，以扩大Hst 5敏感病原体的列表。
Histatin 5 (Hst 5) is an antimicrobial peptide produced in human saliva with antifungal activity for opportunistic pathogen Candida albicans. Hst 5 binds to multiple cations including dimerization-inducing zinc (Zn2+), although the function of this capability is incompletely understood. Hst 5 is taken up by C. albicans and acts on intracellular targets under metal-free conditions; however, Zn2+ is abundant in saliva and may functionally affect Hst 5. We hypothesized that Zn2+ binding would induce membrane-disrupting pores through dimerization. Through the use of Hst 5 and two derivatives, P113 (AA 4-15 of Hst 5) and Hst 5ΔMB (AA 1-3 and 15-19 mutated to Glu), we determined that Zn2+ significantly increases killing activity of Hst 5 and P113 for both C. albicans and Candida glabrata. Cell association assays determined that Zn2+ did not impact initial surface binding by the peptides, but Zn2+ did decrease cell association due to active peptide uptake. ATP efflux assays with Zn2+ suggested rapid membrane permeabilization by Hst 5 and P113 and that Zn2+ affinity correlates to higher membrane disruption ability. High-performance liquid chromatography (HPLC) showed that the higher relative Zn2+ affinity of Hst 5 likely promotes dimerization. Together, these results suggest peptide assembly into fungicidal pore structures in the presence of Zn2+, representing a novel mechanism of action that has exciting potential to expand the list of Hst 5-susceptible pathogens.
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影响因子：
3.6
作者：
Jang WS;Bajwa JS;Sun JN;Edgerton M
通讯作者：
Edgerton M
影响因子：
4.1
作者：
den Hertog, AL;Sang, HWWF;Amerongen, AVN
通讯作者：
Amerongen, AVN
影响因子：
5.8
作者：
Lorenzon, Esteban N.;Nobre, Thatyane M.;Oliveira, Osvaldo N., Jr.
通讯作者：
Oliveira, Osvaldo N., Jr.
影响因子：
2.9
作者：
Arnusch, Christopher J.;Branderhorst, Hilbert;Pieters, Roland J.
通讯作者：
Pieters, Roland J.
影响因子：
2.9
作者：
Conklin, Steven E.;Bridgman, Emma C.;Franz, Katherine J.
通讯作者：
Franz, Katherine J.