Modular determinants of antimicrobial activity in platelet factor-4 family kinocidins
Modular determinants of antimicrobial activity in platelet factor-4 family kinocidins
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DOI：
10.1016/j.bbamem.2006.11.010
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发表时间：
2007-03-01
影响因子：
3.4
通讯作者：
Welch, William H.
中科院分区：
文献类型：
--
作者：
Yeaman, Michael R.;Yount, Nannette Y.;Welch, William H.
哺乳动物血小板含有一系列抗菌肽，称为血小板杀微生物蛋白（PMP）。人和兔PMP包括已知的趋化因子，如血小板因子-4（HPF-4）; PMP-1是HPF-4的兔直向同源物。也发挥直接抗微生物活性的趋化因子被称为激肽。分析了代表哺乳动物PF-4家族成员的共有肽结构域文库，以确定有助于对一组人类病原体的抗微生物活性的结构域。二级构象进行了评估，通过圆二色光谱，并采用分子建模，以研究抗菌功效的结构相关性。对定位于C-末端半聚体（38-74）及其模块结构域（49-63和60-74）的同基因肽敏感或耐药金黄色葡萄球菌、鼠伤寒沙门氏菌和白色念珠菌菌株对的抗微生物活性。增加静电荷和空间体积是功效的一般相关性。结构数据证实了空间分布的电荷，空间体积和推定的二级结构与生物体特异性的功效。cPMP抗微生物半聚体和C-末端肽（60-74）的杀微生物效力在复杂的人血生物基质测定中得以保留。总的来说，这些结果表明，模块化的决定因素所产生的结构组件独立和合作的管理PF-4家族kinocidins对特定的目标病原体的抗微生物功能。(c)2006 Elsevier B. V.保留所有权利。
Mammalian platelets contain an array of antimicrobial peptides, termed platelet microbicidal proteins (PMPs). Human and rabbit PMPs include known chemokines, such as platelet factor-4 (hPF-4); PMP-1 is the rabbit orthologue of hPF-4. Chemokines that also exert direct antimicrobial activity have been termed kinocidins. A consensus peptide domain library representing mammalian PF-4 family members was analyzed to define structural domains contributing to antimicrobial activity against a panel of human pathogens. Secondary conformations were assessed by circular dichroism spectrometry, and molecular modeling was employed to investigate structural correlates of antimicrobial efficacy. Antimicrobial activity against isogenic peptide-susceptible or -resistant Staphylococcus aureus, Salmonella typhimurium, and Candida albicans strain pairs mapped to the C-terminal hemimer (38-74) and modular domains thereof (49-63 and 60-74). Increasing electrostatic charge and steric bulk were general correlates of efficacy. Structural data corroborated spatial distribution of charge, steric bulk and putative secondary structure with organism-specific efficacy. Microbicidal efficacies of the cPMP antimicrobial hemimer and C-terminal peptide (60-74) were retained in a complex human-blood biomatrix assay. Collectively, these results suggest that modular determinants arising from structural components acting independently and cooperatively govern the antimicrobial functions of PF-4 family kinocidins against specific target pathogens. (c) 2006 Elsevier B.V. All rights reserved.