Antimicrobial Protegrin-1 Forms Amyloid-Like Fibrils with Rapid Kinetics Suggesting a Functional Link
Antimicrobial Protegrin-1 Forms Amyloid-Like Fibrils with Rapid Kinetics Suggesting a Functional Link
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DOI：
10.1016/j.bpj.2011.01.072
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发表时间：
2011-04-06
影响因子：
3.4
通讯作者：
Lal, Ratnesh
中科院分区：
文献类型：
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作者：
Jang, Hyunbum;Arce, Fernando Teran;Lal, Ratnesh
Protegrin-1（PG-1）是一种18个残基长的富含半胱氨酸的β折叠抗菌肽（AMP）。PG-1在细胞膜上诱导强烈的细胞毒活性，并作为一种有效的抗生素。早先我们报道了它的细胞毒性是由它的通道形成能力介导的。在这项研究中，我们研究了PG-1与一种定义明确的淀粉样蛋白-β（A β（1-42））肽相比的淀粉样蛋白原纤维形成特性。我们已经使用原子力显微镜（AFM）和硫磺素-T染色研究PG-1纤维生长的动力学和分子动力学模拟，以阐明潜在的机制。PG-1在高亲水性表面（云母）上的AFM图像显示出与A β（1-42）原纤维具有形态相似性的原纤维。原纤维生长的实时AFM成像表明，与A β（1-42）原纤维相比，PG-1原纤维生长遵循相对较快的动力学。原子力显微镜的结果是在从硫磺素-T染色数据的结果密切一致。此外，结果表明PG-1在溶液中形成原纤维。值得注意的是，相比之下，我们在阴离子脂质双层2-二油酰基-sn-甘油基-3-磷酸-L-丝氨酸/1-棕榈酰基-2-油酰基-sn-甘油基-3-磷酸乙醇胺上没有检测到PG-1的纤维状结构;只能观察到小的PG-1寡聚体。分子动力学模拟能够识别膜双层上这些小的低聚物的存在。因此，我们目前的研究结果表明，细胞毒性AMP PG-1是淀粉样蛋白和能够形成原纤维。总的来说，比较富含β的AMP和淀粉样蛋白如A β，除了细胞毒性和淀粉样蛋白原性之外，它们具有共同的结构基序，并且是通道形成的。这些综合性质支持淀粉样蛋白生成肽和富含β折叠的细胞溶解性AMP之间的功能关系，表明淀粉样蛋白通道可能具有抗菌功能。
Protegrin-1 (PG-1) is an 18 residues long, cysteine-rich beta-sheet antimicrobial peptide (AMP). PG-1 induces strong cytotoxic activities on cell membrane and acts as a potent antibiotic agent. Earlier we reported that its cytotoxicity is mediated by its channel-forming ability. In this study, we have examined the amyloidogenic fibril formation properties of PG-1 in comparison with a well-defined amyloid, the amyloid-beta (A beta(1-42)) peptide. We have used atomic force microscopy (AFM) and thioflavin-T staining to investigate the kinetics of PG-1 fibrils growth and molecular dynamics simulations to elucidate the underlying mechanism. AFM images of PG-1 on a highly hydrophilic surface (mica) show fibrils with morphological similarities to A beta(1-42) fibrils. Real-time AFM imaging of fibril growth suggests that PG-1 fibril growth follows a relatively fast kinetics compared to the A beta(1-42) fibrils. The AFM results are in close agreement with results from thioflavin-T staining data. Furthermore, the results indicate that PG-1 forms fibrils in solution. Significantly, in contrast, we do not detect fibrillar structures of PG-1 on an anionic lipid bilayer 2-dioleoyl-sn-glycero-3-phospho-L-serine/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine; only small PG-1 oligomers can be observed. Molecular dynamics simulations are able to identify the presence of these small oligomers on the membrane bilayer. Thus, our current results show that cytotoxic AMP PG-1 is amyloidogenic and capable of forming fibrils. Overall, comparing beta-rich AMPs and amyloids such as A beta, in addition to cytotoxicity and amyloidogenicity, they share a common structural motif, and are channel forming. These combined properties support a functional relationship between amyloidogenic peptides and beta-sheet-rich cytolytic AMPs, suggesting that amyloids channels may have an antimicrobial function.