Najarzadeh Zahra, Nielsen Janni, Farzadfard Azad, Sereikaite Vita, Strømgaard Kristian, Meyer Rikke Louise, Otzen Daniel Erik
Interdisciplinary Nanoscience Centre (iNANO), Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C, Denmark.
Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark.
ACS Omega. 2021 Aug 16;6(34):21960-21970. doi: 10.1021/acsomega.1c02333. eCollection 2021 Aug 31.
Functional amyloids are highly organized protein/peptide structures that promote biofilm formation in different bacteria. One such example is provided by a family of 20-45 residue-long peptides called phenol-soluble modulins (PSMs) from . External components such as eukaryotic host proteins, which alter self-assembly of bacterial amyloids, can affect the biofilm matrix. Here, we studied the effect of the highly prevalent human plasma protein fibrinogen (Fg) on fibrillation of PSMs. Fg inhibits or suppresses fibrillation of most PSMs tested (PSMα1, PSMβ1, and PSMβ2) except for PSMα3, whose already rapid aggregation is accelerated even further by Fg but leads to amorphous β-rich aggregates rather than fibrils. Fg also induces PSMβ2 to form amorphous aggregates and diverts PSMα1 into off-pathway oligomers which consist of both Fg and PSMα1 and cannot seed fibrillation. Peptide arrays showed that Fg bound to the N-terminus of PSMα1, while it bound to the entire length of PSMα3 (except the C terminus) and to the C-termini of PSMβ1 and PSMβ2. The latter peptides are all positively charged, while Fg is negatively charged at physiological pH. The positive charges complement Fg's net negative charge of -7.6 at pH 7.4. Fg's ability to inhibit PSM fibrillation reveals a potential host-defense mechanism to prevent bacterial biofilm growth and infections in the human body.
功能性淀粉样蛋白是高度有序的蛋白质/肽结构，可促进不同细菌中的生物膜形成。一个这样的例子是来自金黄色葡萄球菌的一类长度为20 - 45个残基的肽，称为酚溶性调节素（PSM）。诸如真核宿主蛋白之类的外部成分可改变细菌淀粉样蛋白的自组装，进而影响生物膜基质。在此，我们研究了高度普遍存在的人类血浆蛋白纤维蛋白原（Fg）对PSM原纤维形成的影响。Fg抑制或抑制了大多数测试的PSM（PSMα1、PSMβ1和PSMβ2）的原纤维形成，但PSMα3除外，其原本快速的聚集被Fg进一步加速，但导致形成富含β片层的无定形聚集体而非原纤维。Fg还诱导PSMβ2形成无定形聚集体，并使PSMα1转变为偏离途径的寡聚体，该寡聚体由Fg和PSMα1组成，不能引发原纤维形成。肽阵列显示，Fg与PSMα1的N端结合，而与PSMα3的全长（除C端外）以及PSMβ1和PSMβ2的C端结合。后几种肽均带正电荷，而Fg在生理pH值下带负电荷。正电荷补充了Fg在pH 7.4时 - 7.6的净负电荷。Fg抑制PSM原纤维形成的能力揭示了一种潜在的宿主防御机制，可防止人体中的细菌生物膜生长和感染。
