An M protein coiled coil unfurls and exposes its hydrophobic core to capture LL-37.
An M protein coiled coil unfurls and exposes its hydrophobic core to capture LL-37.
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一种M蛋白的卷曲螺旋结构展开，暴露出其疏水核心以捕获LL - 37。
DOI：
10.7554/elife.77989
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发表时间：
2022-06-21
期刊：
影响因子：
7.7
通讯作者：
Ghosh, Partho
中科院分区：
文献类型：
--
作者：
Kolesinski, Piotr;Wang, Kuei-Chen;Hirose, Yujiro;Nizet, Victor;Ghosh, Partho
化脓性链球菌（Strep A）的表面相关卷曲螺旋M蛋白通过与选定蛋白质相互作用使人类免疫力丧失。然而，卷曲螺旋缺乏蛋白质-蛋白质相互作用位点的典型特征，因此理解M蛋白如何实现特异性结合（例如，与人抗微生物肽LL-37），从而导致其中和是具有挑战性的。LL-37与M87蛋白（一种来自一种新出现的威胁菌株的抗原性M蛋白变体）的复合物的晶体结构揭示了一种新的相互作用模式。M87卷曲螺旋展开并不对称地暴露其疏水核心以捕获LL-37。单个LL-37分子在晶体中被M87结合，但在溶液中补充了额外的LL-37分子，这与“蛋白质陷阱”中和机制一致。经验证，结晶学可视化的相互作用模式对M87 Strep A菌株中的LL-37耐药性有显著贡献，并被鉴定为在人群中普遍存在的许多其他M蛋白类型中是保守的。我们的研究结果提供了具体的细节治疗抑制LL-37中和M蛋白。我们与许多不同的细菌分享我们的环境。有些细菌对我们的健康有益，如肠道细菌，但其他细菌如果感染并在身体组织内传播，可能会导致严重的疾病。例如，细菌化脓性链球菌可以引起从皮肤感染到快速传播的深层组织感染的各种疾病，使其绰号为“食肉细菌”。为了防止感染，我们的身体已经发展出针对致病细菌的防御机制。这些包括抗菌分子，如LL-37，这是一种在皮肤上产生的小蛋白质。LL-37通过刺穿细菌的细胞膜（相当于我们的皮肤）来杀死细菌;换句话说，它就像一个微小的化学飞镖，“弹出”细菌细胞。然而，一些细菌，包括S.化脓菌可以解除这些防御S.化脓性链球菌用所谓的M蛋白捕获LL-37的表面，从而阻止LL-37到达并破坏下层膜。然而，目前还不清楚这两种蛋白质究竟是如何相互作用的，特别是因为LL-37是一种简单的分子，缺乏允许大多数蛋白质相互结合的结构特征。Kolesibrski等人着手确定M蛋白如何“抓住”LL-37。一种称为X射线晶体学的技术使他们能够逐个原子地观察分子，并在捕获LL-37后检查M蛋白的构型。这些实验选择的M蛋白（M87）来自与特别严重的疾病相关的菌株，被认为是一种新出现的健康威胁。结果表明，M87本身展开，从而暴露出通常隐藏的特定部分。这样，它就可以捕获LL-37，就像一只手张开抓住一个物体一样。Kolesibrski等人揭示了一种关键的分子机制，使致病细菌能够入侵我们的免疫防御。确定M87的哪些区域参与捕获LL-37可能有助于设计更有效的治疗方法来对抗S。化脓性感染
Surface-associated, coiled-coil M proteins of Streptococcus pyogenes (Strep A) disable human immunity through interaction with select proteins. However, coiled coils lack features typical of protein–protein interaction sites, and it is therefore challenging to understand how M proteins achieve specific binding, for example, with the human antimicrobial peptide LL-37, leading to its neutralization. The crystal structure of a complex of LL-37 with M87 protein, an antigenic M protein variant from a strain that is an emerging threat, revealed a novel interaction mode. The M87 coiled coil unfurled and asymmetrically exposed its hydrophobic core to capture LL-37. A single LL-37 molecule was bound by M87 in the crystal, but in solution additional LL-37 molecules were recruited, consistent with a ‘protein trap’ neutralization mechanism. The interaction mode visualized crystallographically was verified to contribute significantly to LL-37 resistance in an M87 Strep A strain and was identified to be conserved in a number of other M protein types that are prevalent in human populations. Our results provide specific detail for therapeutic inhibition of LL-37 neutralization by M proteins. We share our environment with many different bacteria. Some are beneficial for our health, like gut bacteria, but others can cause severe disease if they infect and spread within the body’s tissues. For example, the bacterium Streptococcus pyogenes can cause conditions ranging from skin infections to a rapidly spreading deep-tissue infection, giving it the nickname “flesh-eating bacterium”. To prevent infection, our bodies have developed defence mechanisms that target disease-causing bacteria. These include antimicrobial molecules, such as LL-37, which is a small protein produced on the skin. LL-37 kills bacteria by puncturing their cell membrane (the bacterial equivalent of our skin); in other words, it acts like a tiny chemical dart that ‘pops’ the bacterial cell. However, some bacteria, including S. pyogenes, can disarm these defences. S. pyogenes captures LL-37 on its surface with so called M proteins, which prevent LL-37 from reaching and destroying the underlying membrane. However, it was unknown how exactly the two proteins interact, especially since LL-37 is a simple molecule that lacks the structural features that allow most proteins to bind to each other. Kolesiński et al. set out to determine how the M protein can ‘grab’ LL-37. A technique called X-ray crystallography allowed them to visualise the molecules atom by atom and to examine the configuration of the M protein after it had captured LL-37. The M protein selected for these experiments (M87) came from a strain associated with particularly severe disease, considered to be an emerging health threat. The results showed that M87 uncurled itself, thereby exposing specific parts that normally remain hidden. This way, it could capture LL-37, like a hand opening to grab an object. Kolesiński et al. have revealed a key molecular mechanism that enables a disease-causing bacterium to invade our immune defences. Identifying which regions of M87 are involved in capturing LL-37 may help design more effective therapies to combat S. pyogenes infections.