小柯机器人

瑞士巴塞尔大学Sebastian Hiller等研究人员合作揭示细胞死亡中NINJ1介导质膜断裂的结构基础。2023年5月17日，《自然》杂志在线发表了这项成果。

研究人员解析了ninjurin-1（NINJ1）的结构和它使膜破裂的机制。超分辨率显微镜显示，NINJ1在垂死的细胞膜上聚集成结构多样的集合体，特别是具有分支形态的大型丝状集合体。NINJ1丝的冷冻电镜结构显示了一个紧密的跨膜α-片的栅栏状阵列。丝的方向性和稳定性是由两个两面性的α-螺旋体定义的，它们将相邻的丝亚单位相互连接。NINJ1丝具有一个亲水侧和一个疏水侧，分子动力学模拟显示它可以稳定地覆盖膜边缘。所产生的超分子排列的功能通过定点诱变得到了验证。因此，这些数据表明，在细胞死亡过程中，NINJ1的细胞外α-螺旋插入到质膜中，使NINJ1单体聚合成两极丝，使质膜破裂。因此，膜蛋白NINJ1是真核细胞膜的一个互动成分，在应对细胞死亡的激活方面发挥着一个内置断点的作用。

据了解，真核细胞可以经历不同形式的程序性细胞死亡，其中许多最终以质膜破裂作为决定性的终端事件。长期以来，人们认为质膜破裂是由渗透压驱动的，但最近已被证明在许多情况下是一个主动的过程，由蛋白NINJ1介导。

附：英文原文

Title: Structural basis of NINJ1-mediated plasma membrane rupture in cell death

Author: Degen, Morris, Santos, Jos Carlos, Pluhackova, Kristyna, Cebrero, Gonzalo, Ramos, Saray, Jankevicius, Gytis, Hartenian, Ella, Guillerm, Undina, Mari, Stefania A., Kohl, Bastian, Mller, Daniel J., Schanda, Paul, Maier, Timm, Perez, Camilo, Sieben, Christian, Broz, Petr, Hiller, Sebastian

Issue&Volume: 2023-05-17

Abstract: Eukaryotic cells can undergo different forms of programmed cell death, many of which culminate in plasma membrane rupture as the defining terminal event1,2,3,4,5,6,7. Plasma membrane rupture was long thought to be driven by osmotic pressure, but it has recently been shown to be in many cases an active process, mediated by the protein ninjurin-18 (NINJ1). Here we resolve the structure of NINJ1 and the mechanism by which it ruptures membranes. Super-resolution microscopy reveals that NINJ1 clusters into structurally diverse assemblies in the membranes of dying cells, in particular large, filamentous assemblies with branched morphology. A cryo-electron microscopy structure of NINJ1 filaments shows a tightly packed fence-like array of transmembrane α-helices. Filament directionality and stability is defined by two amphipathic α-helices that interlink adjacent filament subunits. The NINJ1 filament features a hydrophilic side and a hydrophobic side, and molecular dynamics simulations show that it can stably cap membrane edges. The function of the resulting supramolecular arrangement was validated by site-directed mutagenesis. Our data thus suggest that, during lytic cell death, the extracellular α-helices of NINJ1 insert into the plasma membrane to polymerize NINJ1 monomers into amphipathic filaments that rupture the plasma membrane. The membrane protein NINJ1 is therefore an interactive component of the eukaryotic cell membrane that functions as an in-built breaking point in response to activation of cell death.

DOI: 10.1038/s41586-023-05991-z

Source: https://www.nature.com/articles/s41586-023-05991-z

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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