Supplementary material for 'Structural basis for ninjurin-1 mediated plasma membrane rupture in lytic cell death'

Eukaryotic cells can undergo different forms of programmed cell death, many of which culminate in plasma membrane rupture (PMR) as the defining terminal event. PMR was long thought to be driven by osmotic pressure, until it was recently shown to be in many cases an active process, mediated by the protein ninjurin-1 (NINJ1). Here, we studied whether the newly resolved cryo-electron microscopy NINJ1 filaments are capable to cap membrane edges by multiscaling molecular dynamics simulations. Site-directed mutagenesis was employed to validate the function of the resulting supramolecular arrangement. The membrane protein NINJ1 is thus an interactive component of the eukaryotic cell membrane that functions as an in-built breaking point in response to activation of cell death.

真核细胞可发生多种形式的程序性细胞死亡，其中多数以质膜破裂（plasma membrane rupture, PMR）作为标志性的终末事件。长期以来，质膜破裂被认为由渗透压驱动，直至近期研究表明，在多数情况下该过程是由神经元损伤诱导蛋白1（ninjurin-1, NINJ1）介导的主动过程。本研究通过多尺度分子动力学模拟（multiscaling molecular dynamics simulations），探究了新近通过低温电子显微镜（cryo-electron microscopy）解析得到的NINJ1丝状体是否能够封合膜边缘，并采用定点诱变（site-directed mutagenesis）技术验证了所获得的超分子组装结构的功能。综上，膜蛋白NINJ1作为真核细胞膜的相互作用组分，在细胞死亡程序激活时可充当内置断裂位点发挥功能。