Li Shixin, Huang Fang, Xia Tie, Shi Yan, Yue Tongtao
College of Bioscience and Biotechnology and Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education, Yangzhou University, Yangzhou, Jiangsu 225009, China.
State Key Laboratory of Heavy Oil Processing, College of Chemical Engineering, China University of Petroleum (East China), Qingdao, Shandong 266580, China.
Langmuir. 2023 May 2;39(17):5995-6005. doi: 10.1021/acs.langmuir.2c03492. Epub 2023 Apr 22.
Phosphatidylinositol 4,5-bisphosphate (PIP) is an important molecule located at the inner leaflet of cell membrane, where it serves as anchoring sites for a cohort of membrane-associated molecules and as a broad-reaching signaling intermediate. The lipid raft is thought as the major platform recruiting proteins for signal transduction and also known to mediate PIP accumulation across the membrane. While the significance of this cross-membrane coupling is increasingly appreciated, it remains unclear whether and how PIP senses the dynamic change of the ordered lipid domains over the packed hydrophobic core of the bilayer. Herein, by means of molecular dynamic simulation, we reveal that inner PIP molecules can sense the outer lipid domain via inter-leaflet coupling, and the coupling manner is dictated by the acyl chain length of sphingomyelin (SM) partitioned to the lipid domain. Shorter SM promotes membrane domain registration, whereby PIP accumulates beneath the domain across the membrane. In contrast, the anti-registration is thermodynamically preferred if the lipid domain has longer SM due to the hydrophobic mismatch between the corresponding acyl chains in SM and PIP. In this case, PIP is expelled by the domain with a higher diffusivity. These results provide molecular insights into the regulatory mechanism of correlation between the outer lipid domain and inner PIP, both of which are critical components for cell signal transduction.
磷脂酰肌醇4,5-二磷酸（PIP）是一种位于细胞膜内小叶的重要分子，在那里它作为一群膜相关分子的锚定位点，并作为一种广泛的信号中间体。脂筏被认为是招募蛋白质进行信号转导的主要平台，并且也已知介导PIP跨膜积累。虽然这种跨膜偶联的重要性越来越受到重视，但PIP是否以及如何感知双层堆积疏水核心上有序脂域的动态变化仍不清楚。在此，通过分子动力学模拟，我们揭示了内部PIP分子可以通过叶间偶联感知外部脂域，并且偶联方式由分配到脂域的鞘磷脂（SM）的酰基链长度决定。较短的SM促进膜域对齐，从而使PIP跨膜积累在域下方。相反，如果脂域具有较长的SM，由于SM和PIP中相应酰基链之间的疏水不匹配，反对齐在热力学上是优选的。在这种情况下，PIP以较高的扩散率被该域排出。这些结果为外部脂域和内部PIP之间相关性的调节机制提供了分子见解，这两者都是细胞信号转导的关键组成部分。
