当前位置: X-MOL 学术Biophys. J. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Molecular mechanism of CD44 homodimerization modulated by palmitoylation and membrane environments
Biophysical Journal ( IF 3.4 ) Pub Date : 2022-06-22 , DOI: 10.1016/j.bpj.2022.06.021
Ziyi Ma 1 , Sai Shi 2 , Meina Ren 1 , Chunli Pang 1 , Yong Zhan 2 , Hailong An 2 , Fude Sun 1
Affiliation  

The homodimerization of CD44 plays a key role in an intercellular-to-extracellular signal transduction and tumor progression. Acylated modification and specific membrane environments have been reported to mediate translocation and oligomerization of CD44; however, the underlying molecular mechanism remains elusive. In this study, extensive molecular dynamics simulations are performed to characterize the dimerization of palmitoylated CD44 variants in different bilayer environments. CD44 forms homodimer depending on the cysteines on the juxta-membrane domains, and the dimerization efficiency and packing configurations are defected by their palmitoylated modifications. In the phase-segregated (raft included) membrane, homodimerization of the palmitoylated CD44 is hardly observed, whereas PIP2 addition compensates to realize dimerization. However, the structure of CD44 homodimer formed in the phase-segregated bilayer turns susceptive and PIP2 addition allows for an extensive conformation of the cytoplasmic domain, a proposal prerequisite to access the cytoskeleton linker proteins. The results unravel a delicate competitive relationship between PIP2, lipid raft, and palmitoylation in mediating protein homodimerization, which helps to clarify the dynamic dimer conformations and involved cellular signaling of the CD44 likewise proteins.



中文翻译:

棕榈酰化和膜环境调节CD44同二聚化的分子机制

CD44 的同二聚化在细胞间到细胞外的信号转导和肿瘤进展中起着关键作用。据报道,酰化修饰和特定的膜环境可介导 CD44 的易位和寡聚化;然而,潜在的分子机制仍然难以捉摸。在这项研究中,进行了广泛的分子动力学模拟来表征不同双层环境中棕榈酰化 CD44 变体的二聚化。CD44根据近膜结构域上的半胱氨酸形成同型二聚体,并且二聚化效率和包装构型因其棕榈酰化修饰而受到缺陷。在相分离(包括筏)膜中,几乎观察不到棕榈酰化 CD44 的同二聚化,而添加 PIP2 则补偿以实现二聚化。然而,相分离双层中形成的 CD44 同二聚体的结构变得敏感,并且 PIP2 的添加允许细胞质结构域的广泛构象,这是访问细胞骨架连接蛋白的建议先决条件。结果揭示了 PIP2、脂筏和棕榈酰化在介导蛋白质同二聚化中的微妙竞争关系,这有助于阐明动态二聚体构象并涉及 CD44 同样蛋白质的细胞信号传导。

更新日期:2022-06-22
down
wechat
bug