Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
Sci Rep. 2018 Jul 11;8(1):10477. doi: 10.1038/s41598-018-28692-4.
FARP1 is a multi-domain protein that is involved in regulating neuronal development through interacting with cell surface proteins such as class A Plexins and SynCAM 1. The N-terminal FERM domain in FARP1 is known to both promote membrane localization and mediate these protein interactions, for which the underlying molecular mechanisms remain unclear. Here we determined the crystal structures of the FERM domain of FARP1 from zebrafish, and those of FARP2 (a close homolog of FARP1) from mouse and zebrafish. These FERM domains adopt the three-leaved clover fold that is typical of all FERM domains. Our structures reveal a positively charged surface patch that is highly conserved in the FERM domain of FARP1 and FARP2. In vitro lipid-binding experiments showed that the FARP1 FERM domain binds specifically to several types of phospholipid, which is dependent on the positively charged surface patch. We further determined through cell-based analyses that this surface patch on the FERM domain underlies the localization of FARP1 to the plasma membrane, and that FERM domain interactions recruit it to postsynaptic sites in neurons.
FARP1 是一种具有多个结构域的蛋白，通过与细胞表面蛋白（如 A 类 Plexin 和 SynCAM1）相互作用，参与调控神经元发育。FARP1 的 N 端 FERM 结构域既促进膜定位，又介导这些蛋白相互作用，但潜在的分子机制尚不清楚。本研究解析了来自斑马鱼的 FARPl 和来自小鼠及斑马鱼的 FARP2（FARP1 的密切同源物）FERM 结构域的晶体结构。这些 FERM 结构域呈现三叶型槐叶结构，这是所有 FERM 结构域的典型特征。我们的结构揭示了 FARPl 和 FARP2 的 FERM 结构域高度保守的正电荷表面斑块。体外脂质结合实验表明，FARP1 和 FARP2 的 FERM 结构域特异性结合多种类型的磷脂，这依赖于正电荷表面斑块。通过细胞分析进一步确定，FERM 结构域上的这个表面斑块决定了 FARPl 向质膜的定位，而 FERM 结构域相互作用则将其募集到神经元的突触后位点。
