Laboratory of Microbiology, Showa Pharmaceutical University, Machida, Tokyo, 190-8543, Japan.
Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan.
Nat Commun. 2018 Oct 18;9(1):4330. doi: 10.1038/s41467-018-06797-8.
The MILL family, composed of MILL1 and MILL2, is a group of nonclassical MHC class I molecules that occur in some orders of mammals. It has been reported that mouse MILL2 is involved in wound healing; however, the molecular mechanisms remain unknown. Here, we determine the crystal structure of MILL2 at 2.15 Å resolution, revealing an organization similar to classical MHC class I. However, the α1-α2 domains are not tightly fixed on the α3-βm domains, indicating unusual interdomain flexibility. The groove between the two helices in the α1-α2 domains is too narrow to permit ligand binding. Notably, an unusual basic patch on the α3 domain is involved in the binding to heparan sulfate which is essential for MILL2 interactions with fibroblasts. These findings suggest that MILL2 has a unique structural architecture and physiological role, with binding to heparan sulfate proteoglycans on fibroblasts possibly regulating cellular recruitment in biological events.
MILL 家族由 MILL1 和 MILL2 组成，是一组存在于某些哺乳动物目中的非经典 MHC I 类分子。据报道，小鼠 MILL2 参与伤口愈合，但分子机制尚不清楚。在这里，我们确定了 MILL2 的晶体结构，分辨率为 2.15Å，显示出与经典 MHC I 类相似的结构。然而，α1-α2 结构域没有与 α3-βm 结构域紧密固定，表明其结构域间存在不寻常的柔性。α1-α2 结构域中两个螺旋之间的凹槽太窄，无法容纳配体结合。值得注意的是，α3 结构域上一个不寻常的碱性斑块参与与肝素硫酸酯的结合，这对于 MILL2 与成纤维细胞的相互作用是必不可少的。这些发现表明 MILL2 具有独特的结构架构和生理作用，与成纤维细胞上的肝素硫酸蛋白聚糖结合可能调节生物事件中的细胞募集。
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