College of Chemistry, Fuzhou University, Fuzhou, 350116, Fujian, China.
College of Biological Science and Engineering, Fuzhou University, 350116, Fuzhou, Fujian, China.
Nat Commun. 2022 Mar 29;13(1):1665. doi: 10.1038/s41467-022-29344-y.
Receptor dimerization of urokinase-type plasminogen activator receptor (uPAR) was previously identified at protein level and on cell surface. Recently, a dimeric form of mouse uPAR isoform 2 was proposed to induce kidney disease. Here, we report the crystal structure of human uPAR dimer at 2.96 Å. The structure reveals enormous conformational changes of the dimer compared to the monomeric structure: D1 of uPAR opens up into a large expanded ring that captures a β-hairpin loop of a neighboring uPAR to form an expanded β-sheet, leading to an elongated, highly intertwined dimeric uPAR. Based on the structure, we identify E49P as a mutation promoting dimer formation. The mutation increases receptor binding to the amino terminal fragment of its primary ligand uPA, induces the receptor to distribute to the basal membrane, promotes cell proliferation, and alters cell morphology via β1 integrin signaling. These results reveal the structural basis for uPAR dimerization, its effect on cellular functions, and provide a basis to further study this multifunctional receptor.
尿激酶型纤溶酶原激活物受体（uPAR）的受体二聚化先前在蛋白质水平和细胞表面得到了鉴定。最近，提出了二聚体形式的小鼠 uPAR 同种型 2 诱导肾脏疾病。在这里，我们报告了人 uPAR 二聚体在 2.96Å 的晶体结构。与单体结构相比，该结构揭示了二聚体的巨大构象变化：uPAR 的 D1 打开成一个大的扩展环，捕获相邻 uPAR 的β发夹环，形成扩展的β-折叠，导致长而高度交织的二聚体 uPAR。基于该结构，我们确定 E49P 是促进二聚体形成的突变。该突变增加了受体与其主要配体 uPA 的氨基末端片段的结合，诱导受体分布到基底膜，促进细胞增殖，并通过β1 整合素信号改变细胞形态。这些结果揭示了 uPAR 二聚化的结构基础、对细胞功能的影响，并为进一步研究这种多功能受体提供了基础。
