Finsen Laboratory, Rigshospitalet and Biotech Research and Innovation Centre (BRIC), Copenhagen Biocenter, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark.
J Biol Chem. 2012 Oct 5;287(41):34304-15. doi: 10.1074/jbc.M112.398404. Epub 2012 Aug 15.
The urokinase-type plasminogen activator receptor (uPAR) provides a rendezvous between proteolytic degradation of the extracellular matrix and integrin-mediated adhesion to vitronectin. These processes are, however, tightly linked because the high affinity binding of urokinase regulates the binding of uPAR to matrix-embedded vitronectin. Although crystal structures exist to define the corresponding static bi- and trimolecular receptor complexes, it is evident that the dynamic property of uPAR plays a decisive role in its function. In the present study, we combine small angle x-ray scattering, hydrogen-deuterium exchange, and surface plasmon resonance to develop a structural model describing the allosteric regulation of uPAR. We show that the flexibility of its N-terminal domain provides the key for understanding this allosteric mechanism. Importantly, our model has direct implications for understanding uPAR-assisted cell adhesion and migration as well as for translational research, including targeted intervention therapy and non-invasive tumor imaging in vivo.
尿激酶型纤溶酶原激活物受体 (uPAR) 为细胞外基质的蛋白水解降解和整合素介导的对玻连蛋白的黏附作用提供了一个连接点。然而，这两个过程紧密相连，因为尿激酶的高亲和力结合调节了 uPAR 与基质结合的玻连蛋白的结合。尽管已经存在用于定义相应的静态双分子和三分子受体复合物的晶体结构，但显然 uPAR 的动态特性在其功能中起着决定性的作用。在本研究中，我们结合小角度 X 射线散射、氘氢交换和表面等离子体共振，开发了一个描述 uPAR 变构调节的结构模型。我们表明，其 N 端结构域的灵活性为理解这种变构机制提供了关键。重要的是，我们的模型对理解 uPAR 辅助的细胞黏附和迁移以及转化研究具有直接意义，包括靶向干预治疗和体内非侵入性肿瘤成像。
