A Flexible Multidomain Structure Drives the Function of the Urokinase-type Plasminogen Activator Receptor (uPAR)
A Flexible Multidomain Structure Drives the Function of the Urokinase-type Plasminogen Activator Receptor (uPAR)
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DOI：
10.1074/jbc.m112.398404
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发表时间：
2012-10-05
影响因子：
4.8
通讯作者：
Ploug, Michael
中科院分区：
文献类型：
--
作者：
Mertens, Haydyn D. T.;Kjaergaard, Magnus;Ploug, Michael
尿激酶型纤溶酶原激活剂受体（uPAR）在细胞外基质的蛋白水解降解和整合素介导的玻连蛋白粘附之间提供了交汇处。然而，这些过程是紧密相连的，因为尿激酶的高亲和力结合调节 uPAR 与基质嵌入的玻连蛋白的结合。尽管存在晶体结构来定义相应的静态双分子和三分子受体复合物，但显然 uPAR 的动态特性对其功能起着决定性作用。在本研究中，我们结合小角度 X 射线散射、氢-氘交换和表面等离子体共振，开发了描述 uPAR 变构调节的结构模型。我们证明其 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，我们的模型对于理解 uPAR 辅助的细胞粘附和迁移以及转化研究（包括靶向干预治疗和体内非侵入性肿瘤成像）具有直接意义。
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.