Conformational Regulation of Urokinase Receptor Function IMPACT OF RECEPTOR OCCUPANCY AND EPITOPE-MAPPED MONOCLONAL ANTIBODIES ON LAMELLIPODIA INDUCTION
Conformational Regulation of Urokinase Receptor Function IMPACT OF RECEPTOR OCCUPANCY AND EPITOPE-MAPPED MONOCLONAL ANTIBODIES ON LAMELLIPODIA INDUCTION
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DOI：
10.1074/jbc.m111.220087
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发表时间：
2011-09-23
影响因子：
4.8
通讯作者：
Ploug, Michael
中科院分区：
文献类型：
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作者：
Gardsvoll, Henrik;Jacobsen, Benedikte;Ploug, Michael
尿激酶型纤溶酶原激活物受体（uPAR）是一种糖脂锚定的膜蛋白，在细胞表面聚焦uPA介导的纤溶酶原激活中具有既定作用。与此功能不同，uPAR还调节细胞在富含玻连蛋白基质上的粘附和迁移。尽管uPA和玻连蛋白在uPAR上具有结构上不同的结合位点，但它们在功能上仍然合作，因为uPA结合增强了玻连蛋白基质上的片状伪足的uPAR依赖性诱导。现在，我们提出的数据推进的可能性，这是埋葬的β-发夹在uPA本身的疏水性配体结合腔的uPAR，调节该受体的功能。基于这些数据，我们现在提出了一个模型，在该模型中，固有的域间流动性uPAR在调节其功能中起着重要作用。特别是一个uPAR构象，这是稳定的β-发夹在uPA的接合，有利于正确的组装一个积极的，紧凑的受体结构，刺激板状伪足诱导玻连蛋白。该分子模型对靶向uPAR功能的药物开发具有广泛的意义。
The urokinase-type plasminogen activator receptor ( uPAR) is a glycolipid-anchored membrane protein with an established role in focalizing uPA-mediated plasminogen activation on cell surfaces. Distinct from this function, uPAR also modulates cell adhesion and migration on vitronectin-rich matrices. Although uPA and vitronectin engage structurally distinct binding sites on uPAR, they nonetheless cooperate functionally, as uPA binding potentiates uPAR-dependent induction of lamellipodia on vitronectin matrices. We now present data advancing the possibility that it is the burial of the beta-hairpin in uPA per se into the hydrophobic ligand binding cavity of uPAR that modulates the function of this receptor. Based on these data, we now propose a model in which the inherent interdomain mobility in uPAR plays a major role in modulating its function. Particularly one uPAR conformation, which is stabilized by engagement of the beta-hairpin in uPA, favors the proper assembly of an active, compact receptor structure that stimulates lamellipodia induction on vitronectin. This molecular model has wide implications for drug development targeting uPAR function.