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The spatial molecular pattern of integrin recognition sites and their immobilization to colloidal nanobeads determine α2β1 integrin-dependent platelet activation
Biomaterials ( IF 12.8 ) Pub Date : 2018-03-16 , DOI: 10.1016/j.biomaterials.2018.03.028
Augusto Martins Lima , Seraphine V. Wegner , Ana C. Martins Cavaco , Maria Inacia Estevão-Costa , Raquel Sanz-Soler , Stephan Niland , Georgii Nosov , Jürgen Klingauf , Joachim P. Spatz , Johannes A. Eble

Collagen, a strong platelet activator, is recognized by integrin α2β1 and GPVI. It induces aggregation, if added to suspended platelets, or platelet adhesion if immobilized to a surface. The recombinant non-prolylhydroxylated mini-collagen FC3 triple helix containing one α2β1 integrin binding site is a tool to specifically study how α2β1 integrin activates platelet. Whereas soluble FC3 monomers antagonistically block collagen-induced platelet activation, immobilization of several FC3 molecules to an interface or to colloidal nanobeads determines the agonistic action of FC3. Nanopatterning of FC3 reveals that intermolecular distances below 64 nm between α2β1 integrin binding sites trigger signaling through dot-like clusters of α2β1 integrin, which are visible in high resolution microscopy with dSTORM. Upon signaling, these integrin clusters increase in numbers per platelet, but retain their individual size. Immobilization of several FC3 to 100 nm-sized nanobeads identifies α2β1 integrin-triggered signaling in platelets to occur at a twentyfold slower rate than collagen, which activates platelet in a fast integrative signaling via different platelet receptors. As compared to collagen stimulation, FC3-nanobead-triggered signaling cause a significant stronger activation of the protein kinase BTK, a weak and dispensable activation of PDK1, as well as a distinct phosphorylation pattern of PDB/Akt.



中文翻译:

整合素识别位点的空间分子模式及其对胶体纳米珠的固定决定了α2β1整合素依赖性血小板的活化

胶原蛋白是一种强大的血小板活化剂,被整联蛋白α2β1和GPVI识别。如果添加到悬浮的血小板中,它会诱导聚集;如果固定在表面上,它会引起血小板粘附。含有一个α2β1整联蛋白结合位点的重组非脯氨酰羟基化的微胶原F​​C3三重螺旋是专门研究α2β1整联蛋白如何激活血小板的工具。可溶性FC3单体拮抗胶原蛋白诱导的血小板活化,而将几个FC3分子固定在界面或胶体纳米珠上则决定了FC3的激动作用。FC3的纳米图案显示,α2β1整联蛋白结合位点之间的分子间距离低于64 nm触发了通过α2β1整联蛋白的点状簇发出的信号,这在dSTORM的高分辨率显微镜下可见。发出信号后 这些整联蛋白簇每血小板的数量增加,但保持其个体大小。将数个FC3固定在100 nm大小的纳米珠上,可以确定血小板中α2β1整合素触发的信号传导的速率比胶原蛋白慢20倍,胶原蛋白可以通过不同的血小板受体以快速整合的信号传导方式激活血小板。与胶原蛋白刺激相比,FC3-nanobead触发的信号转导引起蛋白激酶BTK的明显更强的激活,PDK1的弱而可有可无的激活以及PDB / Akt的独特磷酸化模式。它通过不同的血小板受体以快速整合的信号激活血小板。与胶原蛋白刺激相比,FC3-nanobead触发的信号转导引起蛋白激酶BTK的明显更强的激活,PDK1的弱而可有可无的激活以及PDB / Akt的独特磷酸化模式。它通过不同的血小板受体以快速整合的信号激活血小板。与胶原蛋白刺激相比,FC3-nanobead触发的信号转导引起蛋白激酶BTK的明显更强的激活,PDK1的弱而可有可无的激活以及PDB / Akt的独特磷酸化模式。

更新日期:2018-03-16
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