National Heart and Lung Institute, Imperial College London, London, SW7 2AZ, UK.
Department of Biological Science, Florida State University, Tallahassee, FL, 32304, USA.
Sci Rep. 2019 Nov 19;9(1):17104. doi: 10.1038/s41598-019-53176-4.
The collagen receptor DDR1 is a receptor tyrosine kinase that promotes progression of a wide range of human disorders. Little is known about how ligand binding triggers DDR1 kinase activity. We previously reported that collagen induces DDR1 activation through lateral dimer association and phosphorylation between dimers, a process that requires specific transmembrane association. Here we demonstrate ligand-induced DDR1 clustering by widefield and super-resolution imaging and provide evidence for a mechanism whereby DDR1 kinase activity is determined by its molecular density. Ligand binding resulted in initial DDR1 reorganisation into morphologically distinct clusters with unphosphorylated DDR1. Further compaction over time led to clusters with highly aggregated and phosphorylated DDR1. Ligand-induced DDR1 clustering was abolished by transmembrane mutations but did not require kinase activity. Our results significantly advance our understanding of the molecular events underpinning ligand-induced DDR1 kinase activity and provide an explanation for the unusually slow DDR1 activation kinetics.
胶原蛋白受体 DDR1 是一种受体酪氨酸激酶，可促进多种人类疾病的发展。关于配体结合如何触发 DDR1 激酶活性，人们知之甚少。我们之前曾报道过，胶原蛋白通过侧二聚体缔合和二聚体之间的磷酸化诱导 DDR1 激活，这一过程需要特定的跨膜缔合。在这里，我们通过宽场和超分辨率成像演示了配体诱导的 DDR1 聚集，并提供了证据表明 DDR1 激酶活性取决于其分子密度。配体结合导致 DDR1 最初重新组织成具有不同形态的簇，其中 DDR1 没有磷酸化。随着时间的推移进一步紧缩导致具有高度聚集和磷酸化的 DDR1 簇。跨膜突变会破坏配体诱导的 DDR1 聚集，但不需要激酶活性。我们的研究结果大大提高了我们对配体诱导 DDR1 激酶活性的分子事件的理解，并为 DDR1 激活的异常缓慢动力学提供了解释。
