Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas.
Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas; Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas.
Biophys J. 2019 Aug 20;117(4):646-658. doi: 10.1016/j.bpj.2019.07.012. Epub 2019 Jul 16.
Recruitment of receptors into clathrin-coated structures is essential to signal transduction and nutrient uptake. Among the many receptors involved in these processes, a significant fraction forms dimers. Dimerization of identical partners has generally been thought to promote receptor recruitment for uptake because of increased affinity of the dimer for the endocytic machinery. But what happens when receptors with substantially different affinities for the endocytic machinery come together to form a heterodimer? Evidence from diverse receptor classes, including G-protein-coupled receptors and receptor tyrosine kinases, suggests that heterodimerization with a strongly recruited receptor can drive significant recruitment of a receptor that lacks direct interactions with the endocytic machinery. However, a systematic biophysical understanding of this effect has yet to be established. Motivated by the potential of such events to influence cell signaling, here, we investigate the impact of receptor heterodimerization on endocytic recruitment using a family of engineered model receptors. As expected, we find that dimerization of a weakly recruited receptor with a strongly recruited receptor promotes incorporation of the weakly recruited receptor to endocytic structures. However, the effectiveness of this collaborative mechanism depends heavily on the relative strengths of endocytic recruitment of the two receptors that make up the dimer. Specifically, as the strength of endocytic recruitment of the weakly recruited receptor approaches that of the strongly recruited receptor, monomers of each receptor compete with heterodimers for space within endocytic structures. In this regime, the presence of the strongly recruited receptor drives a reduction in incorporation of the weakly recruited receptor into clathrin-coated structures. Similarly, as the strength of the dimer bond between the two receptors is progressively weakened, competition begins to dominate over collaboration. Collectively, these results demonstrate that the impact of receptor heterodimerization on endocytic recruitment is controlled by a delicate balance between collaborative and competitive mechanisms.
受体募集到网格蛋白包被结构对于信号转导和营养摄取至关重要。在涉及这些过程的众多受体中，很大一部分形成二聚体。通常认为，相同配体的二聚化会促进受体的募集，因为二聚体与内吞机制的亲和力增加。但是，当具有显著不同的内吞机制亲和力的受体聚集在一起形成异二聚体时会发生什么情况？来自不同受体类别的证据，包括 G 蛋白偶联受体和受体酪氨酸激酶，表明与强烈募集的受体的异二聚化可以驱动缺乏与内吞机制直接相互作用的受体的显著募集。然而，这种效应的系统生物物理理解尚未建立。受这种事件影响细胞信号的潜力的启发，我们在这里使用一系列工程模型受体研究了受体异二聚化对内吞招募的影响。不出所料，我们发现，弱募集受体与强募集受体的二聚化促进了弱募集受体到内吞结构的掺入。然而，这种协作机制的有效性在很大程度上取决于构成二聚体的两个受体的内吞招募的相对强度。具体来说，随着弱募集受体的内吞招募强度接近强募集受体的内吞招募强度，每个受体的单体与内吞结构内的异二聚体竞争空间。在这种情况下，强募集受体的存在会导致弱募集受体掺入网格蛋白包被结构的减少。同样，随着两个受体之间二聚体键的强度逐渐减弱，竞争开始主导协作。总之，这些结果表明，受体异二聚化对内吞招募的影响受到协作和竞争机制之间微妙平衡的控制。
