Department of Chemistry and Biochemistry, Stern College for Women, Yeshiva University, New York, New York, USA.
Protein Sci. 2013 Aug;22(8):1025-36. doi: 10.1002/pro.2288. Epub 2013 Jun 29.
Oligomerization of G protein-coupled receptors is a recognized mode of regulation of receptor activities, with alternate oligomeric states resulting in different signaling functions. The CXCR4 chemokine receptor is a G protein-coupled receptor that is post-translationally modified by tyrosine sulfation at three sites on its N-terminus (Y7, Y12, Y21), leading to enhanced affinity for its ligand, stromal cell derived factor (SDF-1, also called CXCL12). The complex has been implicated in cancer metastasis and is a therapeutic target in cancer treatment. Using molecular dynamics simulation of NMR-derived structures of the CXCR4 N-terminus in complex with SDF-1, and calculations of electrostatic binding energies for these complexes, we address the role of tyrosine sulfation in this complex. Our results show that sulfation stabilizes the dimeric state of the CXCR4:SDF-1 complex through hydrogen bonding across the dimer interface, conformational changes in residues at the dimer interface, and an enhancement in electrostatic binding energies associated with dimerization. These findings suggest a mechanism through which post-translational modifications such as tyrosine sulfation might regulate downstream function through modulation of the oligomeric state of the modified system.
G 蛋白偶联受体的寡聚化是一种公认的受体活性调节模式，不同的寡聚状态导致不同的信号转导功能。CXCR4 趋化因子受体是一种 G 蛋白偶联受体，其 N 端的三个酪氨酸残基（Y7、Y12、Y21）发生酪氨酸硫酸化修饰，从而增强了对其配体基质细胞衍生因子（SDF-1，也称为 CXCL12）的亲和力。该复合物与癌症转移有关，是癌症治疗的一个治疗靶点。我们使用 CXCR4 N 端与 SDF-1 结合的 NMR 衍生结构的分子动力学模拟以及这些复合物静电结合能的计算，研究了酪氨酸硫酸化在该复合物中的作用。我们的结果表明，硫酸化通过在二聚体界面上形成氢键、二聚体界面处残基的构象变化以及与二聚化相关的静电结合能增强，稳定了 CXCR4：SDF-1 复合物的二聚体状态。这些发现表明，通过修饰系统寡聚状态的调节，翻译后修饰（如酪氨酸硫酸化）可能通过调节下游功能。
