研究人员表示，β-抑制蛋白（βarr）是一种多功能蛋白，参与七种跨膜受体（7TMR）的信号传导和调控，它们之间的相互作用主要由激动剂诱导的受体活化和磷酸化驱动。
研究人员展示了βarr的七种冷冻电镜结构，它们或处于基础状态，或被毒蕈碱受体亚型2（M2R）通过其细胞内第三环激活，或被βarr偏向诱饵D6受体（D6R）激活。这些结构快照与生化、细胞和生物物理实验相结合，使βarrs与7TMR的非典型啮合可视化，还揭示了D6R激活时βarr2羧基末端从β链到α螺旋的结构转变。
这项研究为7TMR-βarr复合物编码的结构和功能多样性提供了前所未有的分子见解，并对探索新的治疗途径具有直接影响。
附：英文原文
Title: Molecular insights into atypical modes of β-arrestin interaction with seven transmembrane receptors
Author: Jagannath Maharana, Fumiya K. Sano, Parishmita Sarma, Manish K. Yadav, Longhan Duan, Tomasz M. Stepniewski, Madhu Chaturvedi, Ashutosh Ranjan, Vinay Singh, Sayantan Saha, Gargi Mahajan, Mohamed Chami, Wataru Shihoya, Jana Selent, Ka Young Chung, Ramanuj Banerjee, Osamu Nureki, Arun K. Shukla
Issue&Volume: 2024-01-05
Abstract: β-arrestins (βarrs) are multifunctional proteins involved in signaling and regulation of seven transmembrane receptors (7TMRs), and their interaction is driven primarily by agonist-induced receptor activation and phosphorylation. Here, we present seven cryo–electron microscopy structures of βarrs either in the basal state, activated by the muscarinic receptor subtype 2 (M2R) through its third intracellular loop, or activated by the βarr-biased decoy D6 receptor (D6R). Combined with biochemical, cellular, and biophysical experiments, these structural snapshots allow the visualization of atypical engagement of βarrs with 7TMRs and also reveal a structural transition in the carboxyl terminus of βarr2 from a β strand to an α helix upon activation by D6R. Our study provides previously unanticipated molecular insights into the structural and functional diversity encoded in 7TMR-βarr complexes with direct implications for exploring novel therapeutic avenues.
DOI: adj3347
Source: https://www.science.org/doi/10.1126/science.adj3347