美国斯坦福大学医学院的Ron O. Dror、Matthieu Masureel等研究人员合作揭示GPCR磷酸化模式如何协调抑制素介导的信号传导。这一研究成果于2020年12月8日在线发表在国际学术期刊《细胞》上。
使用原子级模拟和定点光谱法，研究人员揭示了G蛋白偶联受体（GPCR）的磷酸化如何通过对抑制素的结合和构象来影响其行为。研究人员发现，有利于结合的模式不同于那些倾向于激活相关构象变化的模式。结合和构象都更多地依赖于磷酸根的排列而不是它们的总数，在不同位置的磷酸化有时发挥相反的作用。磷酸化模式选择性地支持各种各样的抑制素构象，从而不同方式影响抑制素位点。
研究人员还揭示了这些现象的分子机制。这项工作揭示了“条形码”猜想的结构基础，并对功能选择性GPCR靶向药物的设计具有重要意义。
据介绍，抑制蛋白与磷酸化的GPCR的结合控制着细胞信号传导的许多方面。对于给定的GPCR，磷酸根的数量和排列方式可能会发生很大变化，并且不同的磷酸化模式会触发不同的抑制素效应。
附：英文原文
Title: How GPCR Phosphorylation Patterns Orchestrate Arrestin-Mediated Signaling
Author: Naomi R. Latorraca, Matthieu Masureel, Scott A. Hollingsworth, Franziska M. Heydenreich, Carl-Mikael Suomivuori, Connor Brinton, Raphael J.L. Townshend, Michel Bouvier, Brian K. Kobilka, Ron O. Dror
Issue&Volume: 2020-12-08
Abstract: Binding of arrestin to phosphorylated G-protein-coupled receptors (GPCRs) controlsmany aspects of cell signaling. The number and arrangement of phosphates may varysubstantially for a given GPCR, and different phosphorylation patterns trigger differentarrestin-mediated effects. Here, we determine how GPCR phosphorylation influencesarrestin behavior by using atomic-level simulations and site-directed spectroscopyto reveal the effects of phosphorylation patterns on arrestin binding and conformation.We find that patterns favoring binding differ from those favoring activation-associatedconformational change. Both binding and conformation depend more on arrangement ofphosphates than on their total number, with phosphorylation at different positionssometimes exerting opposite effects. Phosphorylation patterns selectively favor awide variety of arrestin conformations, differently affecting arrestin sites implicatedin scaffolding distinct signaling proteins. We also reveal molecular mechanisms ofthese phenomena. Our work reveals the structural basis for the long-standing “barcode”hypothesis and has important implications for design of functionally selective GPCR-targeteddrugs.
DOI: 10.1016/j.cell.2020.11.014
Source: https://www.cell.com/cell/fulltext/S0092-8674(20)31531-2