Structural Studies of Arrestin-Mediated GPCR Signaling
演讲人: X. Edward Zhou, Ph.D.
Senior Research Scientist
Laboratory of Structural Sciences, Van Andel Research Institute, USA
G protein-coupled receptors (GPCRs) mediate diverse signaling through G proteins or arrestins. Arrestin binding to GPCRs promotes receptor internalization and signaling through G protein-independent pathways. High-affinity binding of arrestins to GPCRs requires receptor phosphorylation, often at the receptor’s C-terminal tail. We determined the crystal structure of a constitutively active form of human rhodopsin bound to a pre-activated form of mouse visual arrestin by serial femtosecond X-ray laser crystallography. The structure reveals an overall architecture of the rhodopsin-arrestin assembly in which rhodopsin uses distinct structural elements including TM7, Helix 8 and particularly the phosphorylated C-terminal tail to recruit arrestin. The phospho-residues on the C-terminal tail of the receptor form an extensive network of electrostatic interactions with three positively charged pockets in arrestin. Based on these observations, we derived and validated a set of phosphorylation codes that serve as a molecular mechanism for phosphorylation-dependent recruitment of arrestins by GPCRs.
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