期刊
PHARMACOLOGY & THERAPEUTICS
卷 110, 期 3, 页码 465-502出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pharmthera.2005.09.008
关键词
arrestin; G-protein-coupled receptors; desensitization; structure; conformational change
资金
- NEI NIH HHS [R01 EY011500-10, R01 EY011500] Funding Source: Medline
- NINDS NIH HHS [R01 NS045117, R01 NS045117-03] Funding Source: Medline
- NATIONAL EYE INSTITUTE [R01EY011500] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS045117] Funding Source: NIH RePORTER
The 4 mammalian arrestins serve as almost universal regulators of the largest known family of signaling proteins, G-protein-coupled receptors (GPCRs). Arrestins terminate receptor interactions with G proteins, redirect the signaling to a variety of alternative pathways, and orchestrate receptor internalization and subsequent intracellular trafficking. The elucidation of the structural basis and fine molecular mechanisms of the arrestin-receptor interaction paved the way to the targeted manipulation of this interaction from both sides to produce very stable or extremely transient complexes that helped to understand the regulation of many biologically important processes initiated by active GPCRs. The elucidation of the structural basis of arrestin interactions with numerous non-receptor-binding partners is long overdue. It will allow the construction of fully functional arrestins in which the ability to interact with individual partners is specifically disrupted or enhanced by targeted mutagenesis. These custom-designed arrestin mutants will be valuable tools in defining the role of various interactions in the intricate interplay of multiple signaling pathways in the living cell. The identification of arrestin-binding sites for various signaling molecules will also set the stage for designing molecular tools for therapeutic intervention that may prove useful in numerous disorders associated with congenital or acquired disregulation of GPCR signaling. (c) 2005 Elsevier Inc. All rights reserved.
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