Structural determinants governing β-arrestin2 interaction with PDZ proteins and recruitment to CRFR1 |
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| Institution: | 1. Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, University of Ottawa, Ottawa, ON K1H 8M5, Canada;2. Faculty of Pharmacy, Department of Pharmacology and Toxicology, Alexandria University, Alexandria, 21521, Egypt;3. Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA;1. Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, China;2. Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, China;3. Department of Imaging and Minimally Invasive Interventional Center, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, China;4. Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou 510060, China;5. State Key Laboratory of Oncology in South China, 651 Dongfeng Road East, Guangzhou 510060, China;6. Department of Neurosurgery, Xuzhou Medical College Hospital, 99 West Huaihai Road, Xuzhou 221000, China;1. Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario N6A 5B7, Canada;2. Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Dr. Ottawa, Ontario K1H 8M5, Canada |
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| Abstract: | β-Arrestins are multifunctional adaptor proteins best know for their vital role in regulating G protein coupled receptor (GPCR) trafficking and signaling. β-arrestin2 recruitment and receptor internalization of corticotropin-releasing factor receptor 1 (CRFR1), a GPCR whose antagonists have been shown to demonstrate both anxiolytic- and antidepressant-like effects, have previously been shown to be modulated by PDZ proteins. Thus, a structural characterization of the interaction between β-arrestins and PDZ proteins can delineate potential mechanism of PDZ-dependent regulation of GPCR trafficking. Here, we find that the PDZ proteins PSD-95, MAGI1, and PDZK1 interact with β-arrestin2 in a PDZ domain-dependent manner. Further investigation of such interaction using mutational analyses revealed that mutating the alanine residue at 175 residue of β-arrestin2 to phenylalanine impairs interaction with PSD-95. Additionally, A175F mutant of β-arrestin2 shows decreased CRF-stimulated recruitment to CRFR1 and reduced receptor internalization. Thus, our findings show that the interaction between β-arrestins and PDZ proteins is key for CRFR1 trafficking and may be targeted to mitigate impaired CRFR1 signaling in mental and psychiatric disorders. |
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