An Eight Amino Acid Segment Controls Oligomerization and Preferred Conformation of the two Non-visual Arrestins |
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| Affiliation: | 1. Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA;2. The Center for Structural Biology, Vanderbilt University, Nashville, TN 37232, USA;3. Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI 53226, USA;4. The Biophysics Collaborative Access Team (BioCAT), Department of Biological Chemical and Physical Sciences, Illinois Institute of Technology, Chicago, IL 60616, USA;5. University of California Los Angeles, Los Angeles, CA 90095, USA;6. Department of Biochemistry and the Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA;1. Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Montreal, Québec H3A 1A3, Canada;2. Departments of Biochemistry, McGill University, 1160 Pine Avenue West, Montreal, Québec H3A 1A3, Canada;3. Medicine, McGill University, 1160 Pine Avenue West, Montreal, Québec H3A 1A3, Canada;4. Oncology, McGill University, 1160 Pine Avenue West, Montreal, Québec H3A 1A3, Canada;5. Department of Biology, Faculté des sciences, Université de Sherbrooke, Sherbrooke, Québec J1K 2R1, Canada;6. Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec J1K 2R1, Canada;1. Department of Biochemistry & Biophysics, Oregon State University, Corvallis, OR 97331, USA;2. Department of Chemistry & Biochemistry, University of Oregon, Eugene, OR 97403, USA;3. Institute of Molecular Biology, University of Oregon, Eugene, OR 97403, USA;4. Materials Science Institute, University of Oregon, Eugene, OR 97403, USA;1. Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, United States;2. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, United States;3. Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, United States;1. Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan;2. Genomics Research Center, Academia Sinica, Taipei, Taiwan;3. From the Departments of Pharmacology and;6. Biochemistry, Vanderbilt University Medical Center, Nashville, Tennessee 37232,;4. the Molecular Biology Division, Veterans Affairs Medical Center, San Francisco, California 94121, and;5. the Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158 |
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| Abstract: | G protein coupled receptors signal through G proteins or arrestins. A long-standing mystery in the field is why vertebrates have two non-visual arrestins, arrestin-2 and arrestin-3. These isoforms are ~75% identical and 85% similar; each binds numerous receptors, and appear to have many redundant functions, as demonstrated by studies of knockout mice. We previously showed that arrestin-3 can be activated by inositol-hexakisphosphate (IP6). IP6 interacts with the receptor-binding surface of arrestin-3, induces arrestin-3 oligomerization, and this oligomer stabilizes the active conformation of arrestin-3. Here, we compared the impact of IP6 on oligomerization and conformational equilibrium of the highly homologous arrestin-2 and arrestin-3 and found that these two isoforms are regulated differently. In the presence of IP6, arrestin-2 forms “infinite” chains, where each promoter remains in the basal conformation. In contrast, full length and truncated arrestin-3 form trimers and higher-order oligomers in the presence of IP6; we showed previously that trimeric state induces arrestin-3 activation (Chen et al., 2017). Thus, in response to IP6, the two non-visual arrestins oligomerize in different ways in distinct conformations. We identified an insertion of eight residues that is conserved across arrestin-2 homologs, but absent in arrestin-3 that likely accounts for the differences in the IP6 effect. Because IP6 is ubiquitously present in cells, this suggests physiological consequences, including differences in arrestin-2/3 trafficking and JNK3 activation. The functional differences between two non-visual arrestins are in part determined by distinct modes of their oligomerization. The mode of oligomerization might regulate the function of other signaling proteins. |
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| Keywords: | oligomer isoforms signaling protein structure |
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