HTR6 and SSTR3 ciliary targeting relies on both IC3 loops and C-terminal tails
| Autor: | Tetsuo Kobayashi, Paula Moreno, Kirk Mykytyn, Raquel Martin-Morales, Francesc R. Garcia-Gonzalo, Pablo Barbeito, Yuki Tachibana |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Health
Toxicology and Mutagenesis Plant Science Biology Transfection Biochemistry Genetics and Molecular Biology (miscellaneous) 03 medical and health sciences Mice 0302 clinical medicine Microtubule Somatostatin receptor 3 Animals Humans Protein Interaction Domains and Motifs Amino Acid Sequence Cilia Receptors Somatostatin Receptor 5-HT receptor Research Articles 030304 developmental biology G protein-coupled receptor 0303 health sciences Ecology Chemistry Cilium HEK 293 cells Cell Membrane Intracellular Signaling Peptides and Proteins 3. Good health Cell biology Protein Transport HEK293 Cells Gene Knockdown Techniques Receptors Serotonin 030217 neurology & neurosurgery Function (biology) Intracellular Research Article Signal Transduction |
| Zdroj: | Life Science Alliance |
| ISSN: | 2575-1077 |
| Popis: | Ciliary accumulation of G protein–coupled receptors HTR6 and SSTR3 depends on redundant ciliary targeting sequences acting via ciliary trafficking adapters TULP3 and RABL2. G protein-coupled receptors (GPCRs) are the most common pharmacological target in human clinical practice. To perform their functions, many GPCRs must accumulate inside primary cilia, microtubule-based plasma membrane protrusions working as cellular antennae. Nevertheless, the molecular mechanisms underlying GPCR ciliary targeting remain poorly understood. Serotonin receptor 6 (HTR6) and somatostatin receptor 3 (SSTR3) are two brain-enriched ciliary GPCRs involved in cognition and pathologies such as Alzheimer’s disease and cancer. Although the third intracellular loops (IC3) of HTR6 and SSTR3 suffice to target non-ciliary GPCRs to cilia, these IC3s are dispensable for ciliary targeting of HTR6 and SSTR3 themselves, suggesting these GPCRs contain additional ciliary targeting sequences (CTSs). Herein, we discover and characterize novel CTSs in HTR6 and SSTR3 C-terminal tails (CT). These CT-CTSs (CTS2) act redundantly with IC3-CTSs (CTS1), each being sufficient for ciliary targeting. In HTR6, RKQ and LPG motifs are critical for CTS1 and CTS2 function, respectively, whereas in SSTR3 these roles are mostly fulfilled by AP[AS]CQ motifs in IC3 and juxtamembrane residues in CT. Furthermore, we shed light on how these CTSs promote ciliary targeting by modulating binding to ciliary trafficking adapters TULP3 and RABL2. |
| Databáze: | OpenAIRE |
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