BALOUCOUNE Guillaume A. Palmitoylation Modification Regulates G-protein-coupled Receptors Effects

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1 ISSN CN / Q http / / cjbmb bjmu edu cn Chinese Journal of Biochemistry and Molecular Biology ~ 107 G BALOUCOUNE Guillaume A * G G-protein-coupled receptors GPCRs S- S-palmitoylation GPCRs GPCRs GPCRs protein acly transferases PATs thioesterases GPCRs C 4 / 5 GPCRs GPCRs GPCRs GPCRs GPCRs G Q25 Q291 Palmitoylation Modification Regulates G-protein-coupled Receptors Effects LIU JieBALOUCOUNE Guillaume A CHUN Lei * Key Laboratory of Molecular Biophysics of Ministry of EducationSchool of Life Science and Technology Huazhong University of Science and TechnologyWuhan China Abstract G-protein-coupled receptors GPCRs are transmembrane proteinshence a number of their structural and functional features are modulated by both proteins and lipids S-palmitoylationas a classical lipid modificationregulates diverse aspects of GPCRs by affecting the interaction between GPCRs and signal proteins or lipid molecules It is defined as the addition of saturated 16-carbon palmitate acid to specific cysteine residues through the formation of a liable thioester bond The palmitoylation / depalmitoylation dynamics is regulated reversibly by both the palmitoyl acyl transferases PATs and palmitoyl protein thioesterases under various physiological status Many GPCRs are palmitoylated on cysteine residues present in their cytoplasmic termini The insertion of palmitate into the cytoplasmic leaflet of the plasma membrane can create the fouth and / or the fifth intracellular loopthus profoundly affecting GPCRs structuretraffickingsortingsignalingdesensitisationinternalization and oligomerisation Furthermorethe interplay between palmitoylation and other posttranslational modificationssuch as phosphorylationubiquitination and nitrosylationcan regulate the function of GPCRs coordinatively It is expected that the identification of enzymes involved in GPCRs palmitoylation dynamics will be a key to delineate the role of palmitoylation in regulating GPCRs functions Key words G-protein-coupled receptors palmitoylation dynamics signaling No 2012CB * Tel lchuncn@ gamil com Received November Accepted December Supported by Major State Basic Research Development Program of China 973 Program No 2012CB * Corresponding author Tel lchuncn@ gamil com

2 G G-protein-coupled receptors GPCRs C GPCRs 7 1 α H8 4 A H8 C 1 GPCRs GPCRs A Table 1 A C 1 ~ 2 myristoylation prenylation hydroxytryptamine receptor 5-HT 5-HT 5 4 a 5-HT 6 7 a A C H8 C GPCRs metabotropic GPCRs glutamate receptor 4 mglur4 C GPCRs 7 10 GPCRs μ- acyl-biotinyl exchange ABE opioid receptor μ-or 8 C 2 2 C170 C GPCRs V 9 1a V 10 2 vasopressin receptor VR C 2 GPCRs GPCRs G GPCRs 1 1 DHHC Asp-His-His-Cys 2 DHHC 28 1 ABE PAT 3 H click 3 ABE somatostatin receptor 5SSTR5 1 GPCRs 1 2 GPCRs ZDHHC5 N H GPCRs S-

3 2 G 101 Table 1 Partial list of GPCR palmitoylation Cysteine Receptor Flanking sequences C-termini H8-Helix Bovine rhodopsin 11 QFRNCMVTTLCCGKNPLGDDE Human β 2 -adrenergic receptor 12 DFRIAFQELLCLRRSSLKAYG Porcine α 2A -adrenergic receptor 13 HDFRRAFKKILCRGDRKRIV Rat LH / CG receptor 14 DFLLLLSRFGCCKRRAELYRRK Human ET B endothelin receptor 15 RFKNCFKSCLCCWCQSFEEKQ Human muscarinic acetylcholine receptor m2 16 KKTFKHLLMCHYKNIGATR Human thyrotropin receptor 17 VFILLSKFGICKRQAQAYRGQ Human A 1 adenosine receptor 18 FLKIWNDHFRCQPAPPIDEDL Human D 1 dopamine receptor 19 RKAFSTLLGCYRLCPATNNAIE Rat bradykinin B 2 receptor 20 KKSREVYQAICRKGGCMGESV Human chemokine 5 receptor 21 FFQKHIAKRFCKCCSIFQQEAP Canine H 2 histamine receptor 22 FRTAYQQLFRCRPASHNAQET Metabotropic glutamate receptor 4 7 Human prostaglandin receptor 23 VFQRLKLWVCCLCLGPAHGDS Distal 5-hydroxytryptamine receptor 4a 24 CCDDERYKRPPILGQTVPCSTTTINGSTHLRYTVLRYTVL HSGHHQELEKLPIHNDPESLESCF 5-hydroxytryptamine receptor 7a 6 CQYRNINRKLSAAGMHEALKLAERPERPELVLQKSDYC CNLRLPGSSDSRASASRAAGITGVSHCARPCMLF CYEMQAQIYRTETSSTVHNTHPRNGHC Thromboxane A 2 receptor TPβ 25 LLCCARRAARRRHATHGDRPRASGCLA Follicle-stimulating hormone receptor 26 β 1 -Adrenergic receptor 27 i-loop μ-opioid receptor 8 DRYIAVCHPVKALDFRTPRNAK 9 Rat vasopressin receptor V 1a LLQDCVQSFPCCHSMAQKFAK 10 Human vasopressin receptor V 2 SVSSELRSLLCCARGRTPPSLG * C is the cysteine modified by palmitoylation GPCRs 1 protein palmitoyl thioesterase 1 PPT1-1 acyl protein thioesterase 1 APT1 GPCRs β 2-30 β 2 -adrenergic receptor β 2 -AR GPCRs 3 H RNA H 2-bromopalmitate 2-BP 3 H β 2 -AR dopamine D 1 receptor1 D 1 R 34 α 1B FD196 α 1B -adrenergic receptorα 1B -AR 35 FD253 α 2A α 2A -adrenergic receptorα 2A - AR 36 δ- δ-opioid receptor δ-or 8 GPCRs 1A serotonin 1A receptor 37

4 GPCRs receptor C C383 5 β 1 - β 1-23 adrenergic receptor β 1 -AR / C 27 β 1 -AR C392 / C393 C414 Fig min 15 min 27 3 GPCRs Fig 1 The model of C-terminal palmitoylation of GPCRs family A For the member of family A there is a short amphipathic α helix H8 helix at the juxtamembranous - C-termini and the seventh transmenbrance regionwhich can form the forth loop by palmitoylation some of GPCRs also can form the fifth loop by palmitoylation or isoprenylation at GPCRs the distal site s located in C-termini GPCRs G 3 2 GPCRs 3 1 GPCRs GPCRs GPCRs rhodopsin 2 GPCRs X- - H8 GPCRs 4 GPCRs 38 β 2 -AR X- 39 H8 GPCRs CXCR4 chemokine GPCRs CXCR4 receptor CXCR4 H8 C β H8 1 -AR 40 C392 / C393 GPCRs C 27 5 prostaglandin

5 2 G GPCRs Gα GPCRs Gα 3 3 GPCRs D 1 R GPCRs A GPCRs rndothelin receptor A Gαo Gαi Gαq GPCRs C402 C403 C Gαq Gαi 42 2 Gαo C 402 caveolin Gαi A Gαq Gαi 45 3 Gαo 46 1 V 2 cannabinoid receptor 1 CB 1 R C415 β- β-arrestin C415 CB 1 R MAPK Gαs 1 50 CRAC cholesterol interaction / recognition 3 5 GPCRs amino acid sequence consensus CRAC GPCRs PKA G G-protein- CB 1 R 47 coupled receptor kinases GRKs β-arrestin GPCRs PKA GRKs β 2 -AR β-arrestin 32 G 48 GPCRs G 3 4 GPCRs G GPCRs GPCRs A G 2 3 Gα C C GPCRs H8 Gα β-arrestin GPCRs H8 C GPCRs β 2 -AR C341 PKA Gα M 2 V 1a R 9 CCR5 muscarinic acetylcholine receptor 2 M 2 R chemokine CCR5 receptor CCR5 51 Gαo Gαi2 16 GPCRs V 2 R 10 β-arrestin Gα β 2 -AR 341 C341G GPCRs V 2 R thyroid stimulating hormone receptor β 2 - HSTR 52 CCR5 51 GPCRs AR Gαs 12 A protein kinase A PKA β-arrestin

6 HT 7 a R 24 C328 / Y352 C329 C328 / C329 β-arrestin2 4 2 C386 β 2 -AR 341 Wnt Wnt 3 6 GPCRs GPCR LRP6 GPCRs β 2 - LRP6 AR LRP GPCRs LRP6-57 GPCRs N1E-115 GPCRs 1A fluorescence resonance energy transfer FRET FRET 1 FRET FRET synthetase NOS L- nitric oxideno S- S- 1A nitrosylation FRET NO morpholinosydnonimine SIN NO 4 1 GPCRs NO G β 2 -AR 54 A3 NOS adenosine receptor V 1a R 9 CCR5 51 GPCRs GPCRs M 2 R 16 1 Gα V 2 R 10 B 2 bradykininb 2 6 lipoprotein receptor-related proteins 6 LRP6 nitric oxide β 2 -AR GPCRs receptor 56 C356

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