Role of C-terminal Membrane-proximal Basic Residues in Cell Surface Trafficking of HIV Coreceptor GPR15 Protein

Okamoto, Yoh; Bernstein, Joshua; Shikano, Sojin

doi:10.1074/jbc.m112.445817

Cited by 11 publications

(11 citation statements)

References 36 publications

(52 reference statements)

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“…The positive role of MPBRs in antero-290 grade trafficking was reported for the HIV coreceptor GPR15 and Golgi-291 resident glycosyltransferases [15,17]. The C-terminal 10-12 residues 292 following the TM segment in human GPCRs are considered the mem-293 brane proximal residues, with +1 being the most proximal to the TM 294 [15,27]. A majority of the mutants which displayed reduced surface 295 expression in our study fall in the MPBR of T2R4 C-terminus, with 296 Thr291 being the most proximal and Leu303 the most distal residue 297 ( Fig.…”

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confidence: 94%

“…The C-terminal MPBRs were also required 288 for both cell surface expression and signaling of melanin-concentrating 289 hormone receptor 1, MCH1R [16]. The positive role of MPBRs in antero-290 grade trafficking was reported for the HIV coreceptor GPR15 and Golgi-291 resident glycosyltransferases [15,17]. The C-terminal 10-12 residues 292 following the TM segment in human GPCRs are considered the mem-293 brane proximal residues, with +1 being the most proximal to the TM 294 [15,27].…”

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confidence: 95%

“…Sequence analysis of human GPCRs showed that basic residues 67 are frequent in the membrane-proximal region of the C-terminus. 68 Mutation of the C-terminal membrane-proximal basic residues (MPBRs) 69 results in a marked reduction in the cell surface expression of multi-70 ple GPCRs [7,[15][16][17][18], thus, suggesting that these residues are critically 71 involved in mediating the anterograde trafficking of a broad range 72 of membrane proteins, including GPCRs. The sense of taste has a sig-73 nificant impact on food selection, nutrition and health.…”

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confidence: 99%

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The structure–function role of C-terminus in human bitter taste receptor T2R4 signaling

Upadhyaya

Singh

Bhullar

et al. 2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Bitter taste, in humans, is sensed by 25 G protein-coupled receptors, referred to as bitter taste receptors (T2Rs). The diverse roles of T2Rs in various extraoral tissues have implicated them as a potential target for therapeutic intervention. Structure-function studies have provided insights into the role of transmembrane and loop regions in the activation mechanism of T2Rs. However, studies aimed at deciphering the role of their carboxyl-terminus (C-terminus) are limited. In this study, we identified a KLK/R motif in the C-terminus that is conserved in 19 of the 25 T2Rs. Using site-directed mutagenesis we studied the role of 16 residues in the C-terminus of T2R4. The C-terminus of T2R4 is polybasic with 6 of the 16 residues consisting of lysines, constituting two separate KK motifs. We analyzed the effect of the C-terminus mutations on plasma membrane trafficking, and characterized their function in response to the T2R4 agonist quinine. The majority of the mutants showed defective receptor trafficking with ≤50% expression on the cell surface. Interestingly, mutation of the distal Lys296 of the KLK motif in T2R4 resulted in constitutive activity. The K296A mutant displayed five-fold basal activity over wild type T2R4, while the conservative substitution K296R showed wild type characteristics. The Lys294, Leu295 and Lys296 of the KLK motif in T2R4 were found to perform crucial roles, both, in receptor trafficking and function. Results from this study provide unique mechanistic insights into the structure-function role of the C-terminus in T2R signaling.

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confidence: 94%

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confidence: 95%

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confidence: 99%

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The structure–function role of C-terminus in human bitter taste receptor T2R4 signaling

Upadhyaya

Singh

Bhullar

et al. 2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…1 The protein is expressed on the cell membrane and it is considered a chemokine receptor (also designated as BOB/GPR15) and it functions as a co-receptor for the human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2). 3,4 GPR15 is a heterotrimeric G-protein-coupled receptor that controls the specific homing of FOXP3-positive regulatory T-cells (T-regs). 5 Accumulating evidence indicate that GPR15 regulates the innate immunity and it is involved in the pathogenesis of diverse diseases like Crohn's disease and rheumatoid arthritis.…”

Section: Introductionmentioning

confidence: 99%

Activation of GPR15 and its involvement in the biological effects of smoking

Kõks

2017

Exp Biol Med (Maywood)

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The review describes an orphan receptor GPR15 that has recently been found to be influenced by smoking. This makes GPR15 very sensitive and adequate biomarker for smoking and smoking studies. Also, activation of GPR15 by smoking could help to explain its effects on health. AbstractSmoking is one of the most significant modifiable environmental risk factors for many diseases. Smoking causes excessive mortality worldwide. Despite decades of long research, there has not been a clear understanding regarding the molecular mechanism that makes smoking harmful to health. Some recent studies have found that smoking influences most significantly the expression and methylation of GPR15. GPR15 is an orphan receptor that is involved in the regulation of the innate immunity and the T-cell trafficking in the intestinal epithelium. Further studies have confirmed that GPR15 is very strongly involved in smoking and smoking-induced molecular changes. Therefore, the altered expression and epigenetic regulation of GPR15 could have a significant role in the health impact of smoking.

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“…Another important progress achieved over the past years is that a number of specific motifs embedded within the receptors have been revealed to be required for the cell surface transport of GPCRs, such as the E(x) 3 LL motif in vasopressin receptor 2 (V2R), the F/Y(x) 3 F(x) 3 F motif in dopamine D1 receptor (D1R) and neuropeptide Y receptor type 2, the FN(x) 2 LL(x) 3 L motif in vasopressin V1b/V3 receptor, the F(x) 6 LL motif in α 2B ‐adrenergic receptor (AR), angiotensin II (Ang II) type 1 receptor (AT1R), α 1B ‐AR, β 2 ‐AR and M1‐muscarinic receptor (MR), the YS motif in α 2A ‐AR and α 2B ‐AR, the VxPx motif in rhodopsin, the RRR and R(x) 3 R(x) 4 R motifs in α 2B ‐AR, di‐acidic and di‐basic motifs in AT1R, AT2R and GPR15, and serine‐rich motifs in melanocortin 5 receptor . These motifs may regulate receptor correct folding, function as independent export signals to dictate receptor exit from the ER or the Golgi or as retention motifs to prevent receptor export from intracellular compartments, or provide docking sites for regulatory proteins.…”

Section: Anterograde Transport Of Gpcrsmentioning

confidence: 99%

Mechanisms of the anterograde trafficking of GPCRs: Regulation of AT1R transport by interacting proteins and motifs

Zhang

2018

Traffic

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Anterograde cell surface transport of nascent G protein‐coupled receptors (GPCRs) en route from the endoplasmic reticulum (ER) through the Golgi apparatus represents a crucial checkpoint to control the amount of the receptors at the functional destination and the strength of receptor activation‐elicited cellular responses. However, as compared with extensively studied internalization and recycling processes, the molecular mechanisms of cell surface trafficking of GPCRs are relatively less defined. Here, we will review the current advances in understanding the ER‐Golgi‐cell surface transport of GPCRs and use angiotensin II type 1 receptor as a representative GPCR to discuss emerging roles of receptor‐interacting proteins and specific motifs embedded within the receptors in controlling the forward traffic of GPCRs along the biosynthetic pathway.

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Role of C-terminal Membrane-proximal Basic Residues in Cell Surface Trafficking of HIV Coreceptor GPR15 Protein

Cited by 11 publications

References 36 publications

The structure–function role of C-terminus in human bitter taste receptor T2R4 signaling

The structure–function role of C-terminus in human bitter taste receptor T2R4 signaling

Activation of GPR15 and its involvement in the biological effects of smoking

Mechanisms of the anterograde trafficking of GPCRs: Regulation of AT1R transport by interacting proteins and motifs

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