Ubiquitination is a post-translational modification that targets proteins for degradation but can also regulate other cellular processes such as endocytosis, trafficking and DNA repair. We investigate ubiquitination of the dopamine D4 receptor (D4R) which belongs to the superfamily of G protein-coupled receptors (GPCR). Several polymorphic variants of the D4R exist, which differ in the number of 16-amino acid repeats in the third intracellular loop (IC3) of the receptor. The functional role of this polymorphic region is not known but persons with the seven-repeat allele show a predisposition to develop attention deficit hyperactivity disorder (ADHD). We identified a protein, KLHL12, which specifically interacts with this polymorphic region and enhances ubiquitination of the D4R. We have tested the influence of KLHL12 on the ubiquitination of the most common D4R polymorphic variants and found that KLHL12 strongly promotes ubiquitination of the two- and four-repeat variant but has hardly any effect on ubiquitination of the seven-repeat D4R. This suggests that differential ubiquitination of the D4R may have functional implications. Moreover, we were able to demonstrate that KLHL12-mediated D4R ubiquitination does not lead to receptor degradation. Next, we aimed to identify specific residues in the sequence of D4R which undergo ubiquitination and observed that the lysine-less receptor mutant is still ubiquitinated. Subsequently, we have tested the hypothesis whether KLHL12 could promote ubiquitination on non-lysine residues of the D4R. The importance of the cysteine and serine/threonine residues in the ubiquitination process of the receptor was examined and the obtained results confirmed that D4R can be ubiquitinated on non-lysine residues. In this review we summarize our data on D4R ubiquitination and put this in the light of other GPCR ubiquitination studies.
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Endoplasmic reticulumendosome contact sites. This pseudo-colored electron microscopy image shows the formation of inter-organelle membrane contact sites between late endosomes (magenta) and the endoplasmic reticulum (ER; green). This tethering results from the interaction between two ER-anchored proteins (VAP-A and VAP-B) and the late endosomeanchored protein STARD3NL. Mitochondria: brown; nucleus: blue. For further details see pp. 493-498. Image kindly provided by Fabien Alpy. - PDF Icon PDF LinkTable of Contents
Review Article|
April 11 2016
Dopamine D4 receptor ubiquitination
Kamila Skieterska;
Kamila Skieterska
*Laboratory of GPCR Expression and Signal Transduction (L-GEST), Ghent University, Proeftuinstraat 86, 9000 Gent, Belgium
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Pieter Rondou;
Pieter Rondou
*Laboratory of GPCR Expression and Signal Transduction (L-GEST), Ghent University, Proeftuinstraat 86, 9000 Gent, Belgium
†Center for Medical Genetics Ghent, Ghent University, De Pintelaan 185, 9000 Gent, Belgium
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Kathleen Van Craenenbroeck
Kathleen Van Craenenbroeck
1
*Laboratory of GPCR Expression and Signal Transduction (L-GEST), Ghent University, Proeftuinstraat 86, 9000 Gent, Belgium
1To whom correspondence should be addressed (email kathleen.vancraenenbroeck@ugent.be).
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Publisher: Portland Press Ltd
Received:
February 11 2016
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2016 Authors; published by Portland Press Limited
2016
Biochem Soc Trans (2016) 44 (2): 601–605.
Article history
Received:
February 11 2016
Citation
Kamila Skieterska, Pieter Rondou, Kathleen Van Craenenbroeck; Dopamine D4 receptor ubiquitination. Biochem Soc Trans 15 April 2016; 44 (2): 601–605. doi: https://doi.org/10.1042/BST20150281
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