Detail Information of Post-Translational Modifications

General Information of Drug Transporter (DT)
DT ID	DTD0455 Transporter Info
Gene Name	SLC6A3
Transporter Name	Sodium-dependent dopamine transporter
Gene ID	6531
UniProt ID	Q01959

Post-Translational Modification of This DT
Overview ofSLC6A3 Modification Sites with Functional and Structural Information
Sequence	M S K S K C S V G L M S S V V A P A K E P N A V G P K E V E L I L V K E Q N G V Q L T S S T L T N P R Q S P V E A Q D R E T W G K K I D F L L S V I G F A V D L A N V W R F P Y L C Y K N G G G A F L V P Y L L F M V I A G M P L F Y M E L A L G Q F N R E G A A G V W K I C P I L K G V G F T V I L I S L Y V G F F Y N V I I A W A L H Y L F S S F T T E L P W I H C N N S W N S P N C S D A H P G D S S G D S S G L N D T F G T T P A A E Y F E R G V L H L H Q S H G I D D L G P P R W Q L T A C L V L V I V L L Y F S L W K G V K T S G K V V W I T A T M P Y V V L T A L L L R G V T L P G A I D G I R A Y L S V D F Y R L C E A S V W I D A A T Q V C F S L G V G F G V L I A F S S Y N K F T N N C Y R D A I V T T S I N S L T S F S S G F V V F S F L G Y M A Q K H S V P I G D V A K D G P G L I F I I Y P E A I A T L P L S S A W A V V F F I M L L T L G I D S A M G G M E S V I T G L I D E F Q L L H R H R E L F T L F I V L A T F L L S L F C V T N G G I Y V F T L L D H F A A G T S I L F G V L I E A I G V A W F Y G V G Q F S D D I Q Q M T G Q R P S L Y W R L C W K L V S P C F L L F V V V V S I V T F R P P H Y G A Y I F P D W A N A L G W V I A T S S M A M V P I Y A A Y K F C S L P G S F R E K L A Y A I A P E K D R E L V D R G E V R Q F T L R H W L K V
PTM type	X-N-glycosylation X-Oxidation X-Phosphorylation X-Phosphorylation X-S-palmitoylation X-Ubiquitination X-Ubiquitination X: Amino Acid

N-glycosylation
Asparagine	3 PTM Phenomena Related to This Residue		Click to Show/Hide the Full List
PTM Phenomenon1	Prevention of N-glycosylation reduced both surface and intracellular DAT			[1]
Role of PTM	Surface Expression Modulation
Affected Drug/Substrate	Dopamine	Results for Drug	Decreasing the transport of dopamine
Modified Residue	Asparagine	Modified Location	181
Modified State	Asparagine to Glutamine mutation
Experimental Material(s)	Human embryonic kidney 293 (HEK293) cells
Experimental Method	Co-Immunoprecipitation
Detailed Description	Removal of the N-glycosylation at SLC6A3 Asparagine 181 (i.e. Asparagine to Glutamine mutation) have been reported to prevention of N-glycosylation reduced both surface and intracellular DAT.
PTM Phenomenon2	Prevention of N-glycosylation reduced both surface and intracellular DAT			[1]
Role of PTM	Surface Expression Modulation
Affected Drug/Substrate	Dopamine	Results for Drug	Decreasing the transport of dopamine
Modified Residue	Asparagine	Modified Location	188
Modified State	Asparagine to Glutamine mutation
Experimental Material(s)	Human embryonic kidney 293 (HEK293) cells
Experimental Method	Co-Immunoprecipitation
Detailed Description	Removal of the N-glycosylation at SLC6A3 Asparagine 188 (i.e. Asparagine to Glutamine mutation) have been reported to prevention of N-glycosylation reduced both surface and intracellular DAT.
PTM Phenomenon3	Prevention of N-glycosylation reduced both surface and intracellular DAT			[1]
Role of PTM	Surface Expression Modulation
Affected Drug/Substrate	Dopamine	Results for Drug	Decreasing the transport of dopamine
Modified Residue	Asparagine	Modified Location	205
Modified State	Asparagine to Glutamine mutation
Experimental Material(s)	Human embryonic kidney 293 (HEK293) cells
Experimental Method	Co-Immunoprecipitation
Detailed Description	Removal of the N-glycosylation at SLC6A3 Asparagine 205 (i.e. Asparagine to Glutamine mutation) have been reported to prevention of N-glycosylation reduced both surface and intracellular DAT.
Oxidation
Cystine	1 PTM Phenomena Related to This Residue		Click to Show/Hide the Full List
PTM Phenomenon1	Have the potential to influence SLC6A3			[2]
Role of PTM	Potential impacts
Modified Residue	Cystine	Modified Location	90
Experimental Method	Co-Immunoprecipitation
Detailed Description	Oxidation at SLC6A3 Cystine 90 has the potential to affect its expression or activity.
Phosphorylation
Serine	8 PTM Phenomena Related to This Residue		Click to Show/Hide the Full List
PTM Phenomenon1	Decreasing the Vmax of SLC6A3			[3]
Role of PTM	Crosstalk with Other PTMs
Modified Residue	Serine	Modified Location	7
Experimental Material(s)	Pig kidney epithelial (LLC-PK1) cells
Experimental Method	Co-Immunoprecipitation
Detailed Description	Low S-palmitoylation at Cysteine 580 with high Phosphorylation at Serine 7 of SLC6A3 have been reported to decrease its transport Vmax.
PTM Phenomenon2	Have the potential to influence SLC6A3			[4]
Role of PTM	Potential impacts
Modified Residue	Serine	Modified Location	2
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A3 Serine 2 has the potential to affect its expression or activity.
PTM Phenomenon3	Have the potential to influence SLC6A3			[4]
Role of PTM	Potential impacts
Modified Residue	Serine	Modified Location	4
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A3 Serine 4 has the potential to affect its expression or activity.
PTM Phenomenon4	Have the potential to influence SLC6A3			[4], [5]
Role of PTM	Potential impacts
Modified Residue	Serine	Modified Location	7
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A3 Serine 7 has the potential to affect its expression or activity.
PTM Phenomenon5	Have the potential to influence SLC6A3			[4], [5]
Role of PTM	Potential impacts
Modified Residue	Serine	Modified Location	12
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A3 Serine 12 has the potential to affect its expression or activity.
PTM Phenomenon6	Have the potential to influence SLC6A3			[4], [5]
Role of PTM	Potential impacts
Modified Residue	Serine	Modified Location	13
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A3 Serine 13 has the potential to affect its expression or activity.
PTM Phenomenon7	Have the potential to influence SLC6A3			[6]
Role of PTM	Potential impacts
Modified Residue	Serine	Modified Location	53
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A3 Serine 53 has the potential to affect its expression or activity.
PTM Phenomenon8	Have the potential to influence SLC6A3			[7]
Role of PTM	Potential impacts
Modified Residue	Serine	Modified Location	262
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A3 Serine 262 has the potential to affect its expression or activity.
Threonine	8 PTM Phenomena Related to This Residue		Click to Show/Hide the Full List
PTM Phenomenon1	.			[8]
Role of PTM	Potential impacts
Modified Residue	Threonine	Modified Location	48
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A3 Threonine 48 has the potential to affect its expression or activity.
PTM Phenomenon2	.			[8]
Role of PTM	Potential impacts
Modified Residue	Threonine	Modified Location	48
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A3 Threonine 48 has the potential to affect its expression or activity.
PTM Phenomenon3	.			[8]
Role of PTM	Potential impacts
Modified Residue	Threonine	Modified Location	48
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A3 Threonine 48 has the potential to affect its expression or activity.
PTM Phenomenon4	Have the potential to influence SLC6A3			[5], [9]
Role of PTM	Potential impacts
Modified Residue	Threonine	Modified Location	62
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A3 Threonine 62 has the potential to affect its expression or activity.
PTM Phenomenon5	Have the potential to influence SLC6A3			[7], [10]
Role of PTM	Potential impacts
Modified Residue	Threonine	Modified Location	261
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A3 Threonine 261 has the potential to affect its expression or activity.
PTM Phenomenon6	Have the potential to influence SLC6A3			[7]
Role of PTM	Potential impacts
Modified Residue	Threonine	Modified Location	269
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A3 Threonine 269 has the potential to affect its expression or activity.
PTM Phenomenon7	Have the potential to influence SLC6A3			[7]
Role of PTM	Potential impacts
Modified Residue	Threonine	Modified Location	271
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A3 Threonine 271 has the potential to affect its expression or activity.
PTM Phenomenon8	Have the potential to influence SLC6A3			[11], [12]
Role of PTM	Potential impacts
Modified Residue	Threonine	Modified Location	613
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A3 Threonine 613 has the potential to affect its expression or activity.
Unclear Residue	1 PTM Phenomena Related to This Residue		Click to Show/Hide the Full List
PTM Phenomenon1	Impairing the function of SLC6A3			[13], [14]
Role of PTM	Trafficking to Plasma Membrane
Related Enzyme	Protein kinase C alpha type (PRKCA)
Studied Phenotype	Pheochromocytoma [ICD11:5A75]
Experimental Material(s)	Rat pheochromocytoma (PC12) cells
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A3 have been reported to impaire its transport function.
S-palmitoylation
Cysteine	1 PTM Phenomena Related to This Residue		Click to Show/Hide the Full List
PTM Phenomenon1	Decreasing the Vmax of SLC6A3			[3]
Role of PTM	Crosstalk with Other PTMs
Modified Residue	Cysteine	Modified Location	580
Experimental Material(s)	Pig kidney epithelial (LLC-PK1) cells
Experimental Method	Co-Immunoprecipitation
Detailed Description	Low S-palmitoylation at Cysteine 580 with high Phosphorylation at Serine 7 of SLC6A3 have been reported to decrease its transport Vmax.
Unclear Residue	1 PTM Phenomena Related to This Residue		Click to Show/Hide the Full List
PTM Phenomenon1	Enhancing the kinetics of SLC6A3			[3], [15]
Role of PTM	On/Off Switch
Related Enzyme	palmitoyl acyltransferases (ZDHHC1)
Experimental Method	Co-Immunoprecipitation
Detailed Description	S-palmitoylation at SLC6A3 have been reported to enhance its transport kinetics.
Ubiquitination
Lysine	2 PTM Phenomena Related to This Residue		Click to Show/Hide the Full List
PTM Phenomenon1	.			[8]
Role of PTM	Potential impacts
Modified Residue	Lysine	Modified Location	5
Experimental Method	Co-Immunoprecipitation
Detailed Description	Ubiquitination at SLC6A3 Lysine 5 has the potential to affect its expression or activity.
PTM Phenomenon2	.			[8]
Role of PTM	Potential impacts
Modified Residue	Lysine	Modified Location	5
Experimental Method	Co-Immunoprecipitation
Detailed Description	Ubiquitination at SLC6A3 Lysine 5 has the potential to affect its expression or activity.
Unclear Residue	1 PTM Phenomena Related to This Residue		Click to Show/Hide the Full List
PTM Phenomenon1	Accelerating the endocytosis of SLC6A3			[16]
Role of PTM	Degradation via Proteosome
Related Enzyme	Protein kinase C alpha type (PRKCA)
Experimental Method	Co-Immunoprecipitation
Detailed Description	Ubiquitination at SLC6A3 have been reported to accelerate its endocytosis, thereby affecting its expression or activity.

References
1	The role of N-glycosylation in function and surface trafficking of the human dopamine transporter. J Biol Chem. 2004 May 14;279(20):21012-20.
2	A Quantitative Tissue-Specific Landscape of Protein Redox Regulation during Aging. Cell. 2020 Mar 5;180(5):968-983.e24.
3	Reciprocal Phosphorylation and Palmitoylation Control Dopamine Transporter Kinetics. J Biol Chem. 2015 Nov 27;290(48):29095-105.
4	Calmodulin kinase II interacts with the dopamine transporter C terminus to regulate amphetamine-induced reverse transport. Neuron. 2006 Aug 17;51(4):417-29.
5	Systematic functional prioritization of protein posttranslational modifications. Cell. 2012 Jul 20;150(2):413-25.
6	Quantitative phosphoproteomics of Alzheimer's disease reveals cross-talk between kinases and small heat shock proteins. Proteomics. 2015 Jan;15(2-3):508-519.
7	iTRAQ labeling is superior to mTRAQ for quantitative global proteomics and phosphoproteomics. Mol Cell Proteomics. 2012 Jun;11(6):M111.014423.
8	ActiveDriverDB: human disease mutations and genome variation in post-translational modification sites of proteins. Nucleic Acids Res. 2018;46(D1):D901-D910.
9	A juxtamembrane mutation in the N terminus of the dopamine transporter induces preference for an inward-facing conformation. Mol Pharmacol. 2009 Mar;75(3):514-24.
10	Phosphorylation of the norepinephrine transporter at threonine 258 and serine 259 is linked to protein kinase C-mediated transporter internalization. J Biol Chem. 2006 Aug 18;281(33):23326-40.
11	Ischemia in tumors induces early and sustained phosphorylation changes in stress kinase pathways but does not affect global protein levels. Mol Cell Proteomics. 2014 Jul;13(7):1690-704.
12	Attention deficit/hyperactivity disorder-derived coding variation in the dopamine transporter disrupts microdomain targeting and trafficking regulation. J Neurosci. 2012 Apr 18;32(16):5385-97.
13	Differential targeting of the dopamine transporter to recycling or degradative pathways during amphetamine- or PKC-regulated endocytosis in dopamine neurons. FASEB J. 2013 Aug;27(8):2995-3007.
14	Membrane trafficking regulates the activity of the human dopamine transporter. J Neurosci. 1999 Sep 15;19(18):7699-710.
15	Palmitoylation mechanisms in dopamine transporter regulation. J Chem Neuroanat. 2017 Oct;83-84:3-9.
16	RNA interference screen reveals an essential role of Nedd4-2 in dopamine transporter ubiquitination and endocytosis. J Neurosci. 2006 Aug 2;26(31):8195-205.

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Detail Information of Post-Translational Modifications

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