Detail Information of Post-Translational Modifications

General Information of Drug Transporter (DT)
DT ID	DTD0456 Transporter Info
Gene Name	SLC6A4
Transporter Name	Sodium-dependent serotonin transporter
Gene ID	6532
UniProt ID	P31645

Post-Translational Modification of This DT
Overview ofSLC6A4 Modification Sites with Functional and Structural Information
Sequence	M E T T P L N S Q K Q L S A C E D G E D C Q E N G V L Q K V V P T P G D K V E S G Q I S N G Y S A V P S P G A G D D T R H S I P A T T T T L V A E L H Q G E R E T W G K K V D F L L S V I G Y A V D L G N V W R F P Y I C Y Q N G G G A F L L P Y T I M A I F G G I P L F Y M E L A L G Q Y H R N G C I S I W R K I C P I F K G I G Y A I C I I A F Y I A S Y Y N T I M A W A L Y Y L I S S F T D Q L P W T S C K N S W N T G N C T N Y F S E D N I T W T L H S T S P A E E F Y T R H V L Q I H R S K G L Q D L G G I S W Q L A L C I M L I F T V I Y F S I W K G V K T S G K V V W V T A T F P Y I I L S V L L V R G A T L P G A W R G V L F Y L K P N W Q K L L E T G V W I D A A A Q I F F S L G P G F G V L L A F A S Y N K F N N N C Y Q D A L V T S V V N C M T S F V S G F V I F T V L G Y M A E M R N E D V S E V A K D A G P S L L F I T Y A E A I A N M P A S T F F A I I F F L M L I T L G L D S T F A G L E G V I T A V L D E F P H V W A K R R E R F V L A V V I T C F F G S L V T L T F G G A Y V V K L L E E Y A T G P A V L T V A L I E A V A V S W F Y G I T Q F C R D V K E M L G F S P G W F W R I C W V A I S P L F L L F I I C S F L M S P P Q L R L F Q Y N Y P Y W S I I L G Y C I G T S S F I C I P T Y I A Y R L I I T P G T F K E R I I K S I T P E T P T E I P C G D I R L N A V
PTM type	X-N-glycosylation X-Palmitoylation X-Palmitoylation X-Phosphorylation X-Phosphorylation X-Ubiquitination X: Amino Acid

N-glycosylation
Asparagine	2 PTM Phenomena Related to This Residue		Click to Show/Hide the Full List
PTM Phenomenon1	Have the potential to influence SLC6A4			[1]
Role of PTM	Potential impacts
Modified Residue	Asparagine	Modified Location	208
Experimental Method	Co-Immunoprecipitation
Detailed Description	N-linked Glycosylation at SLC6A4 Asparagine 208 has the potential to affect its expression or activity.
PTM Phenomenon2	Have the potential to influence SLC6A4			[1]
Role of PTM	Potential impacts
Modified Residue	Asparagine	Modified Location	217
Experimental Method	Co-Immunoprecipitation
Detailed Description	N-linked Glycosylation at SLC6A4 Asparagine 217 has the potential to affect its expression or activity.
Palmitoylation
Asparticacid	1 PTM Phenomena Related to This Residue		Click to Show/Hide the Full List
PTM Phenomenon1	Have the potential to influence SLC6A4			[2]
Role of PTM	Potential impacts
Modified Residue	Asparticacid
Studied Phenotype	Huntington's disease [ICD11:8A01.10]
Experimental Method	Co-Immunoprecipitation
Detailed Description	Palmitoylation at SLC6A4 Asparticacid 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	.			[2]
Role of PTM	Influencing the Disease Progression
Experimental Method	Co-Immunoprecipitation
Detailed Description	Palmitoylation-dependent clustering of PSD-95 has been shown to enhance synaptic localization in Huntington's disease models, suggesting a role in neuronal signaling.
Phosphorylation
Serine	13 PTM Phenomena Related to This Residue		Click to Show/Hide the Full List
PTM Phenomenon1	.			[3]
Role of PTM	Potential impacts
Modified Residue	Serine	Modified Location	13
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A4 Serine 13 has the potential to affect its expression or activity.
PTM Phenomenon2	.			[3]
Role of PTM	Potential impacts
Modified Residue	Serine	Modified Location	13
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A4 Serine 13 has the potential to affect its expression or activity.
PTM Phenomenon3	Have the potential to influence SLC6A4			[4]
Role of PTM	Potential impacts
Modified Residue	Serine	Modified Location	40
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A4 Serine 40 has the potential to affect its expression or activity.
PTM Phenomenon4	Have the potential to influence SLC6A4			[4]
Role of PTM	Potential impacts
Modified Residue	Serine	Modified Location	44
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A4 Serine 44 has the potential to affect its expression or activity.
PTM Phenomenon5	Have the potential to influence SLC6A4			[4]
Role of PTM	Potential impacts
Modified Residue	Serine	Modified Location	48
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A4 Serine 48 has the potential to affect its expression or activity.
PTM Phenomenon6	Have the potential to influence SLC6A4			[4]
Role of PTM	Potential impacts
Modified Residue	Serine	Modified Location	52
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A4 Serine 52 has the potential to affect its expression or activity.
PTM Phenomenon7	Have the potential to influence SLC6A4			[4], [5]
Role of PTM	Potential impacts
Modified Residue	Serine	Modified Location	62
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A4 Serine 62 has the potential to affect its expression or activity.
PTM Phenomenon8	Have the potential to influence SLC6A4			[6]
Role of PTM	Potential impacts
Modified Residue	Serine	Modified Location	91
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A4 Serine 91 has the potential to affect its expression or activity.
PTM Phenomenon9	Have the potential to influence SLC6A4			[7]
Role of PTM	Potential impacts
Modified Residue	Serine	Modified Location	149
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A4 Serine 149 has the potential to affect its expression or activity.
PTM Phenomenon10	.			[3]
Role of PTM	Potential impacts
Modified Residue	Serine	Modified Location	277
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A4 Serine 277 has the potential to affect its expression or activity.
PTM Phenomenon11	.			[3]
Role of PTM	Potential impacts
Modified Residue	Serine	Modified Location	277
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A4 Serine 277 has the potential to affect its expression or activity.
PTM Phenomenon12	Have the potential to influence SLC6A4			[8]
Role of PTM	Potential impacts
Modified Residue	Serine	Modified Location	559
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A4 Serine 559 has the potential to affect its expression or activity.
PTM Phenomenon13	Have the potential to influence SLC6A4			[7], [9]
Role of PTM	Potential impacts
Modified Residue	Serine	Modified Location	611
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A4 Serine 611 has the potential to affect its expression or activity.
Threonine	12 PTM Phenomena Related to This Residue		Click to Show/Hide the Full List
PTM Phenomenon1	Enhancing the activity of SLC6A4			[10]
Role of PTM	On/Off Switch
Affected Drug/Substrate	5-Hydroxytryptamine	Results for Drug	Increasing the transport of 5-Hydroxytryptamine
Modified Residue	Threonine	Modified Location	276
Related Enzyme	cGMP-dependent protein kinase 1 (PRKG1)
Experimental Material(s)	Chinese hamster ovary subclone (CHO-K1) cells
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A4 Threonine 276 have been reported to enhance its transport activity.
PTM Phenomenon2	Have the potential to influence SLC6A4			[4]
Role of PTM	Potential impacts
Modified Residue	Threonine	Modified Location	59
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A4 Threonine 59 has the potential to affect its expression or activity.
PTM Phenomenon3	Have the potential to influence SLC6A4			[4]
Role of PTM	Potential impacts
Modified Residue	Threonine	Modified Location	66
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A4 Threonine 66 has the potential to affect its expression or activity.
PTM Phenomenon4	Have the potential to influence SLC6A4			[4]
Role of PTM	Potential impacts
Modified Residue	Threonine	Modified Location	67
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A4 Threonine 67 has the potential to affect its expression or activity.
PTM Phenomenon5	Have the potential to influence SLC6A4			[4]
Role of PTM	Potential impacts
Modified Residue	Threonine	Modified Location	68
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A4 Threonine 68 has the potential to affect its expression or activity.
PTM Phenomenon6	Have the potential to influence SLC6A4			[4]
Role of PTM	Potential impacts
Modified Residue	Threonine	Modified Location	69
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A4 Threonine 69 has the potential to affect its expression or activity.
PTM Phenomenon7	Have the potential to influence SLC6A4			[11]
Role of PTM	Potential impacts
Modified Residue	Threonine	Modified Location	81
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A4 Threonine 81 has the potential to affect its expression or activity.
PTM Phenomenon8	.			[3]
Role of PTM	Potential impacts
Modified Residue	Threonine	Modified Location	603
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A4 Threonine 603 has the potential to affect its expression or activity.
PTM Phenomenon9	.			[3]
Role of PTM	Potential impacts
Modified Residue	Threonine	Modified Location	603
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A4 Threonine 603 has the potential to affect its expression or activity.
PTM Phenomenon10	Have the potential to influence SLC6A4			[9], [12]
Role of PTM	Potential impacts
Modified Residue	Threonine	Modified Location	613
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A4 Threonine 613 has the potential to affect its expression or activity.
PTM Phenomenon11	Have the potential to influence SLC6A4			[1], [9]
Role of PTM	Potential impacts
Modified Residue	Threonine	Modified Location	616
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A4 Threonine 616 has the potential to affect its expression or activity.
PTM Phenomenon12	Have the potential to influence SLC6A4			[7]
Role of PTM	Potential impacts
Modified Residue	Threonine	Modified Location	618
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A4 Threonine 618 has the potential to affect its expression or activity.
Tyrosine	3 PTM Phenomena Related to This Residue		Click to Show/Hide the Full List
PTM Phenomenon1	Enhancing the stability of SLC6A4 protein and its transport activity			[13]
Role of PTM	Protein Stability
Affected Drug/Substrate	5-Hydroxytryptamine	Results for Drug	Increasing uptake of 5-Hydroxytryptamine
Modified Residue	Tyrosine
Experimental Material(s)	Human placental trophoblast cells
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC6A4 Tyrosine have been reported to enhance its protein stability and transport activity.
PTM Phenomenon2	Impairing the function of SLC6A4			[13]
Role of PTM	Surface Expression Modulation
Affected Drug/Substrate	5-Hydroxytryptamine	Results for Drug	Decreasing the transport of 5-Hydroxytryptamine
Modified Residue	Tyrosine	Modified Location	47
Modified State	Tyrosine to Phenylalanine mutation
Experimental Material(s)	Human placental trophoblast cells
Experimental Method	Co-Immunoprecipitation
Detailed Description	Removal of the Phosphorylation at SLC6A4 Tyrosine 47 (i.e. Tyrosine to Phenylalanine mutation) have been reported to impaire its transport function.
PTM Phenomenon3	Impairing the function of SLC6A4			[13]
Role of PTM	Surface Expression Modulation
Affected Drug/Substrate	5-Hydroxytryptamine	Results for Drug	Decreasing the transport of 5-Hydroxytryptamine
Modified Residue	Tyrosine	Modified Location	142
Modified State	Tyrosine to Phenylalanine mutation
Experimental Material(s)	Human placental trophoblast cells
Experimental Method	Co-Immunoprecipitation
Detailed Description	Removal of the Phosphorylation at SLC6A4 Tyrosine 142 (i.e. Tyrosine to Phenylalanine mutation) have been reported to impaire its transport function.
Ubiquitination
Unclear Residue	1 PTM Phenomena Related to This Residue		Click to Show/Hide the Full List
PTM Phenomenon1	Affecting the SERT expression levels and uptake activity			[14]
Role of PTM	Degradation via Proteosome
Related Enzyme	E3 ubiquitin-protein ligase synoviolin (HDR1)
Experimental Material(s)	African green monkey kidney fibroblast-like (COS-7) cells
Experimental Method	Co-Immunoprecipitation
Detailed Description	Ubiquitination at SLC6A4 have been reported to affect its expression levels and uptake activity.

References
1	X-ray structures and mechanism of the human serotonin transporter. Nature. 2016 Apr 21;532(7599):334-9.
2	Bidirectional control of postsynaptic density-95 (PSD-95) clustering by Huntingtin. J Biol Chem. 2014 Feb 7;289(6):3518-28.
3	ActiveDriverDB: human disease mutations and genome variation in post-translational modification sites of proteins. Nucleic Acids Res. 2018;46(D1):D901-D910.
4	Phosphoproteins in extracellular vesicles as candidate markers for breast cancer. Proc Natl Acad Sci U S A. 2017 Mar 21;114(12):3175-3180.
5	Temporal quantitative phosphoproteomics of ADP stimulation reveals novel central nodes in platelet activation and inhibition. Blood. 2017 Jan 12;129(2):e1-e12.
6	Determination of Site-Specific Phosphorylation Ratios in Proteins with Targeted Mass Spectrometry. J Proteome Res. 2018 Apr 6;17(4):1654-1663.
7	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.
8	Toward a comprehensive characterization of a human cancer cell phosphoproteome. J Proteome Res. 2013 Jan 4;12(1):260-71.
9	UniProt: a worldwide hub of protein knowledge. Nucleic Acids Res. 2019 Jan 8;47(D1):D506-D515.
10	Phosphorylation of threonine residue 276 is required for acute regulation of serotonin transporter by cyclic GMP. J Biol Chem. 2007 Apr 20;282(16):11639-47.
11	The N terminus of monoamine transporters is a lever required for the action of amphetamines. J Biol Chem. 2010 Apr 2;285(14):10924-38.
12	Phosphoproteome resource for systems biology research. Methods Mol Biol. 2011;694:307-22.
13	Tyrosine phosphorylation of the human serotonin transporter: a role in the transporter stability and function. Mol Pharmacol. 2012 Jan;81(1):73-85.
14	Role of the E3 ubiquitin ligase HRD1 in the regulation of serotonin transporter function. Biochem Biophys Res Commun. 2021 Jan 1;534:583-589.

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Detail Information of Post-Translational Modifications

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