Detail Information of Post-Translational Modifications

General Information of Drug Transporter (DT)
DT ID	DTD0024 Transporter Info
Gene Name	SLC22A6
Transporter Name	Organic anion transporter 1
Gene ID	9356
UniProt ID	Q4U2R8

Post-Translational Modification of This DT
Overview ofSLC22A6 Modification Sites with Functional and Structural Information
Sequence	M A F N D L L Q Q V G G V G R F Q Q I Q V T L V V L P L L L M A S H N T L Q N F T A A I P T H H C R P P A D A N L S K N G G L E V W L P R D R Q G Q P E S C L R F T S P Q W G L P F L N G T E A N G T G A T E P C T D G W I Y D N S T F P S T I V T E W D L V C S H R A L R Q L A Q S L Y M V G V L L G A M V F G Y L A D R L G R R K V L I L N Y L Q T A V S G T C A A F A P N F P I Y C A F R L L S G M A L A G I S L N C M T L N V E W M P I H T R A C V G T L I G Y V Y S L G Q F L L A G V A Y A V P H W R H L Q L L V S A P F F A F F I Y S W F F I E S A R W H S S S G R L D L T L R A L Q R V A R I N G K R E E G A K L S M E V L R A S L Q K E L T M G K G Q A S A M E L L R C P T L R H L F L C L S M L W F A T S F A Y Y G L V M D L Q G F G V S I Y L I Q V I F G A V D L P A K L V G F L V I N S L G R R P A Q M A A L L L A G I C I L L N G V I P Q D Q S I V R T S L A V L G K G C L A A S F N C I F L Y T G E L Y P T M I R Q T G M G M G S T M A R V G S I V S P L V S M T A E L Y P S M P L F I Y G A V P V A A S A V T V L L P E T L G Q P L P D T V Q D L E S R W A P T Q K E A G I Y P R K G K Q T R Q Q Q E H Q K Y M V P L Q A S A Q E K N G L
PTM type	X-Deubiquitination X-N-glycosylation X-Phosphorylation X-Ubiquitination X: Amino Acid

Deubiquitination
Unclear Residue	1 PTM Phenomena Related to This Residue		Click to Show/Hide the Full List
PTM Phenomenon1	Increasing SLC22A6 expression at the cell surface and an increased OAT1 transporter activity in cultured cells			[1]
Role of PTM	Surface Expression Modulation
Related Enzyme	Ubiquitin carboxyl-terminal hydrolase 8 (USP8)
Experimental Material(s)	African green monkey kidney fibroblast-like (COS-7) cells
Experimental Method	Co-Immunoprecipitation
Detailed Description	Deubiquitination at SLC22A6 have been reported to increase its expression at the cell surface and transport activity in cultured cells.
N-glycosylation
Asparagine	5 PTM Phenomena Related to This Residue		Click to Show/Hide the Full List
PTM Phenomenon1	Critically important for SLC22A6 to the plasma membrane			[2], [3]
Role of PTM	Surface Expression Modulation
Modified Residue	Asparagine	Modified Location	113
Experimental Method	Co-Immunoprecipitation
Detailed Description	Glycosylation at SLC22A6 Asparagine 113 have been reported to be critically important for its transporter to the plasma membrane.
PTM Phenomenon2	Have the potential to influence SLC22A6			[3]
Role of PTM	Potential impacts
Modified Residue	Asparagine	Modified Location	39
Experimental Method	Co-Immunoprecipitation
Detailed Description	N-linked Glycosylation at SLC22A6 Asparagine 39 has the potential to affect its expression or activity.
PTM Phenomenon3	Have the potential to influence SLC22A6			[3]
Role of PTM	Potential impacts
Modified Residue	Asparagine	Modified Location	56
Experimental Method	Co-Immunoprecipitation
Detailed Description	N-linked Glycosylation at SLC22A6 Asparagine 56 has the potential to affect its expression or activity.
PTM Phenomenon4	Have the potential to influence SLC22A6			[3]
Role of PTM	Potential impacts
Modified Residue	Asparagine	Modified Location	92
Experimental Method	Co-Immunoprecipitation
Detailed Description	N-linked Glycosylation at SLC22A6 Asparagine 92 has the potential to affect its expression or activity.
PTM Phenomenon5	Have the potential to influence SLC22A6			[3]
Role of PTM	Potential impacts
Modified Residue	Asparagine	Modified Location	97
Experimental Method	Co-Immunoprecipitation
Detailed Description	N-linked Glycosylation at SLC22A6 Asparagine 97 has the potential to affect its expression or activity.
Phosphorylation
Serine	3 PTM Phenomena Related to This Residue		Click to Show/Hide the Full List
PTM Phenomenon1	Have the potential to influence SLC22A6			[4]
Role of PTM	Potential impacts
Modified Residue	Serine	Modified Location	139
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC22A6 Serine 139 has the potential to affect its expression or activity.
PTM Phenomenon2	Have the potential to influence SLC22A6			[5]
Role of PTM	Potential impacts
Modified Residue	Serine	Modified Location	203
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC22A6 Serine 203 has the potential to affect its expression or activity.
PTM Phenomenon3	Have the potential to influence SLC22A6			[4]
Role of PTM	Potential impacts
Modified Residue	Serine	Modified Location	462
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC22A6 Serine 462 has the potential to affect its expression or activity.
Threonine	2 PTM Phenomena Related to This Residue		Click to Show/Hide the Full List
PTM Phenomenon1	Have the potential to influence SLC22A6			[4]
Role of PTM	Potential impacts
Modified Residue	Threonine	Modified Location	456
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC22A6 Threonine 456 has the potential to affect its expression or activity.
PTM Phenomenon2	Have the potential to influence SLC22A6			[4]
Role of PTM	Potential impacts
Modified Residue	Threonine	Modified Location	463
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC22A6 Threonine 463 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	Potentially affecting the transporter			[6]
Role of PTM	On/Off Switch
Modified Residue	Tyrosine
Modified State	Tyrosine kinase inhibitors
Experimental Method	Co-Immunoprecipitation
Detailed Description	Removal of the Phosphorylation at SLC22A6 Tyrosine (i.e. Tyrosine kinase inhibitors) have been reported to have the potential to affect the transporter.
PTM Phenomenon2	Have the potential to influence SLC22A6			[4]
Role of PTM	Potential impacts
Modified Residue	Tyrosine	Modified Location	141
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC22A6 Tyrosine 141 has the potential to affect its expression or activity.
PTM Phenomenon3	Have the potential to influence SLC22A6			[4]
Role of PTM	Potential impacts
Modified Residue	Tyrosine	Modified Location	154
Experimental Method	Co-Immunoprecipitation
Detailed Description	Phosphorylation at SLC22A6 Tyrosine 154 has the potential to affect its expression or activity.
Ubiquitination
Lysine	4 PTM Phenomena Related to This Residue		Click to Show/Hide the Full List
PTM Phenomenon1	Inhibiting the activity of SLC22A6 by reducing by its cell-surface expression			[7]
Role of PTM	Trafficking to Plasma Membrane
Modified Residue	Lysine	Modified Location	48
Related Enzyme	Protein kinase C alpha type (PRKCA)
Experimental Material(s)	African green monkey kidney fibroblast-like (COS) cells
Experimental Method	Co-Immunoprecipitation
Detailed Description	Ubiquitination at SLC22A6 Lysine 48 have been reported to inhibit its transport activity.
PTM Phenomenon2	Inhibiting the activity of SLC22A6			[8]
Role of PTM	Trafficking to Plasma Membrane
Modified Residue	Lysine	Modified Location	297
Related Enzyme	Protein kinase C alpha type (PRKCA)
Experimental Material(s)	African green monkey kidney fibroblast-like (COS-7) cells
Experimental Method	Co-Immunoprecipitation
Detailed Description	Ubiquitination at SLC22A6 Lysine 297 have been reported to inhibite its transport activity.
PTM Phenomenon3	Inhibiting the activity of SLC22A6			[8]
Role of PTM	Trafficking to Plasma Membrane
Modified Residue	Lysine	Modified Location	303
Related Enzyme	Protein kinase C alpha type (PRKCA)
Experimental Material(s)	African green monkey kidney fibroblast-like (COS-7) cells
Experimental Method	Co-Immunoprecipitation
Detailed Description	Ubiquitination at SLC22A6 Lysine 303 have been reported to inhibite its transport activity.
PTM Phenomenon4	Inhibiting the activity of SLC22A6			[8]
Role of PTM	Trafficking to Plasma Membrane
Modified Residue	Lysine	Modified Location	315
Related Enzyme	Protein kinase C alpha type (PRKCA)
Experimental Material(s)	African green monkey kidney fibroblast-like (COS-7) cells
Experimental Method	Co-Immunoprecipitation
Detailed Description	Ubiquitination at SLC22A6 Lysine 315 have been reported to inhibite its transport activity.
Unclear Residue	1 PTM Phenomena Related to This Residue		Click to Show/Hide the Full List
PTM Phenomenon1	Decreasing the expression and SLC22A6 activity			[9]
Role of PTM	Degradation via Proteosome
Related Enzyme	E3 ubiquitin-protein ligase NEDD4 (NEDD4) E3 ubiquitin-protein ligase NEDD4-like (NEDD4L)
Experimental Material(s)	African green monkey kidney fibroblast-like (COS-7) cells; Human Embryonic Kidney 293T (HEK-293T) cells
Experimental Method	Co-Immunoprecipitation
Detailed Description	Ubiquitination at SLC22A6 have been reported to decrease its expression and transport activity.

References
1	Regulation of organic anion transporters: Role in physiology, pathophysiology, and drug elimination. Pharmacol Ther. 2021 Jan;217:107647.
2	The antiviral nucleotide analogs cidofovir and adefovir are novel substrates for human and rat renal organic anion transporter 1. Mol Pharmacol. 1999 Sep;56(3):570-80.
3	Role of glycosylation in the organic anion transporter OAT1. J Biol Chem. 2004 Apr 9;279(15):14961-6.
4	Characterization of native protein complexes and protein isoform variation using size-fractionation-based quantitative proteomics. Mol Cell Proteomics. 2013 Dec;12(12):3851-73.
5	Global Ion Suppression Limits the Potential of Mass Spectrometry Based Phosphoproteomics. J Proteome Res. 2019 Jan 4;18(1):493-507.
6	Post-translational modifications of transporters. Pharmacol Ther. 2018 Dec;192:88-99.
7	Lysine 48-linked polyubiquitination of organic anion transporter-1 is essential for its protein kinase C-regulated endocytosis. Mol Pharmacol. 2013 Jan;83(1):217-24.
8	Three ubiquitination sites of organic anion transporter-1 synergistically mediate protein kinase C-dependent endocytosis of the transporter. Mol Pharmacol. 2013 Jul;84(1):139-46.
9	Nedd4-2 but not Nedd4-1 is critical for protein kinase C-regulated ubiquitination, expression, and transport activity of human organic anion transporter 1. Am J Physiol Renal Physiol. 2016 May 1;310(9):F821-31.

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Detail Information of Post-Translational Modifications

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