Hmdb loader
You are using an unsupported browser. Please upgrade your browser to a newer version to get the best experience on Human Metabolome Database.
Identification
HMDB Protein ID HMDBP02966
Secondary Accession Numbers
  • 8481
Name Electrogenic sodium bicarbonate cotransporter 1
Synonyms
  1. Na(+)/HCO3(-) cotransporter
  2. Sodium bicarbonate cotransporter
  3. Solute carrier family 4 member 4
  4. kNBC1
Gene Name SLC4A4
Protein Type Transporter
Biological Properties
General Function Involved in anion transport
Specific Function Electrogenic sodium/bicarbonate cotransporter with a Na(+):HCO3(-) stoichiometry varying from 1:2 to 1:3. May regulate bicarbonate influx/efflux at the basolateral membrane of cells and regulate intracellular pH
Pathways Not Available
Reactions Not Available
GO Classification
Component
membrane
cell part
membrane part
intrinsic to membrane
integral to membrane
Function
inorganic anion exchanger activity
transmembrane transporter activity
substrate-specific transmembrane transporter activity
ion transmembrane transporter activity
anion:anion antiporter activity
transporter activity
anion transmembrane transporter activity
Process
establishment of localization
transport
anion transport
ion transport
Cellular Location
  1. Multi-pass membrane protein
  2. Basolateral cell membrane
Gene Properties
Chromosome Location Chromosome:4
Locus 4q21
SNPs SLC4A4
Gene Sequence
>3240 bp
ATGGAGGATGAAGCTGTCCTGGACAGAGGGGCTTCCTTCCTCAAGCATGTGTGTGATGAA
GAAGAAGTAGAAGGCCACCATACCATTTACATCGGAGTCCATGTGCCGAAGAGTTACAGG
AGAAGGAGACGTCACAAGAGAAAGACAGGGCACAAAGAAAAGAAGGAAAAGGAGAGAATC
TCTGAGAACTACTCTGACAAATCAGATATTGAAAATGCTGATGAATCCAGCAGCAGCATC
CTAAAACCTCTCATCTCTCCTGCTGCAGAACGCATCCGATTCATCTTGGGAGAGGAGGAT
GACAGCCCAGCTCCCCCTCAGCTCTTCACGGAACTGGATGAGCTGCTGGCCGTGGATGGG
CAGGAGATGGAGTGGAAGGAAACAGCCAGGTGGATCAAGTTTGAAGAAAAAGTGGAACAG
GGTGGGGAAAGATGGAGCAAGCCCCATGTGGCCACATTGTCCCTTCATAGTTTATTTGAG
CTGAGGACATGTATGGAGAAAGGATCCATCATGCTTGATCGGGAGGCTTCTTCTCTCCCA
CAGTTGGTGGAGATGATTGTTGACCATCAGATTGAGACAGGCCTATTGAAACCTGAACTT
AAGGATAAGGTGACCTATACTTTGCTCCGGAAGCACCGGCATCAAACCAAGAAATCCAAC
CTTCGGTCCCTGGCTGACATTGGGAAGACAGTCTCCAGTGCAAGTAGGATGTTTACCAAC
CCTGATAATGGTAGCCCAGCCATGACCCATAGGAATCTGACTTCCTCCAGTCTGAATGAC
ATTTCTGATAAACCGGAGAAGGACCAGCTGAAGAATAAGTTCATGAAAAAATTGCCACGT
GATGCAGAAGCTTCCAACGTGCTTGTTGGGGAGGTTGACTTTTTGGATACTCCTTTCATT
GCCTTTGTTAGGCTACAGCAGGCTGTCATGCTGGGTGCCCTGACTGAAGTTCCTGTGCCC
ACAAGGTTCTTGTTCATTCTCTTAGGTCCTAAGGGGAAAGCCAAGTCCTACCACGAGATT
GGCAGAGCCATTGCCACCCTGATGTCTGATGAGGTGTTCCATGACATTGCTTATAAAGCA
AAAGACAGGCACGACCTGATTGCTGGTATTGATGAGTTCCTAGATGAAGTCATCGTCCTT
CCACCTGGGGAATGGGATCCAGCAATTAGGATAGAGCCTCCTAAGAGTCTTCCATCCTCT
GACAAAAGAAAGAATATGTACTCAGGTGGAGAGAATGTTCAGATGAATGGGGATACGCCC
CATGATGGAGGTCACGGAGGAGGAGGACATGGGGATTGTGAAGAATTGCAGCGAACTGGA
CGGTTCTGTGGTGGACTAATTAAAGACATAAAGAGGAAAGCGCCATTTTTTGCCAGTGAT
TTTTATGATGCTTTAAATATTCAAGCTCTTTCGGCAATTCTCTTCATTTATCTGGCAACT
GTAACTAATGCTATCACTTTTGGAGGACTGCTTGGGGATGCCACTGACAACATGCAGGGC
GTGTTGGAGAGTTTCCTGGGCACTGCTGTCTCTGGAGCCATCTTTTGCCTTTTTGCTGGT
CAACCACTCACTATTCTGAGCAGCACCGGACCTGTCCTAGTTTTTGAGAGGCTTCTATTT
AATTTCAGCAAGGACAATAATTTTGACTATTTGGAGTTTCGCCTTTGGATTGGCCTGTGG
TCCGCCTTCCTATGTCTCATTTTGGTAGCCACTGATGCCAGCTTCTTGGTTCAATACTTC
ACACGTTTCACGGAGGAGGGCTTTTCCTCTCTGATTAGCTTCATCTTTATCTATGATGCT
TTCAAGAAGATGATCAAGCTTGCAGATTACTACCCCATCAACTCCAACTTCAAAGTGGGC
TACAACACTCTCTTTTCCTGTACCTGTGTGCCACCTGACCCAGCTAATATCTCAATATCT
AATGACACCACACTGGCCCCAGAGTATTTGCCAACTATGTCTTCTACTGACATGTACCAT
AATACTACCTTTGACTGGGCATTTTTGTCGAAGAAGGAGTGTTCAAAATACGGAGGAAAC
CTCGTCGGGAACAACTGTAATTTTGTTCCTGATATCACACTCATGTCTTTTATCCTCTTC
TTGGGAACCTACACCTCTTCCATGGCTCTGAAAAAATTCAAAACTAGTCCTTATTTTCCA
ACCACAGCAAGAAAACTGATCAGTGATTTTGCCATTATCTTGTCCATTCTCATCTTTTGT
GTAATAGATGCCCTAGTAGGCGTGGACACCCCAAAACTAATTGTGCCAAGTGAGTTCAAG
CCAACAAGTCCAAACCGAGGTTGGTTCGTTCCACCGTTTGGAGAAAACCCCTGGTGGGTG
TGCCTTGCTGCTGCTATCCCGGCTTTGTTGGTCACTATACTGATTTTCATGGACCAACAA
ATTACAGCTGTGATTGTAAACAGGAAAGAACATAAACTCAAGAAAGGAGCAGGGTATCAC
TTGGATCTCTTTTGGGTGGCCATCCTCATGGTTATATGCTCCCTCATGGCTCTTCCGTGG
TATGTAGCTGCTACGGTCATCTCCATTGCTCACATCGACAGTTTGAAGATGGAGACAGAG
ACTTCTGCACCTGGAGAACAACCAAAGTTTCTAGGAGTGAGGGAACAAAGAGTCACTGGA
ACCCTTGTGTTTATTCTGACTGGTCTGTCAGTCTTTATGGCTCCCATCTTGAAGTTTATA
CCCATGCCTGTACTCTATGGTGTGTTCCTGTATATGGGAGTAGCATCCCTTAATGGTGTG
CAGTTCATGGATCGTCTGAAGCTGCTTCTGATGCCTCTGAAGCATCAGCCTGACTTCATC
TACCTGCGTCATGTTCCTCTGCGCAGAGTCCACCTGTTCACTTTCCTGCAGGTGTTGTGT
CTGGCCCTGCTTTGGATCCTCAAGTCAACGGTGGCTGCTATCATTTTTCCAGTAATGATC
TTGGCACTTGTAGCTGTCAGAAAAGGCATGGACTACCTCTTCTCCCAGCATGACCTCAGC
TTCCTGGATGATGTCATTCCAGAAAAGGACAAGAAAAAGAAGGAGGATGAGAAGAAAAAG
AAAAAGAAGAAGGGAAGTCTGGACAGTGACAATGATGATTCTGACTGCCCATACTCAGAA
AAAGTTCCAAGTATTAAAATTCCAATGGACATCATGGAACAGCAACCTTTCCTAAGCGAT
AGCAAACCTTCTGACAGAGAAAGATCACCAACATTCCTTGAACGCCACACATCATGCTGA
Protein Properties
Number of Residues 1079
Molecular Weight 121459.4
Theoretical pI 6.79
Pfam Domain Function
Signals
  • None
Transmembrane Regions
  • 469-488
  • 505-526
  • 555-580
  • 692-710
  • 726-748
  • 778-797
  • 823-847
  • 882-901
  • 950-967
  • 971-986
Protein Sequence
>Electrogenic sodium bicarbonate cotransporter 1
MEDEAVLDRGASFLKHVCDEEEVEGHHTIYIGVHVPKSYRRRRRHKRKTGHKEKKEKERI
SENYSDKSDIENADESSSSILKPLISPAAERIRFILGEEDDSPAPPQLFTELDELLAVDG
QEMEWKETARWIKFEEKVEQGGERWSKPHVATLSLHSLFELRTCMEKGSIMLDREASSLP
QLVEMIVDHQIETGLLKPELKDKVTYTLLRKHRHQTKKSNLRSLADIGKTVSSASRMFTN
PDNGSPAMTHRNLTSSSLNDISDKPEKDQLKNKFMKKLPRDAEASNVLVGEVDFLDTPFI
AFVRLQQAVMLGALTEVPVPTRFLFILLGPKGKAKSYHEIGRAIATLMSDEVFHDIAYKA
KDRHDLIAGIDEFLDEVIVLPPGEWDPAIRIEPPKSLPSSDKRKNMYSGGENVQMNGDTP
HDGGHGGGGHGDCEELQRTGRFCGGLIKDIKRKAPFFASDFYDALNIQALSAILFIYLAT
VTNAITFGGLLGDATDNMQGVLESFLGTAVSGAIFCLFAGQPLTILSSTGPVLVFERLLF
NFSKDNNFDYLEFRLWIGLWSAFLCLILVATDASFLVQYFTRFTEEGFSSLISFIFIYDA
FKKMIKLADYYPINSNFKVGYNTLFSCTCVPPDPANISISNDTTLAPEYLPTMSSTDMYH
NTTFDWAFLSKKECSKYGGNLVGNNCNFVPDITLMSFILFLGTYTSSMALKKFKTSPYFP
TTARKLISDFAIILSILIFCVIDALVGVDTPKLIVPSEFKPTSPNRGWFVPPFGENPWWV
CLAAAIPALLVTILIFMDQQITAVIVNRKEHKLKKGAGYHLDLFWVAILMVICSLMALPW
YVAATVISIAHIDSLKMETETSAPGEQPKFLGVREQRVTGTLVFILTGLSVFMAPILKFI
PMPVLYGVFLYMGVASLNGVQFMDRLKLLLMPLKHQPDFIYLRHVPLRRVHLFTFLQVLC
LALLWILKSTVAAIIFPVMILALVAVRKGMDYLFSQHDLSFLDDVIPEKDKKKKEDEKKK
KKKKGSLDSDNDDSDCPYSEKVPSIKIPMDIMEQQPFLSDSKPSDRERSPTFLERHTSC
GenBank ID Protein 148596928
UniProtKB/Swiss-Prot ID Q9Y6R1
UniProtKB/Swiss-Prot Entry Name S4A4_HUMAN
PDB IDs Not Available
GenBank Gene ID NM_001098484.2
GeneCard ID SLC4A4
GenAtlas ID SLC4A4
HGNC ID HGNC:11030
References
General References
  1. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [PubMed:15489334 ]
  2. Alvarez BV, Loiselle FB, Supuran CT, Schwartz GJ, Casey JR: Direct extracellular interaction between carbonic anhydrase IV and the human NBC1 sodium/bicarbonate co-transporter. Biochemistry. 2003 Oct 28;42(42):12321-9. [PubMed:14567693 ]
  3. Pushkin A, Abuladze N, Gross E, Newman D, Tatishchev S, Lee I, Fedotoff O, Bondar G, Azimov R, Ngyuen M, Kurtz I: Molecular mechanism of kNBC1-carbonic anhydrase II interaction in proximal tubule cells. J Physiol. 2004 Aug 15;559(Pt 1):55-65. Epub 2004 Jun 24. [PubMed:15218065 ]
  4. Burnham CE, Amlal H, Wang Z, Shull GE, Soleimani M: Cloning and functional expression of a human kidney Na+:HCO3- cotransporter. J Biol Chem. 1997 Aug 1;272(31):19111-4. [PubMed:9235899 ]
  5. Abuladze N, Lee I, Newman D, Hwang J, Boorer K, Pushkin A, Kurtz I: Molecular cloning, chromosomal localization, tissue distribution, and functional expression of the human pancreatic sodium bicarbonate cotransporter. J Biol Chem. 1998 Jul 10;273(28):17689-95. [PubMed:9651366 ]
  6. Choi I, Romero MF, Khandoudi N, Bril A, Boron WF: Cloning and characterization of a human electrogenic Na+-HCO-3 cotransporter isoform (hhNBC). Am J Physiol. 1999 Mar;276(3 Pt 1):C576-84. [PubMed:10069984 ]
  7. Sun XC, Bonanno JA: Identification and cloning of the Na/HCO(3-) cotransporter (NBC) in human corneal endothelium. Exp Eye Res. 2003 Sep;77(3):287-95. [PubMed:12907161 ]
  8. Gross E, Hawkins K, Pushkin A, Sassani P, Dukkipati R, Abuladze N, Hopfer U, Kurtz I: Phosphorylation of Ser(982) in the sodium bicarbonate cotransporter kNBC1 shifts the HCO(3)(-) : Na(+) stoichiometry from 3 : 1 to 2 : 1 in murine proximal tubule cells. J Physiol. 2001 Dec 15;537(Pt 3):659-65. [PubMed:11744745 ]
  9. Park K, Hurley PT, Roussa E, Cooper GJ, Smith CP, Thevenod F, Steward MC, Case RM: Expression of a sodium bicarbonate cotransporter in human parotid salivary glands. Arch Oral Biol. 2002 Jan;47(1):1-9. [PubMed:11743927 ]
  10. Gross E, Pushkin A, Abuladze N, Fedotoff O, Kurtz I: Regulation of the sodium bicarbonate cotransporter kNBC1 function: role of Asp(986), Asp(988) and kNBC1-carbonic anhydrase II binding. J Physiol. 2002 Nov 1;544(Pt 3):679-85. [PubMed:12411514 ]
  11. Choi I, Hu L, Rojas JD, Schmitt BM, Boron WF: Role of glycosylation in the renal electrogenic Na+-HCO3- cotransporter (NBCe1). Am J Physiol Renal Physiol. 2003 Jun;284(6):F1199-206. Epub 2003 Feb 25. [PubMed:12604466 ]
  12. Yamada H, Yamazaki S, Moriyama N, Hara C, Horita S, Enomoto Y, Kudo A, Kawakami H, Tanaka Y, Fujita T, Seki G: Localization of NBC-1 variants in human kidney and renal cell carcinoma. Biochem Biophys Res Commun. 2003 Oct 31;310(4):1213-8. [PubMed:14559244 ]
  13. Tatishchev S, Abuladze N, Pushkin A, Newman D, Liu W, Weeks D, Sachs G, Kurtz I: Identification of membrane topography of the electrogenic sodium bicarbonate cotransporter pNBC1 by in vitro transcription/translation. Biochemistry. 2003 Jan 28;42(3):755-65. [PubMed:12534288 ]
  14. Gross E, Fedotoff O, Pushkin A, Abuladze N, Newman D, Kurtz I: Phosphorylation-induced modulation of pNBC1 function: distinct roles for the amino- and carboxy-termini. J Physiol. 2003 Jun 15;549(Pt 3):673-82. Epub 2003 May 2. [PubMed:12730338 ]
  15. Kristensen JM, Kristensen M, Juel C: Expression of Na+/HCO3- co-transporter proteins (NBCs) in rat and human skeletal muscle. Acta Physiol Scand. 2004 Sep;182(1):69-76. [PubMed:15329059 ]
  16. Li HC, Worrell RT, Matthews JB, Husseinzadeh H, Neumeier L, Petrovic S, Conforti L, Soleimani M: Identification of a carboxyl-terminal motif essential for the targeting of Na+-HCO-3 cotransporter NBC1 to the basolateral membrane. J Biol Chem. 2004 Oct 8;279(41):43190-7. Epub 2004 Jul 25. [PubMed:15273250 ]
  17. Yang Z, Alvarez BV, Chakarova C, Jiang L, Karan G, Frederick JM, Zhao Y, Sauve Y, Li X, Zrenner E, Wissinger B, Hollander AI, Katz B, Baehr W, Cremers FP, Casey JR, Bhattacharya SS, Zhang K: Mutant carbonic anhydrase 4 impairs pH regulation and causes retinal photoreceptor degeneration. Hum Mol Genet. 2005 Jan 15;14(2):255-65. Epub 2004 Nov 24. [PubMed:15563508 ]
  18. Abuladze N, Azimov R, Newman D, Sassani P, Liu W, Tatishchev S, Pushkin A, Kurtz I: Critical amino acid residues involved in the electrogenic sodium-bicarbonate cotransporter kNBC1-mediated transport. J Physiol. 2005 Jun 15;565(Pt 3):717-30. Epub 2005 Apr 7. [PubMed:15817634 ]
  19. Igarashi T, Inatomi J, Sekine T, Cha SH, Kanai Y, Kunimi M, Tsukamoto K, Satoh H, Shimadzu M, Tozawa F, Mori T, Shiobara M, Seki G, Endou H: Mutations in SLC4A4 cause permanent isolated proximal renal tubular acidosis with ocular abnormalities. Nat Genet. 1999 Nov;23(3):264-6. [PubMed:10545938 ]
  20. Dinour D, Chang MH, Satoh J, Smith BL, Angle N, Knecht A, Serban I, Holtzman EJ, Romero MF: A novel missense mutation in the sodium bicarbonate cotransporter (NBCe1/SLC4A4) causes proximal tubular acidosis and glaucoma through ion transport defects. J Biol Chem. 2004 Dec 10;279(50):52238-46. Epub 2004 Oct 7. [PubMed:15471865 ]
  21. Li HC, Szigligeti P, Worrell RT, Matthews JB, Conforti L, Soleimani M: Missense mutations in Na+:HCO3- cotransporter NBC1 show abnormal trafficking in polarized kidney cells: a basis of proximal renal tubular acidosis. Am J Physiol Renal Physiol. 2005 Jul;289(1):F61-71. Epub 2005 Feb 15. [PubMed:15713912 ]
  22. Horita S, Yamada H, Inatomi J, Moriyama N, Sekine T, Igarashi T, Endo Y, Dasouki M, Ekim M, Al-Gazali L, Shimadzu M, Seki G, Fujita T: Functional analysis of NBC1 mutants associated with proximal renal tubular acidosis and ocular abnormalities. J Am Soc Nephrol. 2005 Aug;16(8):2270-8. Epub 2005 Jun 1. [PubMed:15930088 ]