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2.A.36.1.13
Na /H exchanger-1 (NHE1).  Stoichiometry = 1:1. TMS VI of NHE1 is a discontinuous pore-lining helix with residues Asn(227), Ile(233), and Leu(243) lining the translocation pore (Tzeng et al., 2010). (orthologous to NHE1 of rat, TC# 2.A.36.1.1). It regulates internal pH in human monocytes and is important in heart disease and cancer (Tsai et al. 2015). Structural studies have been performed using NMR and EPR (Lee et al., 2011; Nygaard et al. 2011).  Extracytoplasmic loops contribute to ion coordination and inhibitor sensitivity (Lee et al. 2012).  The regulation of NHE1 has been reviewed (Wakabayashi et al. 2013).  CD44 (LHR, MDU2, MDU3, MIC4; P16070) regulates breast cancer metastasis by regulating NHE1 expression (Chang et al. 2014).  The role of NHE1 in kidney proximal tubule functions, including pH regulation, vectorial Na+ transport, cell volume control and cell survival has been reviewed (Parker et al. 2015).  Helix M9 and the adjacent exofacial re-entrant loop 5 between M9 and M10 (EL5) are important elements involved in cation transport and inhibitor sensitivity (Jinadasa et al. 2015).  A 12 TMS topology has been confirmed (Liu et al. 2015).  Mutations  cause Lichtenstein-Knorr syndrome, an autosomal recessive condition that associates sensorineural hearing loss with cerebellar ataxia (Guissart et al. 2015). Cleaved FAS ligand (transmembrane CD95L; 1 TMS; P48023) activates NHE1 through the Akt/ROCK1 signalling pathway to stimulate cell motility (Monet et al. 2016). NHE1 may contribute to internal pH and motility of mammalian sperm (Muzzachi et al. 2018). The intracellular loop, IL5 is critical for proton sensing and ion transport (Wong et al. 2018). NHE1 and CD44 (the hyaluronan receptor with 742 aas and 2 TMSs, one at the N-terminus and one at the C-terminus (P16070)) appear to play important roles in cardiac remodeling (Suleiman et al. 2018).

Accession Number:P19634
Protein Name:Sodium/hydrogen exchanger 1
Length:815
Molecular Weight:90763.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:12
Location1 / Topology2 / Orientation3: Membrane1 / Multi-pass membrane protein2
Substrate Na+, H+

Cross database links:

Genevestigator: P19634 P19634
eggNOG: prNOG14086 COG0025
HEGENOM: HBG444842 HOG000247044
Entrez Gene ID: 6548   
Pfam: PF00999   
Drugbank: Drugbank Link   
KEGG: hsa:6548    hsa:6548   

Gene Ontology

GO:0016021 C:integral to membrane
GO:0015385 F:sodium:hydrogen antiporter activity
GO:0006885 P:regulation of pH
GO:0016323 C:basolateral plasma membrane
GO:0005624 C:membrane fraction
GO:0045121 C:membrane raft
GO:0005886 C:plasma membrane
GO:0015299 F:solute:hydrogen antiporter activity
GO:0030154 P:cell differentiation
GO:0016049 P:cell growth
GO:0007243 P:intracellular protein kinase cascade
GO:0045768 P:positive regulation of anti-apoptosis
GO:0001101 P:response to acid
GO:0010447 P:response to acidity
GO:0042493 P:response to drug
GO:0014070 P:response to organic cyclic compound

References (44)

[1] “Molecular cloning, primary structure, and expression of the human growth factor-activatable Na+/H+ antiporter.”  Sardet C.et.al.   2536298
[2] “Growth factors induce phosphorylation of the Na+/H+ antiporter, glycoprotein of 110 kD.”  Sardet C.et.al.   2154036
[3] “Molecular cloning and expression of a cDNA encoding the rabbit ileal villus cell basolateral membrane Na+/H+ exchanger.”  Tse C.-M.et.al.   1712287
[4] “Cloning and analysis of the human myocardial Na+/H+ exchanger.”  Fliegel L.et.al.   8283968
[5] “Silent polymorphisms within the coding region of human sodium/hydrogen exchanger isoform-1 cDNA in peripheral blood mononuclear cells of leukemia patients: a comparison with healthy controls.”  Garden O.A.et.al.   10913675
[6] “The DNA sequence and biological annotation of human chromosome 1.”  Gregory S.G.et.al.   16710414
[7] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[8] “The Na+/H+ exchanger NHE-1 possesses N- and O-linked glycosylation restricted to the first N-terminal extracellular domain.”  Counillon L.et.al.   8068684
[9] “Topological analysis of NHE1, the ubiquitous Na+/H+ exchanger using chymotryptic cleavage.”  Shrode L.D.et.al.   9688597
[10] “A novel topology model of the human Na(+)/H(+) exchanger isoform 1.”  Wakabayashi S.et.al.   10713111
[11] “Human homolog of mouse tescalcin associates with Na(+)/H(+) exchanger type-1.”  Mailaender J.et.al.   11696366
[12] “Calcineurin homologous protein as an essential cofactor for Na+/H+ exchangers.”  Pang T.et.al.   11350981
[13] “Expression of calcineurin B homologous protein 2 protects serum deprivation-induced cell death by serum-independent activation of Na+/H+ exchanger.”  Pang T.et.al.   12226101
[14] “The Na+/H+ exchanger cytoplasmic tail: structure, function, and interactions with tescalcin.”  Li X.et.al.   12809501
[15] “Proline residues in transmembrane segment IV are critical for activity, expression and targeting of the Na+/H+ exchanger isoform 1.”  Slepkov E.R.et.al.   14680478
[16] “ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage.”  Matsuoka S.et.al.   17525332
[17] “Phosphoproteome of resting human platelets.”  Zahedi R.P.et.al.   18088087
[18] “A quantitative atlas of mitotic phosphorylation.”  Dephoure N.et.al.   18669648
[19] “Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions.”  Mayya V.et.al.   19690332
[20] “Structural and functional characterization of transmembrane segment IV of the NHE1 isoform of the Na+/H+ exchanger.”  Slepkov E.R.et.al.   15677483
[21] “Crystal structure of CHP2 complexed with NHE1-cytosolic region and an implication for pH regulation.”  Ammar Y.B.et.al.   16710297
[22] “Solution structure of the cytoplasmic region of Na+/H+ exchanger 1 complexed with essential cofactor calcineurin B homologous protein 1.”  Mishima M.et.al.   17050540
[23] “Molecular cloning, primary structure, and expression of the human growth factor-activatable Na+/H+ antiporter.”  Sardet C.et.al.   2536298
[24] “Growth factors induce phosphorylation of the Na+/H+ antiporter, glycoprotein of 110 kD.”  Sardet C.et.al.   2154036
[25] “Molecular cloning and expression of a cDNA encoding the rabbit ileal villus cell basolateral membrane Na+/H+ exchanger.”  Tse C.-M.et.al.   1712287
[26] “Cloning and analysis of the human myocardial Na+/H+ exchanger.”  Fliegel L.et.al.   8283968
[27] “Silent polymorphisms within the coding region of human sodium/hydrogen exchanger isoform-1 cDNA in peripheral blood mononuclear cells of leukemia patients: a comparison with healthy controls.”  Garden O.A.et.al.   10913675
[28] “The DNA sequence and biological annotation of human chromosome 1.”  Gregory S.G.et.al.   16710414
[29] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[30] “The Na+/H+ exchanger NHE-1 possesses N- and O-linked glycosylation restricted to the first N-terminal extracellular domain.”  Counillon L.et.al.   8068684
[31] “Topological analysis of NHE1, the ubiquitous Na+/H+ exchanger using chymotryptic cleavage.”  Shrode L.D.et.al.   9688597
[32] “A novel topology model of the human Na(+)/H(+) exchanger isoform 1.”  Wakabayashi S.et.al.   10713111
[33] “Human homolog of mouse tescalcin associates with Na(+)/H(+) exchanger type-1.”  Mailaender J.et.al.   11696366
[34] “Calcineurin homologous protein as an essential cofactor for Na+/H+ exchangers.”  Pang T.et.al.   11350981
[35] “Expression of calcineurin B homologous protein 2 protects serum deprivation-induced cell death by serum-independent activation of Na+/H+ exchanger.”  Pang T.et.al.   12226101
[36] “The Na+/H+ exchanger cytoplasmic tail: structure, function, and interactions with tescalcin.”  Li X.et.al.   12809501
[37] “Proline residues in transmembrane segment IV are critical for activity, expression and targeting of the Na+/H+ exchanger isoform 1.”  Slepkov E.R.et.al.   14680478
[38] “ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage.”  Matsuoka S.et.al.   17525332
[39] “Phosphoproteome of resting human platelets.”  Zahedi R.P.et.al.   18088087
[40] “A quantitative atlas of mitotic phosphorylation.”  Dephoure N.et.al.   18669648
[41] “Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions.”  Mayya V.et.al.   19690332
[42] “Structural and functional characterization of transmembrane segment IV of the NHE1 isoform of the Na+/H+ exchanger.”  Slepkov E.R.et.al.   15677483
[43] “Crystal structure of CHP2 complexed with NHE1-cytosolic region and an implication for pH regulation.”  Ammar Y.B.et.al.   16710297
[44] “Solution structure of the cytoplasmic region of Na+/H+ exchanger 1 complexed with essential cofactor calcineurin B homologous protein 1.”  Mishima M.et.al.   17050540
Structure:
1Y4E   2BEC   2E30   2KBV   2L0E   2MDF   2YGG     

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FASTA formatted sequence
1:	MVLRSGICGL SPHRIFPSLL VVVALVGLLP VLRSHGLQLS PTASTIRSSE PPRERSIGDV 
61:	TTAPPEVTPE SRPVNHSVTD HGMKPRKAFP VLGIDYTHVR TPFEISLWIL LACLMKIGFH 
121:	VIPTISSIVP ESCLLIVVGL LVGGLIKGVG ETPPFLQSDV FFLFLLPPII LDAGYFLPLR 
181:	QFTENLGTIL IFAVVGTLWN AFFLGGLMYA VCLVGGEQIN NIGLLDNLLF GSIISAVDPV 
241:	AVLAVFEEIH INELLHILVF GESLLNDAVT VVLYHLFEEF ANYEHVGIVD IFLGFLSFFV 
301:	VALGGVLVGV VYGVIAAFTS RFTSHIRVIE PLFVFLYSYM AYLSAELFHL SGIMALIASG 
361:	VVMRPYVEAN ISHKSHTTIK YFLKMWSSVS ETLIFIFLGV STVAGSHHWN WTFVISTLLF 
421:	CLIARVLGVL GLTWFINKFR IVKLTPKDQF IIAYGGLRGA IAFSLGYLLD KKHFPMCDLF 
481:	LTAIITVIFF TVFVQGMTIR PLVDLLAVKK KQETKRSINE EIHTQFLDHL LTGIEDICGH 
541:	YGHHHWKDKL NRFNKKYVKK CLIAGERSKE PQLIAFYHKM EMKQAIELVE SGGMGKIPSA 
601:	VSTVSMQNIH PKSLPSERIL PALSKDKEEE IRKILRNNLQ KTRQRLRSYN RHTLVADPYE 
661:	EAWNQMLLRR QKARQLEQKI NNYLTVPAHK LDSPTMSRAR IGSDPLAYEP KEDLPVITID 
721:	PASPQSPESV DLVNEELKGK VLGLSRDPAK VAEEDEDDDG GIMMRSKETS SPGTDDVFTP 
781:	APSDSPSSQR IQRCLSDPGP HPEPGEGEPF FPKGQ