P26431 (SL9A1_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Sodium/hydrogen exchanger 1

Alternative name(s):
Na(+)/H(+) exchanger 1
Short name=NHE-1
Solute carrier family 9 member 1

Gene names

Name:	Slc9a1
Synonyms:	Nhe1

Organism

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Dipnotetrapodomorpha › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	820 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Involved in pH regulation to eliminate acids generated by active metabolism or to counter adverse environmental conditions. Major proton extruding system driven by the inward sodium ion chemical gradient. Plays an important role in signal transduction.
Subunit structure	Interacts with calmodulin and TESC. Interacts (via the juxtamembrane region of the cytoplasmic C-terminus domain) with CHP1; the interaction occurs at the plasma membrane in a calcium-dependent manner. Interacts with CHP2; the interaction occurs in a calcium-dependent manner By similarity. Oligomer. Interacts with CHP1, CHP2 and TESC. Ref.3 Ref.4 Ref.5
Subcellular location	Endoplasmic reticulum membrane; Multi-pass membrane protein. Membrane; Multi-pass membrane protein. Cell membrane; Multi-pass membrane protein. Note: Colocalizes with and CHP2 at the plasma membrane By similarity. Colocalizes with CHP1 at the reticulum endoplasmic and plasma membrane.
Tissue specificity	Not tissue specific.
Post-translational modification	N-glycosylated and O-glycosylated in the N-terminal region. Ref.2 Ref.5 Ubiquitinated, leading to its degradation by the proteasome. Ubiquitination is reduced by CHP1. Ref.5
Sequence similarities	Belongs to the monovalent cation:proton antiporter 1 (CPA1) transporter (TC 2.A.36) family. [View classification]
Caution	The region between transmembrane regions M4 and M5 and between M6 and M7 (also termed intracellular loops IL2 and IL4, respectively) seem to be localized at least in part in the membrane. The hydrophobic region H10 is proposed to be located within the membrane. Although Ref.4 show that TESC-binding results in the maturation and accumulation of SLC9A1 at the cell surface, previous studies with human SLC9A1 report that TESC-binding results in a decrease in activity. Although Ref.4 show that they CHP1 and TESC bind at the same C-terminal site, previous studies with human SLC9A1 report that they bind to different sites.

Ontologies

Keywords
Biological process	Antiport Ion transport Sodium transport Transport
Cellular component	Cell membrane Endoplasmic reticulum Membrane
Domain	Transmembrane Transmembrane helix
Ligand	Calmodulin-binding Sodium
PTM	Glycoprotein Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	cardiac muscle cell differentiation Inferred from electronic annotation. Source: Ensembl cell differentiation Inferred from expression pattern PubMed 16495213. Source: RGD cell growth Inferred from expression pattern PubMed 15452191. Source: RGD cellular response to acidity Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of apoptotic process Inferred from mutant phenotype PubMed 17552965. Source: RGD neuron death Inferred from mutant phenotype PubMed 19328212. Source: RGD positive regulation of action potential Inferred from mutant phenotype PubMed 18319243. Source: RGD positive regulation of cell growth Inferred from mutant phenotype PubMed 19687166. Source: RGD positive regulation of intracellular protein kinase cascade Inferred from mutant phenotype PubMed 14600156. Source: RGD positive regulation of mitochondrial membrane permeability Inferred from mutant phenotype PubMed 21297023. Source: RGD regulation of intracellular pH Inferred from sequence or structural similarity. Source: UniProtKB regulation of sensory perception of pain Inferred from mutant phenotype PubMed 21763398. Source: RGD regulation of the force of heart contraction Inferred from mutant phenotype PubMed 21659487. Source: RGD response to acid Inferred from sequence or structural similarity. Source: UniProtKB response to drug Inferred from expression pattern PubMed 15452191. Source: RGD response to organic cyclic compound Inferred from direct assay PubMed 17308111. Source: RGD sodium ion export Inferred from sequence or structural similarity. Source: UniProtKB
Cellular_component	basolateral plasma membrane Inferred from direct assay PubMed 9438178. Source: RGD endoplasmic reticulum Inferred from direct assay Ref.5. Source: UniProtKB endoplasmic reticulum membrane Inferred from electronic annotation. Source: UniProtKB-SubCell integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW membrane raft Inferred from direct assay PubMed 16002403. Source: RGD mitochondrion Inferred from direct assay PubMed 21297023. Source: RGD
Molecular_function	calcium-dependent protein binding Inferred from sequence or structural similarity. Source: UniProtKB sodium:hydrogen antiporter activity Inferred from direct assay Ref.4. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Chp2	Q810D1	2	EBI-77471,EBI-6146708

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 820	820	Sodium/hydrogen exchanger 1		PRO_0000052351
Regions
	Topological domain	1 – 12	12	Cytoplasmic Potential
	Transmembrane	13 – 33	21	Helical; Name=M1; Potential
	Topological domain	34 – 105	72	Extracellular Potential
	Transmembrane	106 – 131	26	Helical; Name=M2; Potential
	Topological domain	132 – 133	2	Cytoplasmic Potential
	Transmembrane	134 – 153	20	Helical; Name=M3; Potential
	Topological domain	154 – 158	5	Extracellular Potential
	Transmembrane	159 – 178	20	Helical; Name=M4; Potential
	Topological domain	179 – 195	17	Cytoplasmic Potential
	Transmembrane	196 – 215	20	Helical; Name=M5; Potential
	Topological domain	216 – 231	16	Extracellular Potential
	Transmembrane	232 – 251	20	Helical; Name=M6; Potential
	Topological domain	252 – 260	9	Cytoplasmic Potential
	Transmembrane	261 – 280	20	Helical; Name=M7; Potential
	Topological domain	281 – 298	18	Extracellular Potential
	Transmembrane	299 – 319	21	Helical; Name=M8; Potential
	Topological domain	320 – 342	23	Cytoplasmic Potential
	Transmembrane	343 – 362	20	Helical; Name=M9; Potential
	Topological domain	363 – 385	23	Extracellular Potential
	Intramembrane	386 – 406	21	Name=H10; By similarity
	Topological domain	407 – 414	8	Extracellular Potential
	Transmembrane	415 – 434	20	Helical; Name=M10; Potential
	Topological domain	435 – 452	18	Cytoplasmic Potential
	Transmembrane	453 – 474	22	Helical; Name=M11; Potential
	Topological domain	475 – 483	9	Extracellular Potential
	Transmembrane	484 – 503	20	Helical; Name=M12; Potential
	Topological domain	504 – 820	317	Cytoplasmic Potential
	Region	520 – 543	24	Interaction with CHP2 By similarity
Sites
	Site	165	1	Channel pore-lining By similarity
Amino acid modifications
	Modified residue	603	1	Phosphoserine By similarity
	Modified residue	609	1	Phosphoserine By similarity
	Modified residue	697	1	Phosphoserine By similarity
	Modified residue	701	1	Phosphoserine By similarity
	Modified residue	707	1	Phosphoserine By similarity
	Modified residue	727	1	Phosphoserine By similarity
	Modified residue	730	1	Phosphoserine By similarity
	Modified residue	733	1	Phosphoserine By similarity
	Modified residue	790	1	Phosphoserine By similarity
	Glycosylation	374	1	N-linked (GlcNAc...) Potential
Experimental info
	Mutagenesis	522 – 538	17	INEEI…LLTGI → QNEEQHTQQLDHQQTGQ: Abolishes interaction with TESC and markedly reduces transporter activity. Does not alter its cell membrane localization. Ref.5
	Mutagenesis	530 – 535	6	FLDHLL → AADHAA: Abolishes interaction with TESC and markedly reduces transporter activity. Does not alter its cell membrane localization. Ref.4
	Mutagenesis	530 – 535	6	FLDHLL → QQDHQQ: Abolishes interaction with TESC and markedly reduces transporter activity. Does not alter its cell membrane localization. Ref.4
	Mutagenesis	530 – 535	6	FLDHLL → RRDHRR: Abolishes interaction with TESC and markedly reduces transporter activity. Does not alter its cell membrane localization. Ref.4

Sequences

	Sequence		Length	Mass (Da)
	P26431 [UniParc]. Last modified October 1, 1996. Version 2. Checksum: 58398DE74A9642FB	FASTA	820	91,647
	10 20 30 40 50 60 MMLRWSGIWG LYPPRIFPSL LVVVALVGLL PVLRSHGLQL NPTASTIRGS EPPRERSIGD 70 80 90 100 110 120 VTTAPSEPLH HPDDRNLTNL YIEHGAKPVR KAFPVLDIDY LHVRTPFEIS LWILLACLMK 130 140 150 160 170 180 IGFHVIPTIS SIVPESCLLI VVGLLVGGLI KGVGETPPFL QSDVFFLFLL PPIILDAGYF 190 200 210 220 230 240 LPLRQFTENL GTILIFAVVG TLWNAFFLGG LLYAVCLVGG EQINNIGLLD TLLFGSIISA 250 260 270 280 290 300 VDPVAVLAVF EEIHINELLH ILVFGESLLN DAVTVVLYHL FEEFASYEYV GISDIFLGFL 310 320 330 340 350 360 SFFVVSLGGV FVGVVYGVIA AFTSRFTSHI RVIEPLFVFL YSYMAYLSAE LFHLSGIMAL 370 380 390 400 410 420 IASGVVMRPY VEANISHKSH TTIKYFLKMW SSVSETLIFI FLGVSTVAGS HQWNWTFVIS 430 440 450 460 470 480 TLLFCLIARV LGVLVLTWFI NKFRIVKLTP KDQFIIAYGG LRGAIAFSLG YLLDKKHFPM 490 500 510 520 530 540 CDLFLTAIIT VIFFTVFVQG MTIRPLVDLL AVKKKQETKR SINEEIHTQF LDHLLTGIED 550 560 570 580 590 600 ICGHYGHHHW KDKLNRFNKK YVKKCLIAGE RSKEPQLIAF YHKMEMKQAI ELVESGGMGK 610 620 630 640 650 660 IPSAVSTVSM QNIHPKSAAS ERILPALSKD KEEEIRKILR SNLQKTRQRL RSYNRHTLVA 670 680 690 700 710 720 DPYEEAWNQM LLRRQKARQL EQKITNYLTV PAHKLDSPTM SRARIGSDPL AYEPKADLPV 730 740 750 760 770 780 ITIDPASPQS PESVDLVNEE LKGKVLGLKR GPRTTPEEEE EDEDGVIMIR SKEPSSPGTD 790 800 810 820 DVFTPGPSDS PGSQRIQRCL SDPGPHPEPG EGEPFIPKGQ

References

[1]	"Molecular cloning of putative members of the Na/H exchanger gene family. cDNA cloning, deduced amino acid sequence, and mRNA tissue expression of the rat Na/H exchanger NHE-1 and two structurally related proteins." Orlowski J., Kandasamy R.A., Shull G.E. J. Biol. Chem. 267:9331-9339(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Strain: Sprague-Dawley. Tissue: Heart.
[2]	"Topological analysis of NHE1, the ubiquitous Na+/H+ exchanger using chymotryptic cleavage." Shrode L.D., Gan B.S., D'Souza S.J., Orlowski J., Grinstein S. Am. J. Physiol. 275:C431-C439(1998) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION.
[3]	"Calcineurin homologous protein isoform 2 (CHP2), Na+/H+ exchangers-binding protein, is expressed in intestinal epithelium." Inoue H., Nakamura Y., Nagita M., Takai T., Masuda M., Nakamura N., Kanazawa H. Biol. Pharm. Bull. 26:148-155(2003) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH CHP1 AND CHP2.
[4]	"Calcineurin B homologous protein 3 promotes the biosynthetic maturation, cell surface stability, and optimal transport of the Na+/H+ exchanger NHE1 isoform." Zaun H.C., Shrier A., Orlowski J. J. Biol. Chem. 283:12456-12467(2008) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH TESC, MUTAGENESIS OF 530-PHE--LEU-535.
[5]	"Dual functional significance of calcineurin homologous protein 1 binding to Na(+)/H(+) exchanger isoform 1." Matsushita M., Tanaka H., Mitsui K., Kanazawa H. Am. J. Physiol. 301:C280-C288(2011) [PubMed] [Europe PMC] [Abstract] Cited for: OLIGOMERIZATION, GLYCOSYLATION, UBIQUITINATION, MUTAGENESIS OF 522-ILE--ILE-538.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	M85299 mRNA. Translation: AAA98479.1.
IPI	IPI00193369.
PIR	A40204.
RefSeq	NP_036784.1. NM_012652.1.
UniGene	Rn.5025.
3D structure databases
ProteinModelPortal	P26431.
SMR	P26431. Positions 159-184, 254-279, 342-369, 507-549.
ModBase	Search...
Protein-protein interaction databases
IntAct	P26431. 3 interactions.
STRING	10116.ENSRNOP00000011049.
Protein family/group databases
TCDB	2.A.36.1.1. the monovalent cation:proton antiporter-1 (cpa1) family.
PTM databases
PhosphoSite	P26431.
Proteomic databases
PaxDb	P26431.
PRIDE	P26431.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSRNOT00000011049; ENSRNOP00000011049; ENSRNOG00000007982.
GeneID	24782.
KEGG	rno:24782.
UCSC	RGD:3718. rat.
Organism-specific databases
CTD	6548.
RGD	3718. Slc9a1.
Phylogenomic databases
eggNOG	COG0025.
GeneTree	ENSGT00560000077158.
HOGENOM	HOG000247044.
HOVERGEN	HBG052615.
InParanoid	P26431.
KO	K05742.
OMA	YDRVGIV.
OrthoDB	EOG7XWPN4.
Gene expression databases
Genevestigator	P26431.
Family and domain databases
InterPro	IPR006153. Cation/H_exchanger. IPR018422. Cation/H_exchanger_CPA1. IPR001970. Na/H_exchanger_1. IPR004709. NaH_exchanger. [Graphical view]
PANTHER	PTHR10110. PTHR10110. 1 hit.
Pfam	PF00999. Na_H_Exchanger. 1 hit. [Graphical view]
PRINTS	PR01084. NAHEXCHNGR. PR01085. NAHEXCHNGR1.
TIGRFAMs	TIGR00840. b_cpa1. 1 hit.
ProtoNet	Search...
Other
BindingDB	P26431.
ChEMBL	CHEMBL2577.
NextBio	604392.
PRO	P26431.

Entry information

Entry name

SL9A1_RAT

Accession

Primary (citable) accession number: P26431

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 1, 1992
Last sequence update:	October 1, 1996
Last modified:	November 13, 2013
This is version 122 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program