Q5T2W1 (NHRF3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Na(+)/H(+) exchange regulatory cofactor NHE-RF3
Short name=NHERF-3

Alternative name(s):
CFTR-associated protein of 70 kDa
Na(+)/H(+) exchanger regulatory factor 3
Na/Pi cotransporter C-terminal-associated protein 1
Short name=NaPi-Cap1
PDZ domain-containing protein 1
Sodium-hydrogen exchanger regulatory factor 3

Gene names

Name:	PDZK1
Synonyms:	CAP70, NHERF3, PDZD1

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	519 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	A scaffold protein that connects plasma membrane proteins and regulatory components, regulating their surface expression in epithelial cells apical domains. May be involved in the coordination of a diverse range of regulatory processes for ion transport and second messenger cascades. In complex with SLC9A3R1, may cluster proteins that are functionally dependent in a mutual fashion and modulate the trafficking and the activity of the associated membrane proteins. May play a role in the cellular mechanisms associated with multidrug resistance through its interaction with ABCC2 and PDZK1IP1. May potentiate the CFTR chloride channel activity. May function to connect SCARB1 with the cellular machineries for intracellular cholesterol transport and/or metabolism. May be involved in the regulation of proximal tubular Na+-dependent inorganic phosphate cotransport therefore playing an important role in tubule function By similarity.
Subunit structure	Interacts with PDZK1IP1 and ABCC2. Binds to the C-terminal region of SLC26A3. Interacts via its PDZ1 domain with the C-terminal domain of SCARB1. Forms a heterodimeric complex with SLC9A3R1. Interacts with AKAP2, BCR, CFTR, SLC22A12, SLC22A4, SLC22A5, SLC26A6, SLC9A3R2 and SLC17A1. Component of a complex, composed of PDZK1, SYNGAP1, KLHL17 and NMDA receptors. Interacts (via PDZ1 domain) directly with KLHL17; the interaction is important for integrity of actin cytoskeleton structures in neurons By similarity. Ref.1 Ref.5 Ref.7 Ref.8
Subcellular location	Cytoplasm By similarity. Membrane; Peripheral membrane protein By similarity. Note: Associated with peripheral membranes. Localizes to the apical compartment of proximal tubular cells and to sinusoidal liver membranes By similarity.
Tissue specificity	Expression is limited to epithelial cells. Expressed in the kidney (brush border of proximal tubule), pancreas, liver, and small intestine. Expressed at a lower level in the adrenal cortex, testis and stomach. Overexpressed in breast, renal and lung carcinomas. Ref.1 Ref.5 Ref.6
Domain	The PDZ 2 and 3 domains seem to be involved in the interaction with SLC26A3 By similarity. Interaction with the C-terminus of CFTR could be mediated through independent binding of PDZ 1, 3 and 4 domains By similarity. The PDZ 1 and 3 domains seem to be involved in the interaction with SLCO1A1 By similarity. The PDZ 1 domain interacts with BCR.
Sequence similarities	Belongs to the NHER family. Contains 4 PDZ (DHR) domains.

Ontologies

Keywords
Cellular component	Cytoplasm Membrane
Coding sequence diversity	Alternative splicing
Domain	Repeat
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	carnitine transport Inferred from direct assay PubMed 15523054. Source: BHF-UCL cell proliferation Traceable author statement Ref.1. Source: UniProtKB drug transport Non-traceable author statement PubMed 16738539. Source: UniProtKB establishment of protein localization to plasma membrane Inferred from electronic annotation. Source: Compara positive regulation of ion transmembrane transport Inferred from direct assay PubMed 15523054. Source: BHF-UCL
Cellular_component	brush border membrane Inferred from sequence or structural similarity PubMed 15523054. Source: BHF-UCL cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	transporter activity Traceable author statement Ref.1. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CFTR	P13569	2	EBI-349819,EBI-349854

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q5T2W1-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q5T2W1-2)

The sequence of this isoform differs from the canonical sequence as follows:
     154-264: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 519

519

Na(+)/H(+) exchange regulatory cofactor NHE-RF3

PRO_0000058287

Regions

Domain

9 – 90

82

PDZ 1

Domain

134 – 215

82

PDZ 2

Domain

243 – 323

81

PDZ 3

Domain

378 – 458

81

PDZ 4

Amino acid modifications

Modified residue

492

1

Phosphoserine By similarity

Modified residue

514

1

Phosphoserine By similarity

Natural variations

Alternative sequence

154 – 264

111

Missing in isoform 2.

VSP_044637

Experimental info

Sequence conflict

195

1

E → K in AAC12264. Ref.1

Sequence conflict

270

1

D → G in BAG60531. Ref.2

Secondary structure

1

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519

Helix Strand Turn

Details...

Beta strand

132 – 139

8

Beta strand

142 – 144

3

Helix

168 – 172

5

Beta strand

176 – 183

8

Helix

193 – 203

11

Beta strand

205 – 211

7

Turn

214 – 216

3

Beta strand

376 – 382

7

Beta strand

385 – 387

3

Beta strand

389 – 392

4

Beta strand

398 – 405

8

Helix

411 – 414

4

Beta strand

422 – 426

5

Beta strand

432 – 434

3

Helix

436 – 443

8

Beta strand

448 – 455

8

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified August 16, 2005. Version 2. Checksum: 98BF707F87CD77A6	FASTA	519	57,129
	10 20 30 40 50 60 MTSTFNPREC KLSKQEGQNY GFFLRIEKDT EGHLVRVVEK CSPAEKAGLQ DGDRVLRING 70 80 90 100 110 120 VFVDKEEHMQ VVDLVRKSGN SVTLLVLDGD SYEKAVKTRV DLKELGQSQK EQGLSDNILS 130 140 150 160 170 180 PVMNGGVQTW TQPRLCYLVK EGGSYGFSLK TVQGKKGVYM TDITPQGVAM RAGVLADDHL 190 200 210 220 230 240 IEVNGENVED ASHEEVVEKV KKSGSRVMFL LVDKETDKRH VEQKIQFKRE TASLKLLPHQ 250 260 270 280 290 300 PRIVEMKKGS NGYGFYLRAG SEQKGQIIKD IDSGSPAEEA GLKNNDLVVA VNGESVETLD 310 320 330 340 350 360 HDSVVEMIRK GGDQTSLLVV DKETDNMYRL AHFSPFLYYQ SQELPNGSVK EAPAPTPTSL 370 380 390 400 410 420 EVSSPPDTTE EVDHKPKLCR LAKGENGYGF HLNAIRGLPG SFIKEVQKGG PADLAGLEDE 430 440 450 460 470 480 DVIIEVNGVN VLDEPYEKVV DRIQSSGKNV TLLVCGKKAY DYFQAKKIPI VSSLADPLDT 490 500 510 PPDSKEGIVV ESNHDSHMAK ERAHSTASHS SSNSEDTEM
	Isoform 2 [UniParc]. Checksum: 6AF5DA3B9EF406E9	FASTA	408	44,665
	10 20 30 40 50 60 MTSTFNPREC KLSKQEGQNY GFFLRIEKDT EGHLVRVVEK CSPAEKAGLQ DGDRVLRING 70 80 90 100 110 120 VFVDKEEHMQ VVDLVRKSGN SVTLLVLDGD SYEKAVKTRV DLKELGQSQK EQGLSDNILS 130 140 150 160 170 180 PVMNGGVQTW TQPRLCYLVK EGGSYGFSLK TVQGQIIKDI DSGSPAEEAG LKNNDLVVAV 190 200 210 220 230 240 NGESVETLDH DSVVEMIRKG GDQTSLLVVD KETDNMYRLA HFSPFLYYQS QELPNGSVKE 250 260 270 280 290 300 APAPTPTSLE VSSPPDTTEE VDHKPKLCRL AKGENGYGFH LNAIRGLPGS FIKEVQKGGP 310 320 330 340 350 360 ADLAGLEDED VIIEVNGVNV LDEPYEKVVD RIQSSGKNVT LLVCGKKAYD YFQAKKIPIV 370 380 390 400 SSLADPLDTP PDSKEGIVVE SNHDSHMAKE RAHSTASHSS SNSEDTEM

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Identification and partial characterization of PDZK1: a novel protein containing PDZ interaction domains." Kocher O., Comella N., Tognazzi K., Brown L.F. Lab. Invest. 78:117-125(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, INTERACTION WITH PDZK1IP1.
[2]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). Tissue: Kidney.
[3]	"The DNA sequence and biological annotation of human chromosome 1." Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R. Nature 441:315-321(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Colon.
[5]	"PDZK1, a novel PDZ domain-containing protein up-regulated in carcinomas and mapped to chromosome 1q21, interacts with cMOAT (MRP2), the multidrug resistance-associated protein." Kocher O., Comella N., Gilchrist A., Pal R., Tognazzi K., Brown L.F., Knoll J.H. Lab. Invest. 79:1161-1170(1999) [PubMed] [Europe PMC] [Abstract] Cited for: TISSUE SPECIFICITY, INTERACTION WITH ABCC2.
[6]	"Accessory protein facilitated CFTR-CFTR interaction, a molecular mechanism to potentiate the chloride channel activity." Wang S., Yue H., Derin R.B., Guggino W.B., Li M. Cell 103:169-179(2000) [PubMed] [Europe PMC] [Abstract] Cited for: TISSUE SPECIFICITY.
[7]	"Bcr (breakpoint cluster region) protein binds to PDZ-domains of scaffold protein PDZK1 and vesicle coat protein Mint3." Malmberg E.K., Andersson C.X., Gentzsch M., Chen J.H., Mengos A., Cui L., Hansson G.C., Riordan J.R. J. Cell Sci. 117:5535-5541(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH BCR.
[8]	"The CFTR associated protein CAP70 interacts with the apical Cl-/HCO3-exchanger DRA in rabbit small intestinal mucosa." Rossmann H., Jacob P., Baisch S., Hassoun R., Meier J., Natour D., Yahya K., Yun C., Biber J., Lackner K.J., Fiehn W., Gregor M., Seidler U., Lamprecht G. Biochemistry 44:4477-4487(2005) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH SLC26A3.
[9]	"Solution structure of PDZ domains of PDZ domain containing protein 1." RIKEN structural genomics initiative (RSGI) Submitted (FEB-2008) to the PDB data bank Cited for: STRUCTURE BY NMR OF 132-224 AND 376-458.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF012281 mRNA. Translation: AAC12264.1.
AK298269 mRNA. Translation: BAG60531.1.
AL390725 Genomic DNA. Translation: CAI13715.1.
AL390725 Genomic DNA. Translation: CAI13716.1.
BC006496 mRNA. Translation: AAH06496.1.
BC006518 mRNA. Translation: AAH06518.1.

IPI

IPI00298067.
IPI00908590.

RefSeq

NP_001188254.1. NM_001201325.1.
NP_001188255.1. NM_001201326.1.
NP_002605.2. NM_002614.4.

UniGene

Hs.444751.
Hs.732345.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2EEI	NMR	-	A	132-224	[»]
2EEJ	NMR	-	A	376-458	[»]
2VSP	X-ray	2.60	A/B/C/D	375-459	[»]
3TMH	X-ray	3.80	A/E/I	375-459	[»]

ProteinModelPortal

Q5T2W1.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q5T2W1. 9 interactions.

MINT

MINT-4999193.

STRING

9606.ENSP00000342143.

PTM databases

PhosphoSite

Q5T2W1.

Polymorphism databases

DMDM

73621372.

Proteomic databases

PaxDb

Q5T2W1.

PRIDE

Q5T2W1.

Protocols and materials databases

DNASU

5174.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000344770; ENSP00000342143; ENSG00000174827.
ENST00000417171; ENSP00000394485; ENSG00000174827.
ENST00000443667; ENSP00000409291; ENSG00000174827.
ENST00000451928; ENSP00000403422; ENSG00000174827.
ENST00000581121; ENSP00000464487; ENSG00000265111.
ENST00000582332; ENSP00000462232; ENSG00000265111.
ENST00000582503; ENSP00000462094; ENSG00000265111.
ENST00000583035; ENSP00000462520; ENSG00000265111.

GeneID

5174.

KEGG

hsa:5174.

UCSC

uc001eon.2. human.

Organism-specific databases

CTD

5174.

GeneCards

GC01P145726.

H-InvDB

HIX0056850.
HIX0178034.

HGNC

HGNC:8821. PDZK1.

HPA

CAB008971.
HPA005755.
HPA006155.

MIM

603831. gene.

neXtProt

NX_Q5T2W1.

PharmGKB

PA33165.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG315208.

HOGENOM

HOG000113782.

HOVERGEN

HBG082115.

InParanoid

Q5T2W1.

OMA

KGQIIKD.

PhylomeDB

Q5T2W1.

Gene expression databases

ArrayExpress

Q5T2W1.

Bgee

Q5T2W1.

CleanEx

HS_PDZK1.

Genevestigator

Q5T2W1.

GermOnline

ENSG00000174827. Homo sapiens.

Family and domain databases

InterPro

IPR001478. PDZ.
[Graphical view]

Pfam

PF00595. PDZ. 4 hits.
[Graphical view]

SMART

SM00228. PDZ. 4 hits.
[Graphical view]

SUPFAM

SSF50156. PDZ. 4 hits.

PROSITE

PS50106. PDZ. 4 hits.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

PDZK1. human.

EvolutionaryTrace

Q5T2W1.

GenomeRNAi

5174.

NextBio

20022.

SOURCE

Search...

Entry information

Entry name

NHRF3_HUMAN

Accession

Primary (citable) accession number: Q5T2W1
Secondary accession number(s): B4DPB9 , E7EU02, O60450, Q5T5P6, Q9BQ41

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 16, 2005
Last sequence update:	August 16, 2005
Last modified:	May 1, 2013
This is version 91 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.