Q86UT5 (NHRF4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Na(+)/H(+) exchange regulatory cofactor NHE-RF4
Short name=NHERF-4

Alternative name(s):
Intestinal and kidney-enriched PDZ protein
Natrium-phosphate cotransporter IIa C-terminal-associated protein 2
Short name=Na/Pi cotransporter C-terminal-associated protein 2
Short name=NaPi-Cap2
PDZ domain-containing protein 2
PDZ domain-containing protein 3
Sodium-hydrogen exchanger regulatory factor 4

Gene names

Name:	PDZD3
Synonyms:	IKEPP, NHERF4, PDZK2
ORF Names:	DLNB27

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	571 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Acts as a regulatory protein that associates with GUCY2C and negatively modulates its heat-stable enterotoxin-mediated activation. Stimulates SLC9A3 activity in the presence of elevated calcium ions. Ref.1 Ref.6
Subunit structure	Interacts with the C-terminal region of GUCY2C. Interacts with the C-terminal region of SLC34A1. Interacts with the C-terminal region SLC9A3 and the interactions decrease in response to elevated calcium ion levels. Ref.1 Ref.6 UniProtKB Q99MJ6
Subcellular location	Cell membrane; Peripheral membrane protein. Cytoplasm. Note: Preferentially accumulates at the apical surface and ileal brush border of intestinal epithelial cells. Ref.1 Ref.6
Tissue specificity	Expressed in kidney and the gastrointestinal tract. Not detected in brain, heart, skeletal muscle or cells of hematopoietic origin. Ref.1
Sequence similarities	Contains 4 PDZ (DHR) domains.

Ontologies

Keywords
Cellular component	Cell membrane Cytoplasm Membrane
Coding sequence diversity	Alternative splicing
Domain	Repeat
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	cGMP-mediated signaling Non-traceable author statement Ref.1. Source: UniProtKB ion transport Non-traceable author statement Ref.1. Source: UniProtKB negative regulation of cGMP biosynthetic process Traceable author statement Ref.1. Source: UniProtKB receptor guanylyl cyclase signaling pathway Inferred by curator Ref.1. Source: UniProtKB response to toxin Traceable author statement Ref.1. Source: UniProtKB water transport Non-traceable author statement Ref.1. Source: UniProtKB
Cellular_component	apical part of cell Inferred from direct assay Ref.1Ref.6. Source: UniProtKB brush border Inferred from direct assay Ref.6. Source: UniProtKB cytosol Traceable author statement Ref.1. Source: UniProtKB subapical complex Inferred from direct assay Ref.1Ref.6. Source: UniProtKB
Molecular_function	guanylate cyclase inhibitor activity Inferred from direct assay Ref.1. Source: UniProtKB ion channel inhibitor activity Traceable author statement Ref.1. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 5 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 Ref.2 (identifier: Q86UT5-1)

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 Ref.1 (identifier: Q86UT5-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-66: Missing.
     67-105: TRQKLPSTLS...PLFCCPPHPP → MEKAADLQDT...LSLAEDHDPY

Isoform 3 (identifier: Q86UT5-3)

The sequence of this isoform differs from the canonical sequence as follows:
     1-66: Missing.
     67-105: TRQKLPSTLS...PLFCCPPHPP → MEKAADLQDT...LSLAEDHDPY
     272-285: Missing.

Note: No experimental confirmation available.

Isoform 4 (identifier: Q86UT5-4)

The sequence of this isoform differs from the canonical sequence as follows:
     355-386: QFLWEVDPGLPAKKAGMQAGDRLVAVAGESVE → EWEPWGRWGKVGLGVGTQAYIHLSVHRRGVPV
     387-571: Missing.

Note: No experimental confirmation available.

Isoform 5 (identifier: Q86UT5-5)

The sequence of this isoform differs from the canonical sequence as follows:
     1-66: Missing.
     67-105: TRQKLPSTLS...PLFCCPPHPP → MEKAADLQDT...LSLAEDHDPY
     287-571: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 571

571

Na(+)/H(+) exchange regulatory cofactor NHE-RF4

PRO_0000058292

Regions

Domain

115 – 196

82

PDZ 1

Domain

223 – 301

79

PDZ 2

Domain

329 – 412

84

PDZ 3

Domain

467 – 548

82

PDZ 4

Natural variations

Alternative sequence

1 – 66

66

Missing in isoform 2, isoform 3 and isoform 5. Ref.1

VSP_051786

Alternative sequence

67 – 105

39

TRQKL…PPHPP → MEKAADLQDTASLTLKFKFN PKLGIDNPVLSLAEDHDPY in isoform 2, isoform 3 and isoform 5. Ref.1

VSP_051787

Alternative sequence

272 – 285

14

Missing in isoform 3. Ref.1

VSP_051788

Alternative sequence

287 – 571

285

Missing in isoform 5. Ref.1

VSP_051789

Alternative sequence

355 – 386

32

QFLWE…GESVE → EWEPWGRWGKVGLGVGTQAY IHLSVHRRGVPV in isoform 4. Ref.1

VSP_051790

Alternative sequence

387 – 571

185

Missing in isoform 4. Ref.1

VSP_051791

Experimental info

Sequence conflict

112

1

R → P in BAB15474. Ref.3

Sequence conflict

125

1

S → G in BAC03780. Ref.3

Sequence conflict

286

1

L → V in BAB15474. Ref.3

Sequence conflict

438

1

R → Q in BAC76050. Ref.2

Sequence conflict

438

1

R → Q in AAH29042. Ref.5

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

571

Helix Strand Turn

Details...

Beta strand

328 – 333

6

Beta strand

341 – 347

7

Beta strand

353 – 360

8

Helix

365 – 368

4

Beta strand

375 – 380

6

Helix

390 – 398

9

Turn

399 – 402

4

Beta strand

403 – 409

7

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified October 5, 2010. Version 2. Checksum: B56CDC91348EE592	FASTA	571	61,032
	10 20 30 40 50 60 MVTPSPPGNH SLSLEAPRLH TASDLLGNHS LGLPLITALV GSRDRRGRVF SPVPVPLPTN 70 80 90 100 110 120 PTTQHPTRQK LPSTLSGHRV CQAHGEPVLG LCPLLPLFCC PPHPPDPWSL ERPRFCLLSK 130 140 150 160 170 180 EEGKSFGFHL QQELGRAGHV VCRVDPGTSA QRQGLQEGDR ILAVNNDVVE HEDYAVVVRR 190 200 210 220 230 240 IRASSPRVLL TVLARHAHDV ARAQLGEDAH LCPTLGPGVR PRLCHIVKDE GGFGFSVTHG 250 260 270 280 290 300 NQGPFWLVLS TGGAAERAGV PPGARLLEVN GVSVEKFTHN QLTRKLWQSG QQVTLLVAGP 310 320 330 340 350 360 EVEEQCRQLG LPLAAPLAEG WALPTKPRCL HLEKGPQGFG FLLREEKGLD GRPGQFLWEV 370 380 390 400 410 420 DPGLPAKKAG MQAGDRLVAV AGESVEGLGH EETVSRIQGQ GSCVSLTVVD PEADRFFSMV 430 440 450 460 470 480 RLSPLLFLEN TEAPASPRGS SSASLVETED PSLEDTSVPS VPLGSRQCFL YPGPGGSYGF 490 500 510 520 530 540 RLSCVASGPR LFISQVTPGG SAARAGLQVG DVILEVNGYP VGGQNDLERL QQLPEAEPPL 550 560 570 CLKLAARSLR GLEAWIPPGA AEDWALASDL L
	Isoform 2 [UniParc]. Checksum: ACDAE2A896787C5D	FASTA	505	54,217
	10 20 30 40 50 60 MEKAADLQDT ASLTLKFKFN PKLGIDNPVL SLAEDHDPYD PWSLERPRFC LLSKEEGKSF 70 80 90 100 110 120 GFHLQQELGR AGHVVCRVDP GTSAQRQGLQ EGDRILAVNN DVVEHEDYAV VVRRIRASSP 130 140 150 160 170 180 RVLLTVLARH AHDVARAQLG EDAHLCPTLG PGVRPRLCHI VKDEGGFGFS VTHGNQGPFW 190 200 210 220 230 240 LVLSTGGAAE RAGVPPGARL LEVNGVSVEK FTHNQLTRKL WQSGQQVTLL VAGPEVEEQC 250 260 270 280 290 300 RQLGLPLAAP LAEGWALPTK PRCLHLEKGP QGFGFLLREE KGLDGRPGQF LWEVDPGLPA 310 320 330 340 350 360 KKAGMQAGDR LVAVAGESVE GLGHEETVSR IQGQGSCVSL TVVDPEADRF FSMVRLSPLL 370 380 390 400 410 420 FLENTEAPAS PRGSSSASLV ETEDPSLEDT SVPSVPLGSR QCFLYPGPGG SYGFRLSCVA 430 440 450 460 470 480 SGPRLFISQV TPGGSAARAG LQVGDVILEV NGYPVGGQND LERLQQLPEA EPPLCLKLAA 490 500 RSLRGLEAWI PPGAAEDWAL ASDLL
	Isoform 3 [UniParc]. Checksum: 46F3C5D292274D56	FASTA	491	52,548
	10 20 30 40 50 60 MEKAADLQDT ASLTLKFKFN PKLGIDNPVL SLAEDHDPYD PWSLERPRFC LLSKEEGKSF 70 80 90 100 110 120 GFHLQQELGR AGHVVCRVDP GTSAQRQGLQ EGDRILAVNN DVVEHEDYAV VVRRIRASSP 130 140 150 160 170 180 RVLLTVLARH AHDVARAQLG EDAHLCPTLG PGVRPRLCHI VKDEGGFGFS VTHGNQGPFW 190 200 210 220 230 240 LVLSTGGAAE RAGVPPGARL LEVNGLWQSG QQVTLLVAGP EVEEQCRQLG LPLAAPLAEG 250 260 270 280 290 300 WALPTKPRCL HLEKGPQGFG FLLREEKGLD GRPGQFLWEV DPGLPAKKAG MQAGDRLVAV 310 320 330 340 350 360 AGESVEGLGH EETVSRIQGQ GSCVSLTVVD PEADRFFSMV RLSPLLFLEN TEAPASPRGS 370 380 390 400 410 420 SSASLVETED PSLEDTSVPS VPLGSRQCFL YPGPGGSYGF RLSCVASGPR LFISQVTPGG 430 440 450 460 470 480 SAARAGLQVG DVILEVNGYP VGGQNDLERL QQLPEAEPPL CLKLAARSLR GLEAWIPPGA 490 AEDWALASDL L
	Isoform 4 [UniParc]. Checksum: BE18E918ECD4009D	FASTA	386	41,888
	10 20 30 40 50 60 MVTPSPPGNH SLSLEAPRLH TASDLLGNHS LGLPLITALV GSRDRRGRVF SPVPVPLPTN 70 80 90 100 110 120 PTTQHPTRQK LPSTLSGHRV CQAHGEPVLG LCPLLPLFCC PPHPPDPWSL ERPRFCLLSK 130 140 150 160 170 180 EEGKSFGFHL QQELGRAGHV VCRVDPGTSA QRQGLQEGDR ILAVNNDVVE HEDYAVVVRR 190 200 210 220 230 240 IRASSPRVLL TVLARHAHDV ARAQLGEDAH LCPTLGPGVR PRLCHIVKDE GGFGFSVTHG 250 260 270 280 290 300 NQGPFWLVLS TGGAAERAGV PPGARLLEVN GVSVEKFTHN QLTRKLWQSG QQVTLLVAGP 310 320 330 340 350 360 EVEEQCRQLG LPLAAPLAEG WALPTKPRCL HLEKGPQGFG FLLREEKGLD GRPGEWEPWG 370 380 RWGKVGLGVG TQAYIHLSVH RRGVPV
	Isoform 5 [UniParc]. Checksum: 87EC9259F8262E0A	FASTA	220	24,105
	10 20 30 40 50 60 MEKAADLQDT ASLTLKFKFN PKLGIDNPVL SLAEDHDPYD PWSLERPRFC LLSKEEGKSF 70 80 90 100 110 120 GFHLQQELGR AGHVVCRVDP GTSAQRQGLQ EGDRILAVNN DVVEHEDYAV VVRRIRASSP 130 140 150 160 170 180 RVLLTVLARH AHDVARAQLG EDAHLCPTLG PGVRPRLCHI VKDEGGFGFS VTHGNQGPFW 190 200 210 220 LVLSTGGAAE RAGVPPGARL LEVNGVSVEK FTHNQLTRKL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A novel PDZ protein regulates the activity of guanylyl cyclase C, the heat-stable enterotoxin receptor." Scott R.O., Thelin W.R., Milgram S.L. J. Biol. Chem. 277:22934-22941(2002) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, INTERACTION WITH GUCY2C, SUBCELLULAR LOCATION, TISSUE SPECIFICITY. Tissue: Intestinal epithelium.
[2]	"Identification of a 500-kb region of common allelic loss in chromosome 11q23 in non-MYCN amplified type of neuroblastoma." Kubo T., Arai Y., Ohira M., Gamou T., Maeno G., Sakiyama T., Toyoda A., Hattori M., Sakaki Y., Nakagawara A., Ohki M. Submitted (OCT-2002) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[3]	"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] (ISOFORMS 4 AND 5). Tissue: Ileal mucosa and Kidney.
[4]	"Human chromosome 11 DNA sequence and analysis including novel gene identification." Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G. , Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S., Sakaki Y. Nature 440:497-500(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"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 3).
[6]	"Elevated intracellular calcium stimulates NHE3 activity by an IKEPP (NHERF4) dependent mechanism." Zachos N.C., Hodson C., Kovbasnjuk O., Li X., Thelin W.R., Cha B., Milgram S., Donowitz M. Cell. Physiol. Biochem. 22:693-704(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH SLC9A3.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AY047359 mRNA. Translation: AAL10686.1.
AB094096 mRNA. Translation: BAC76050.1.
AK026409 mRNA. Translation: BAB15474.1.
AK091966 mRNA. Translation: BAC03780.1.
AP002956 Genomic DNA. No translation available.
BC029042 mRNA. Translation: AAH29042.1.

IPI

IPI00171635.
IPI00384252.
IPI00478167.
IPI00641673.
IPI00646546.

RefSeq

NP_001161940.1. NM_001168468.1.
NP_079067.3. NM_024791.3.

UniGene

Hs.374726.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2V90	X-ray	2.00	A/B/C/D/E/F	326-415	[»]

ProteinModelPortal

Q86UT5.

SMR

Q86UT5. Positions 113-193, 221-415, 464-545.

ModBase

Search...

Protein-protein interaction databases

MINT

MINT-1773252.

STRING

9606.ENSP00000327107.

PTM databases

PhosphoSite

Q86UT5.

Polymorphism databases

DMDM

308153467.

Proteomic databases

PaxDb

Q86UT5.

PRIDE

Q86UT5.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000322712; ENSP00000327107; ENSG00000172367.
ENST00000355547; ENSP00000347742; ENSG00000172367.
ENST00000392817; ENSP00000376564; ENSG00000172367.
ENST00000531114; ENSP00000431164; ENSG00000172367.

GeneID

79849.

KEGG

hsa:79849.

UCSC

uc001pvz.3. human.
uc001pwb.3. human.

Organism-specific databases

CTD

79849.

GeneCards

GC11P119056.

H-InvDB

HIX0201614.

HGNC

HGNC:19891. PDZD3.

HPA

HPA040482.

MIM

607146. gene.

neXtProt

NX_Q86UT5.

PharmGKB

PA134911718.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG262468.

HOGENOM

HOG000048712.

HOVERGEN

HBG080760.

InParanoid

Q86UT5.

OMA

FSMVRLS.

OrthoDB

EOG412M5D.

Gene expression databases

ArrayExpress

Q86UT5.

Bgee

Q86UT5.

CleanEx

HS_PDZD3.

Genevestigator

Q86UT5.

GermOnline

ENSG00000172367. 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

EvolutionaryTrace

Q86UT5.

GenomeRNAi

79849.

NextBio

69555.

SOURCE

Search...

Entry information

Entry name

NHRF4_HUMAN

Accession

Primary (citable) accession number: Q86UT5
Secondary accession number(s): Q8N6R4 , Q8NAW7, Q8NEX7, Q9H5Z3

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 16, 2005
Last sequence update:	October 5, 2010
Last modified:	May 1, 2013
This is version 90 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.