Reviewed, UniProtKB/Swiss-Prot Q14145 (KEAP1_HUMAN)

Names and origin

Protein names

Recommended name:
    Kelch-like ECH-associated protein 1
Alternative name(s):
    Cytosolic inhibitor of Nrf2
      Short name=INrf2
    Kelch-like protein 19

Gene names

Name:	KEAP1
Synonyms:	INRF2, KIAA0132, KLHL19

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	624 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Retains NFE2L2/NRF2 in the cytosol. Functions as substrate adapter protein for the E3 ubiquitin ligase complex formed by CUL3 and RBX1. Targets NFE2L2/NRF2 for ubiquitination and degradation by the proteasome, thus resulting in the suppression of its transcriptional activity and the repression of antioxidant response element-mediated detoxifying enzyme gene expression. May also retain BPTF in the cytosol. Targets PGAM5 for ubiquitination and degradation by the proteasome. Ref.5 Ref.6 Ref.7 Ref.9
Enzyme regulation	Ubiquitination and subsequent degradation of PGAM5 is inhibited by oxidative stress and sulforaphane. Ref.9
Subunit structure	Homodimer. Form a ternary complex with NFE2L2 and PGAM5. Interacts with the N-terminal regulatory domain of NFE2L2/NRF2. Interacts with BPTF and PTMA. Interacts with CUL3. Part of a complex that contains KEAP1, CUL3 and RBX1. Ref.6 Ref.7 Ref.9 Ref.8 Ref.10 Ref.15
Subcellular location	Cytoplasm. Nucleus. Note: Shuttles between cytoplasm and nucleus. Ref.5 Ref.6 Ref.8
Tissue specificity	Broadly expressed, with highest levels in skeletal muscle. Ref.6
Domain	The Kelch repeats mediate interaction with NF2L2/NRF2, BPTF and PGAM5. Ref.9
Post-translational modification	Ubiquitinated and subject to proteasomal degradation. Ref.7
Involvement in disease	Defects in KEAP1 may be involved in non small cell lung carcinomas (NSCLC) and lung adenocarcinoma. Defects in KEAP1 may be a cause of breast cancer.
Sequence similarities	Contains 1 BACK (BTB/Kelch associated) domain. Contains 1 BTB (POZ) domain. Contains 6 Kelch repeats.

Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Polymorphism
Domain	Kelch repeat Repeat
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome
Gene Ontology (GO)
Biological process	regulation of transcription Inferred from electronic annotation. Source: UniProtKB-KW transcription Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	centrosome Inferred from direct assay. Source: HPA nucleus Inferred from direct assay. Source: HPA
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 624

624

Kelch-like ECH-associated protein 1

PRO_0000119093

Regions

Domain

77 – 149

73

BTB

Domain

184 – 286

103

BACK

Repeat

327 – 372

46

Kelch 1

Repeat

373 – 423

51

Kelch 2

Repeat

424 – 470

47

Kelch 3

Repeat

471 – 517

47

Kelch 4

Repeat

518 – 564

47

Kelch 5

Repeat

565 – 611

47

Kelch 6

Motif

301 – 310

10

Nuclear export signal

Amino acid modifications

Modified residue

293

1

Phosphoserine Ref.11

Modified residue

295

1

Phosphoserine Ref.11

Natural variations

Natural variant

23

1

C → Y in a breast cancer sample; somatic mutation. Ref.18

VAR_036084

Natural variant

167

1

V → F in a lung adenocarcinoma patient. Ref.17

VAR_032102

Natural variant

236

1

D → H in a NSCLC cell line. Ref.17

VAR_032103

Natural variant

284

1

Q → L in a lung adenocarcinoma patient. Ref.17

VAR_032104

Natural variant

333

1

G → C in a NSCLC cell line; strongly reduces interaction with NFE2L2 and reduces repression of NFE2L2-dependent gene expression. Ref.17

VAR_032105

Natural variant

349

1

D → N: dbSNP rs1048289. Ref.2

VAR_032106

Natural variant

350

1

G → S in a NSCLC cell line. Ref.17

VAR_032107

Natural variant

364

1

G → C in a lung adenocarcinoma cell line; also in NSCLC cell lines; may be a polymorphism; strongly reduces interaction with NFE2L2 and reduces repression of NFE2L2-dependent gene expression. Ref.16

VAR_032108

Natural variant

430

1

G → C in a lung adenocarcinoma patient; somatic mutation; strongly reduces interaction with NFE2L2 and reduces repression of NFE2L2-dependent gene expression. Ref.16

VAR_032109

Natural variant

522

1

A → V in a breast cancer sample; somatic mutation. Ref.18

VAR_036085

Experimental info

Mutagenesis

125 – 127

3

IEG → AAA: Increases ubiquitination and proteolytic degradation. Ref.7

Mutagenesis

151

1

C → S: Constitutive repression of NFE2L2-dependent gene expression. Promotes increased degradation of NFE2L2. Resistance of ubiquitination of PGAM5 to inhibition by oxidative stress and sulforaphane. Ref.5 Ref.9

Mutagenesis

162 – 164

3

YQI → AAA: Increases ubiquitination and proteolytic degradation. Ref.7

Mutagenesis

273

1

C → S: Abolishes repression of NFE2L2-dependent gene expression. Slows down degradation of NFE2L2. Ref.5

Mutagenesis

288

1

C → S: Abolishes repression of NFE2L2-dependent gene expression. Slows down degradation of NFE2L2. Ref.5

Mutagenesis

308

1

L → A: Loss of export from nucleus; when associated with A-310. Ref.8

Mutagenesis

310

1

L → A: Loss of export from nucleus; when associated with A-308. Ref.8

Mutagenesis

334

1

Y → A: Loss of interaction with NFE2L2. Strongly reduces repression of NFE2L2-dependent gene expression. Loss of interaction with PGAM5. Ref.9 Ref.15

Mutagenesis

380

1

R → A: Loss of interaction with NFE2L2. Abolishes repression of NFE2L2-dependent gene expression. Ref.15

Mutagenesis

382

1

N → A: Loss of interaction with NFE2L2. Strongly reduces repression of NFE2L2-dependent gene expression. Ref.15

Mutagenesis

415

1

R → A: Loss of interaction with NFE2L2. Abolishes repression of NFE2L2-dependent gene expression. Loss of interaction with PGAM5. Ref.9 Ref.15

Mutagenesis

436

1

H → A: Loss of interaction with NFE2L2. Abolishes repression of NFE2L2-dependent gene expression. Ref.15

Mutagenesis

478

1

F → A: Abolishes repression of NFE2L2-dependent gene expression. Ref.15

Mutagenesis

483

1

R → A: Loss of interaction with NFE2L2. Abolishes repression of NFE2L2-dependent gene expression. Loss of interaction with PGAM5. Ref.9 Ref.15

Mutagenesis

525

1

Y → A: Loss of interaction with NFE2L2. Strongly reduces repression of NFE2L2-dependent gene expression. Ref.15

Mutagenesis

572

1

Y → A: Loss of interaction with NFE2L2. Strongly reduces repression of NFE2L2-dependent gene expression. Loss of interaction with PGAM5. Ref.9 Ref.15

Secondary structure

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624

Helix Strand Turn

Details...

Beta strand

327 – 331

5

Beta strand

334 – 338

5

Beta strand

342 – 345

4

Turn

347 – 349

3

Beta strand

352 – 354

3

Beta strand

366 – 370

5

Beta strand

373 – 377

5

Beta strand

380 – 383

4

Beta strand

386 – 389

4

Beta strand

393 – 396

4

Turn

398 – 400

3

Beta strand

403 – 405

3

Beta strand

417 – 421

5

Beta strand

424 – 428

5

Beta strand

440 – 444

5

Turn

445 – 448

4

Beta strand

449 – 452

4

Beta strand

464 – 468

5

Beta strand

471 – 475

5

Beta strand

487 – 491

5

Turn

492 – 495

4

Beta strand

496 – 499

4

Beta strand

511 – 515

5

Beta strand

518 – 522

5

Beta strand

527 – 530

4

Beta strand

534 – 538

5

Turn

539 – 542

4

Beta strand

543 – 547

5

Beta strand

558 – 562

5

Beta strand

565 – 569

5

Beta strand

580 – 585

6

Turn

586 – 589

4

Beta strand

590 – 596

7

Sequences

	Sequence		Length	Mass (Da)
	Q14145-1 [UniParc]. Last modified May 1, 2007. Version 2. Checksum: CE180F3897BB8C97	FASTA	624	69,666
	10 20 30 40 50 60 MQPDPRPSGA GACCRFLPLQ SQCPEGAGDA VMYASTECKA EVTPSQHGNR TFSYTLEDHT 70 80 90 100 110 120 KQAFGIMNEL RLSQQLCDVT LQVKYQDAPA AQFMAHKVVL ASSSPVFKAM FTNGLREQGM 130 140 150 160 170 180 EVVSIEGIHP KVMERLIEFA YTASISMGEK CVLHVMNGAV MYQIDSVVRA CSDFLVQQLD 190 200 210 220 230 240 PSNAIGIANF AEQIGCVELH QRAREYIYMH FGEVAKQEEF FNLSHCQLVT LISRDDLNVR 250 260 270 280 290 300 CESEVFHACI NWVKYDCEQR RFYVQALLRA VRCHSLTPNF LQMQLQKCEI LQSDSRCKDY 310 320 330 340 350 360 LVKIFEELTL HKPTQVMPCR APKVGRLIYT AGGYFRQSLS YLEAYNPSDG TWLRLADLQV 370 380 390 400 410 420 PRSGLAGCVV GGLLYAVGGR NNSPDGNTDS SALDCYNPMT NQWSPCAPMS VPRNRIGVGV 430 440 450 460 470 480 IDGHIYAVGG SHGCIHHNSV ERYEPERDEW HLVAPMLTRR IGVGVAVLNR LLYAVGGFDG 490 500 510 520 530 540 TNRLNSAECY YPERNEWRMI TAMNTIRSGA GVCVLHNCIY AAGGYDGQDQ LNSVERYDVE 550 560 570 580 590 600 TETWTFVAPM KHRRSALGIT VHQGRIYVLG GYDGHTFLDS VECYDPDTDT WSEVTRMTSG 610 620 RSGVGVAVTM EPCRKQIDQQ NCTC

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Human INrf2 gene structure and nucleotide sequence." Dhakshinamoorthy S., Jaiswal A.K. Submitted (MAR-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
[2]	"Prediction of the coding sequences of unidentified human genes. IV. The coding sequences of 40 new genes (KIAA0121-KIAA0160) deduced by analysis of cDNA clones from human cell line KG-1." Nagase T., Seki N., Tanaka A., Ishikawa K., Nomura N. DNA Res. 2:167-174(1995) [PubMed: 8590280] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT ASN-349. Tissue: Bone marrow.
[3]	Ohara O., Nagase T., Kikuno R., Nomura N. Submitted (DEC-2008) to the EMBL/GenBank/DDBJ databases Cited for: SEQUENCE REVISION.
[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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain, Skin and Uterus.
[5]	"Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress." Zhang D.D., Hannink M. Mol. Cell. Biol. 23:8137-8151(2003) [PubMed: 14585973] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF CYS-151; CYS-273 AND CYS-288, SUBCELLULAR LOCATION.
[6]	"Fetal Alz-50 clone 1 interacts with the human orthologue of the Kelch-like Ech-associated protein." Strachan G.D., Morgan K.L., Otis L.L., Caltagarone J., Gittis A., Bowser R., Jordan-Sciutto K.L. Biochemistry 43:12113-12122(2004) [PubMed: 15379550] [Abstract] Cited for: INTERACTION WITH NF2L2/NRF2 AND BPTF, FUNCTION, TISSUE SPECIFICITY, SUBCELLULAR LOCATION.
[7]	"Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex." Zhang D.D., Lo S.-C., Cross J.V., Templeton D.J., Hannink M. Mol. Cell. Biol. 24:10941-10953(2004) [PubMed: 15572695] [Abstract] Cited for: FUNCTION, INTERACTION WITH CUL3 AND RBX1, MUTAGENESIS OF 125-ILE--GLY-127 AND 162-TYR--ILE-164, UBIQUITINATION.
[8]	"Nuclear oncoprotein prothymosin alpha is a partner of Keap1: implications for expression of oxidative stress-protecting genes." Karapetian R.N., Evstafieva A.G., Abaeva I.S., Chichkova N.V., Filonov G.S., Rubtsov Y.P., Sukhacheva E.A., Melnikov S.V., Schneider U., Wanker E.E., Vartapetian A.B. Mol. Cell. Biol. 25:1089-1099(2005) [PubMed: 15657435] [Abstract] Cited for: INTERACTION WITH PTMA, SUBCELLULAR LOCATION, MUTAGENESIS OF LEU-308 AND LEU-310.
[9]	"PGAM5, a Bcl-XL-interacting protein, is a novel substrate for the redox-regulated Keap1-dependent ubiquitin ligase complex." Lo S.-C., Hannink M. J. Biol. Chem. 281:37893-37903(2006) [PubMed: 17046835] [Abstract] Cited for: INTERACTION WITH PGAM5, FUNCTION, ENZYME REGULATION, DOMAIN, MUTAGENESIS OF CYS-151; TYR-334; ARG-415; ARG-483 AND TYR-572.
[10]	"PGAM5 tethers a ternary complex containing Keap1 and Nrf2 to mitochondria." Lo S.-C., Hannink M. Exp. Cell Res. 314:1789-1803(2008) [PubMed: 18387606] [Abstract] Cited for: INTERACTION WITH NFE2L2 AND PGAM5.
[11]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed: 18691976] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-293 AND SER-295, MASS SPECTROMETRY.
[12]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[13]	"Crystallization and initial crystallographic analysis of the Kelch domain from human Keap1." Li X., Zhang D., Hannink M., Beamer L.J. Acta Crystallogr. D 60:2346-2348(2004) [PubMed: 15583386] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 321-609.
[14]	"Conserved solvent and side-chain interactions in the 1.35 Angstrom structure of the Kelch domain of Keap1." Beamer L.J., Li X., Bottoms C.A., Hannink M. Acta Crystallogr. D 61:1335-1342(2005) [PubMed: 16204884] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.35 ANGSTROMS) OF 321-609.
[15]	"Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling." Lo S.-C., Li X., Henzl M.T., Beamer L.J., Hannink M. EMBO J. 25:3605-3617(2006) [PubMed: 16888629] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF 321-609 IN COMPLEX WITH NFE2L2, SUBUNIT, MUTAGENESIS OF TYR-334; ARG-380; ASN-382; ARG-415; HIS-436; PHE-478; ARG-483; TYR-525 AND TYR-572.
[16]	"Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer." Padmanabhan B., Tong K.I., Ohta T., Nakamura Y., Scharlock M., Ohtsuji M., Kang M., Kobayashi A., Yokoyama S., Yamamoto M. Mol. Cell 21:689-700(2006) [PubMed: 16507366] [Abstract] Cited for: VARIANTS CYS-364 AND CYS-430, CHARACTERIZATION OF VARIANTS CYS-364 AND CYS-430.
[17]	"Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer." Singh A., Misra V., Thimmulappa R.K., Lee H., Ames S., Hoque M.O., Herman J.G., Baylin S.B., Sidransky D., Gabrielson E., Brock M.V., Biswal S. PLoS Med. 3:1865-1876(2006) [PubMed: 17020408] [Abstract] Cited for: VARIANTS PHE-167; HIS-236; LEU-284; CYS-333 AND SER-350, CHARACTERIZATION OF VARIANTS HIS-236 AND CYS-333.
[18]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed: 16959974] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] TYR-23 AND VAL-522.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF361892 , AF361888, AF361889, AF361890, AF361891 Genomic DNA. Translation: AAK43722.1.
AF361886 mRNA. Translation: AAK51082.1.
D50922 mRNA. Translation: BAA09481.2. Different initiation.
BC002417 mRNA. Translation: AAH02417.1.
BC002930 mRNA. Translation: AAH02930.1.
BC015945 mRNA. Translation: AAH15945.1.

IPI

IPI00106502.

RefSeq

NP_036421.2.
NP_987096.1.

UniGene

Hs.465870

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1U6D	X-ray	1.85	X	321-609	[»]
1ZGK	X-ray	1.35	A	321-609	[»]
2FLU	X-ray	1.50	X	321-609	[»]

SMR

Q14145. Positions 52-175, 177-273.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q14145. 2 interactions.

STRING

Q14145.

PTM databases

PhosphoSite

Q14145.

Proteomic databases

PRIDE

Q14145.

Genome annotation databases

Ensembl

ENST00000171111; ENSP00000171111; ENSG00000079999; Homo sapiens. [Genome view]
ENST00000393623; ENSP00000377245; ENSG00000079999; Homo sapiens. [Genome view]

GeneID

9817.

KEGG

hsa:9817.

UCSC

uc002moq.1. human.

Organism-specific databases

CTD

9817.

GeneCards

GC19M010457.

HGNC

HGNC:23177. KEAP1.

HPA

CAB025337.
HPA005558.

MIM

606016. gene.

PharmGKB

PA134887774.

HUGE

Search...

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG13838.

HOGENOM

HBG713858.

HOVERGEN

Q14145.

InParanoid

Q14145.

OMA

TLQVKYE.

OrthoDB

EOG9BS05G.

PhylomeDB

Q14145.

Gene expression databases

ArrayExpress

Q14145.

Bgee

Q14145.

CleanEx

HS_KEAP1.

Genevestigator

Q14145.

GermOnline

ENSG00000079999. Homo sapiens.

Family and domain databases

InterPro

IPR011705. BACK.
IPR000210. BTB/POZ-like.
IPR011333. BTB/POZ_fold.
IPR013069. BTB_POZ.
IPR011043. Gal_Oxase/kelch_b-propeller.
IPR017096. Kelch-like_gigaxonin.
IPR015915. Kelch-typ_b-propeller.
IPR006652. Kelch_1.
IPR013089. Kelch_related.
[Graphical view]

Gene3D

G3DSA:3.30.710.10. BTB/POZ_fold. 1 hit.
G3DSA:2.120.10.80. Kelch-typ_b-propeller. 1 hit.

PANTHER

PTHR23230. Kelch_related. 1 hit.

Pfam

PF07707. BACK. 1 hit.
PF00651. BTB. 1 hit.
PF01344. Kelch_1. 6 hits.
[Graphical view]

PIRSF

PIRSF037037. Kelch-like_protein_gigaxonin. 1 hit.

SMART

SM00875. BACK. 1 hit.
SM00225. BTB. 1 hit.
SM00612. Kelch. 6 hits.
[Graphical view]

PROSITE

PS50097. BTB. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

36968.

SOURCE

Search...

Entry information

Entry name

KEAP1_HUMAN

Accession

Primary (citable) accession number: Q14145
Secondary accession number(s): Q6LEP0, Q9BPY9

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 27, 2001
Last sequence update:	May 1, 2007
Last modified:	January 19, 2010
This is version 101 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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.