Q13351 (KLF1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Krueppel-like factor 1

Alternative name(s):
Erythroid krueppel-like transcription factor
Short name=EKLF

Gene names

Name:	KLF1
Synonyms:	EKLF

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

General annotation (Comments)

Function	Transcription regulator of erythrocyte development that probably serves as a general switch factor during erythropoiesis. Is a dual regulator of fetal-to-adult globin switching. Binds to the CACCC box in the beta-globin gene promoter and acts as a preferential activator of this gene. Furthermore, it binds to the BCL11A promoter and activates expression of BCL11A, which in turn represses the HBG1 and HBG2 genes. This dual activity ensures that, in most adults, fetal hemoglobin levels are low. Able to activate CD44 and AQP1 promoters. When sumoylated, acts as a transcriptional repressor by promoting interaction with CDH2/MI2beta and also represses megakaryocytic differentiation By similarity. Ref.6 Ref.7
Subunit structure	Interacts with CBP and EP300; the interactions enhance the transactivation activity. Interacts with PCAF; the interaction does not acetylate EKLF and inhibits its transactivation activity By similarity. Ref.5
Subcellular location	Nucleus. Note: Colocalizes with SUMO1 in nuclear speckles By similarity. Ref.6
Tissue specificity	Expression restricted to adult bone marrow and fetal liver. Not expressed in myeloid nor lymphoid cell lines. Ref.1 Ref.2
Post-translational modification	Acetylated; can be acetylated on both Lys-274 and Lys-288. Acetylation on Lys-274 (by CBP) appears to be the major site affecting EKLF transactivation activity By similarity. Sumoylated; sumoylation, promoted by PIAS1, leads to repression of megakaryocyte differentiation. Also promotes the interaction with the CDH4 subunit of the NuRD repression complex By similarity. Phosphorylated primarily on serine residues in the transactivation domain. Phosphorylation on Thr-23 is critical for the transactivation activity By similarity.
Polymorphism	Genetic variations in KLF1 underlie the fetal hemoglobin quantitative trait locus 6 (HBFQTL6) [MIM:613566]. Classic hereditary persistence of fetal hemoglobin (HPFH) is characterized by a substantial elevation of fetal hemoglobin (HbF) in adult red blood cells. There are no other phenotypic or hematologic manifestations. In healthy adults, fetal hemoglobin (HbF) is present at residual levels (less than 0.06% of total hemoglobin) with over 20-fold variation. Ten to fifteen percent of adults fall within the upper tail of the distribution. Genetic variations in KLF1 underlie the blood group-Lutheran inhibitor (In(Lu)) phenotype [MIM:111150]; also known as dominant Lu (a-b-) phenotype. In(Lu) is characterized phenotypically by the apparent absence of the Lu antigen (BCAM) on red blood cells during serologic tests: Lu(a-b-).
Involvement in disease	Congenital dyserythropoietic anemia 4 (CDA4) [MIM:613673]: A blood disorder characterized by ineffective erythropoiesis and hemolysis resulting in anemia. Circulating erythroblasts and erythroblasts in the bone marrow show various morphologic abnormalities. Affected individuals with CDA4 also have increased levels of fetal hemoglobin. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.6
Sequence similarities	Belongs to the krueppel C2H2-type zinc-finger protein family. Contains 3 C2H2-type zinc fingers.

Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Nucleus
Coding sequence diversity	Polymorphism
Disease	Congenital dyserythropoietic anemia Disease mutation Hereditary hemolytic anemia
Domain	Repeat Zinc-finger
Ligand	DNA-binding Metal-binding Zinc
Molecular function	Activator
PTM	Acetylation Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	chromatin remodeling Inferred from electronic annotation. Source: Compara embryonic hemopoiesis Inferred from electronic annotation. Source: Compara erythrocyte differentiation Inferred from mutant phenotype Ref.6. Source: UniProtKB erythrocyte maturation Inferred from electronic annotation. Source: Compara in utero embryonic development Inferred from electronic annotation. Source: Compara liver development Inferred from electronic annotation. Source: Compara positive regulation of transcription, DNA-dependent Inferred from direct assay Ref.7Ref.6. Source: UniProtKB transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	nuclear chromatin Inferred from direct assay PubMed 21539536. Source: BHF-UCL
Molecular_function	core promoter proximal region sequence-specific DNA binding Inferred from direct assay PubMed 21539536. Source: BHF-UCL sequence-specific DNA binding transcription factor activity Traceable author statement Ref.1PubMed 9778250. Source: ProtInc zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 362

362

Krueppel-like factor 1

PRO_0000047160

Regions

Zinc finger

279 – 303

25

C2H2-type 1

Zinc finger

309 – 333

25

C2H2-type 2

Zinc finger

339 – 361

23

C2H2-type 3

Compositional bias

1 – 263

263

Pro-rich

Compositional bias

61 – 76

16

Asp/Glu-rich (acidic)

Amino acid modifications

Modified residue

23

1

Phosphothreonine; by CK2 Probable

Modified residue

274

1

N6-acetyllysine By similarity

Modified residue

288

1

N6-acetyllysine By similarity

Cross-link

54

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) By similarity

Natural variations

Natural variant

102

1

S → P. Ref.4 Ref.6
Corresponds to variant rs2072597 [ dbSNP | Ensembl ].

VAR_043981

Natural variant

182

1

F → L.
Corresponds to variant rs2072596 [ dbSNP | Ensembl ].

VAR_043982

Natural variant

299

1

H → Y in blood group-In(Lu). Ref.8

VAR_058108

Natural variant

325

1

E → K in CDA4; has a dominant-negative effect on the transcriptional activation of CD44 and AQP1 promoters. Ref.6

VAR_064901

Natural variant

328

1

R → H in blood group-In(Lu). Ref.8

VAR_058109

Natural variant

328

1

R → L in blood group-In(Lu). Ref.8

VAR_058110

Natural variant

331

1

R → G in blood group-In(Lu). Ref.8

VAR_058111

Experimental info

Sequence conflict

163

1

A → G in AAC51108. Ref.2

Sequence conflict

173

1

P → A in AAC51108. Ref.2

Sequence conflict

184

1

R → G in AAC51108. Ref.2

Sequence conflict

192

1

A → E in AAC51108. Ref.2

Secondary structure

1

.

.

.

.

.

362

Helix Strand Turn

Details...

Beta strand

64 – 67

4

Beta strand

70 – 75

6

Sequences

	Sequence		Length	Mass (Da)
	Q13351 [UniParc]. Last modified November 1, 1996. Version 1. Checksum: 6E9A48A2B6A37C76	FASTA	362	38,221
	10 20 30 40 50 60 MATAETALPS ISTLTALGPF PDTQDDFLKW WRSEEAQDMG PGPPDPTEPP LHVKSEDQPG 70 80 90 100 110 120 EEEDDERGAD ATWDLDLLLT NFSGPEPGGA PQTCALAPSE ASGAQYPPPP ETLGAYAGGP 130 140 150 160 170 180 GLVAGLLGSE DHSGWVRPAL RARAPDAFVG PALAPAPAPE PKALALQPVY PGPGAGSSGG 190 200 210 220 230 240 YFPRTGLSVP AASGAPYGLL SGYPAMYPAP QYQGHFQLFR GLQGPAPGPA TSPSFLSCLG 250 260 270 280 290 300 PGTVGTGLGG TAEDPGVIAE TAPSKRGRRS WARKRQAAHT CAHPGCGKSY TKSSHLKAHL 310 320 330 340 350 360 RTHTGEKPYA CTWEGCGWRF ARSDELTRHY RKHTGQRPFR CQLCPRAFSR SDHLALHMKR HL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Isolation, genomic structure, and expression of human erythroid Kruppel-like factor (EKLF)." Bieker J.J. DNA Cell Biol. 15:347-352(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], TISSUE SPECIFICITY.
[2]	"The human erythroid-specific transcription factor EKLF localizes to chromosome 19p13.12-p13.13." van Ree J.H., Roskrow M.A., Becher A.M., McNall R., Valentine V.A., Jane S.M., Cunningham J.M. Genomics 39:393-395(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY.
[3]	"The DNA sequence and biology of human chromosome 19." Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., Carrano A.V. , Caoile C., Chan Y.M., Christensen M., Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., Rubin E.M., Lucas S.M. Nature 428:529-535(2004) [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], VARIANT PRO-102. Tissue: Lung.
[5]	"Acetylation and modulation of erythroid Krueppel-like factor (EKLF) activity by interaction with histone acetyltransferases." Zhang W., Bieker J.J. Proc. Natl. Acad. Sci. U.S.A. 95:9855-9860(1998) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION, INTERACTION WITH CBP; EP300 AND PCAF.
[6]	"A dominant mutation in the gene encoding the erythroid transcription factor KLF1 causes a congenital dyserythropoietic anemia." Arnaud L., Saison C., Helias V., Lucien N., Steschenko D., Giarratana M.C., Prehu C., Foliguet B., Montout L., de Brevern A.G., Francina A., Ripoche P., Fenneteau O., Da Costa L., Peyrard T., Coghlan G., Illum N., Birgens H. , Tamary H., Iolascon A., Delaunay J., Tchernia G., Cartron J.P. Am. J. Hum. Genet. 87:721-727(2010) [PubMed] [Europe PMC] [Abstract] Cited for: ROLE IN ERYTHROPOIESIS, FUNCTION AS TRANSCRIPTIONAL ACTIVATOR OF CD44 AND AQP1, SUBCELLULAR LOCATION, VARIANT PRO-102, VARIANT CDA4 LYS-325, CHARACTERIZATION OF VARIANT CDA4 LYS-325.
[7]	"Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin." Borg J., Papadopoulos P., Georgitsi M., Gutierrez L., Grech G., Fanis P., Phylactides M., Verkerk A.J., van der Spek P.J., Scerri C.A., Cassar W., Galdies R., van Ijcken W., Ozgur Z., Gillemans N., Hou J., Bugeja M., Grosveld F.G. , von Lindern M., Felice A.E., Patrinos G.P., Philipsen S. Nat. Genet. 42:801-805(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION AS REGULATOR OF FETAL-TO-ADULT GLOBIN SWITCHING, INVOLVEMENT IN HBFQTL6.
[8]	"Mutations in EKLF/KLF1 form the molecular basis of the rare blood group In(Lu) phenotype." Singleton B.K., Burton N.M., Green C., Brady R.L., Anstee D.J. Blood 112:2081-2088(2008) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS BLOOD GROUP-IN(LU) TYR-299; LEU-328; HIS-328 AND GLY-331.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U37106 Genomic DNA. Translation: AAC50562.1.
U65404 mRNA. Translation: AAC51108.1.
AD000092 Genomic DNA. Translation: AAB51173.1.
BC033580 mRNA. Translation: AAH33580.1.

IPI

IPI00012816.

PIR

T45072.

RefSeq

NP_006554.1. NM_006563.3.

UniGene

Hs.37860.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2L2I	NMR	-	B	51-90	[»]

ProteinModelPortal

Q13351.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-43776N.

MINT

MINT-1891495.

STRING

9606.ENSP00000264834.

PTM databases

PhosphoSite

Q13351.

Polymorphism databases

DMDM

2501699.

Proteomic databases

PaxDb

Q13351.

PRIDE

Q13351.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000264834; ENSP00000264834; ENSG00000105610.

GeneID

10661.

KEGG

hsa:10661.

UCSC

uc002mvo.3. human.

Organism-specific databases

CTD

10661.

GeneCards

GC19M012995.

HGNC

HGNC:6345. KLF1.

HPA

HPA051850.

MIM

111150. phenotype.
600599. gene.
613566. phenotype.
613673. phenotype.

neXtProt

NX_Q13351.

Orphanet

293825. Congenital dyserythropoietic anemia due to KLF1 mutation.
46532. Hereditary persistence of fetal hemoglobin - beta-thalassemia.
251380. Hereditary persistence of fetal hemoglobin - sickle cell disease.

PharmGKB

PA30131.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG5048.

HOGENOM

HOG000060173.

HOVERGEN

HBG006220.

InParanoid

Q13351.

KO

K09204.

OMA

QYQGHFQ.

OrthoDB

EOG48SGTT.

PhylomeDB

Q13351.

Gene expression databases

ArrayExpress

Q13351.

Bgee

Q13351.

CleanEx

HS_KLF1.

Genevestigator

Q13351.

GermOnline

ENSG00000105610. Homo sapiens.

Family and domain databases

Gene3D

3.30.160.60. 3 hits.

InterPro

IPR007087. Znf_C2H2.
IPR015880. Znf_C2H2-like.
IPR013087. Znf_C2H2/integrase_DNA-bd.
[Graphical view]

SMART

SM00355. ZnF_C2H2. 3 hits.
[Graphical view]

PROSITE

PS00028. ZINC_FINGER_C2H2_1. 3 hits.
PS50157. ZINC_FINGER_C2H2_2. 3 hits.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

Q13351.

GenomeRNAi

10661.

NextBio

40543.

SOURCE

Search...

Entry information

Entry name

KLF1_HUMAN

Accession

Primary (citable) accession number: Q13351
Secondary accession number(s): Q6PIJ5, Q92899

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	November 1, 1996
Last modified:	May 1, 2013
This is version 114 of the entry and version 1 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.