Zinc endopeptidase with endothelin-3-converting enzyme activity. Cleaves EDN1, EDN2 and EDN3, with a marked preference for EDN3. (updated: March 4, 2015)

Protein identification was indicated in the following studies:

Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.

Methods

The following articles were analysed to gather the proteome content of erythrocytes.

The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.

Publication	Identification ¹	Uniprot mapping ²	Not mapped / Obsolete	TrEMBL	Swiss-Prot
Goodman (2013)	2289 (gene list)	2278	53	20599	2269
Lange (2014)	1234	1234	7	28	1224
Hegedus (2015)	2638	2622	0	235	2387
Wilson (2016)	1658	1528	170	291	1068
d'Alessandro (2017)	1826	1817	2	0	1815
Bryk (2017)	2090	2060	10	108	1942
Chu (2018)	1853	1804	55	362	1387

¹ as available in the article and/or in supplementary material
² uniprot mapping returns all protein isoforms as one entry

The compilation of older studies can be retrieved from the Red Blood Cell Collection database.

The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.

No sequence conservation computed yet.

Protein sequence (FASTA)

Protein coevolution profile (FreeContact)

Multiple Sequence Alignment (Muscle)

This protein is annotated as membranous in Gene Ontology, is annotated as membranous in UniProt, is predicted to be membranous by TOPCONS.

Topcons

Total structural coverage: 6%

Model score: 59

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Variant	Description
	dbSNP:rs8175974
	KEL24 antigen
	KEL1/K antigen
	KEL25 antigen
	KEL27 antigen
	KEL21/Kp(c) antigen
	KEL3/Kp(a) antigen
	KEL17 antigen
	KEL22 antigen
	KEL23 antigen
	KEL26 antigen
	KEL19 antigen
	KEL10/Ul(a) antigen
	KEL12 antigen
	KEL6/Js(a) antigen
	dbSNP:rs8176048

No binding partner found

Biological Process

Cellular calcium ion homeostasis

Cellular magnesium ion homeostasis

G protein-coupled receptor signaling pathway

Myelination

Negative regulation of potassium ion transmembrane transport

Protein processing

Regulation of axon diameter

Regulation of cell size

Skeletal muscle fiber development

Vasoconstriction

Cellular Component

Cytosol

Integral component of membrane

Nucleoplasm

Obsolete cell

Plasma membrane

Molecular Function

Metal ion binding

Metalloendopeptidase activity

The reference OMIM entry for this protein is 110900

Blood group--kell system; kel

A number sign (#) is used with this entry because more than 25 antigens of the Kell blood group system are determined by variation in the KEL gene on chromosome 7q33 (KEL; {613883}). A single antigen, Kx, is carried by the XK gene ({314850}) on chromosome Xp21.

Description

The Kell blood group system is formed by 2 disulfide-linked proteins, Kell and XK. The Kell protein is a type II membrane glycoprotein sharing sequence homology with members of the M13 family of zinc-dependent metalloproteases and possessing enzymatic activity characteristic of that group (summary by {2:Claperon et al., 2007}). The Kell blood group system is highly polymorphic, expressing over 25 antigens that have been classified in to 5 antithetical sets of high and low prevalence antigens with the others being independently expressed or having unknown antithetical partners. The different phenotypes are due to single-nucleotide mutations that result in an amino acid substitution (summary by {10:Sha et al., 2006}). See, for example, Kell (designated K or K1)/Cellano (k, K2) (T193M; {613883.0001}). {15:Yu et al. (2001)} noted that the Kell antigens are the most potent immunogens aside from the A and B antigens of the ABO system ({616093}) and the D antigen ({111680}) of the Rh system (see {111700}).

Clinical Features

K1 is a strong immunogen; its antibodies can cause severe reactions if incompatible blood is transfused and may cause hemolytic disease of the newborn of sensitized mothers (summary by {7:Lee et al., 1995}). Newborns with hemolytic anemia caused by anti-Kell antibodies present signs of suppressed erythropoiesis, suggesting that anti-Kell antibodies suppress erythropoiesis at the progenitor level (summary by {1:Camara-Clayette et al., 2001}). Consequently, neither maternal antibody titers nor amniotic bilirubin levels are good predictors of the severity of the disease (summary by {14:Westhoff and Reid, 2004}). The lack of Kell antigens, K(0), can be caused by several different gene defects. K-null individuals do not have any obvious defect (summary by {14:Westhoff and Reid, 2004}). Weakened Kell antigens and absence of the Kx antigen at the surface of red blood cells define the McLeod phenotype ({300842}). Although this phenotype is related to Kell, it is the Kx antigen which is either deleted or mutated and no longer able to bind Kell (summary by {2:Claperon et al., 2007}). While K-null red cells have no detectable Kell surface antigens, an enhanced level of Kx antigens differentiates the K-null from the McLeod phenotype (summary by {14:Westhoff and Reid, 2004}). The McLeod phenotype also includes acanthocytosis and neurologic abnormalities.

Population Genetics

Kell antigens show population variations. K has an incidence of 9% in Caucasians but is much less common in other ethnic backgrounds (summary by {14:Westhoff and Reid, 2004}). The KEL6 antigen (see {613883.0003}) has an incidence of 20% in persons of African heritage but occurs in only about 1% of Caucasians (summary by {6:Lee et al., 2003}). Although it is very rare, the K-null phenotype is widely distributed and has been identified in Europeans, Japanese, Africans, and Indians (summary by {15:Yu et al., 2001}).

Mapping

{4,3:Conneally et al. (1974, 1976)} found Kell and PTC ({171200}) to be closely linked: total lod = 10.78 at theta = 0.045. {5:Keats et al. (1978)} raised the question of linkage of Kell and PTC to Jk-Km-Co, then thought to be on chromosome 7. {11:Sp ... More on the omim web site

The reference OMIM entry for this protein is 613883

Kell blood group metalloendopeptidase; kel
Kell blood group glycoprotein
Kell blood group antigen

DESCRIPTION

The KEL gene encodes the Kell blood group protein, a metalloendopeptidase that preferentially cleaves big endothelin-3 (131242) to produce bioactive endothelin-3. Kell is a polymorphic protein; the more than 25 antigens of the Kell blood group (110900) result from point mutations resulting in single amino acid substitutions (summary by Sha et al., 2006).

CLONING

KEL antigens reside on a 93-kD membrane glycoprotein that is surface exposed and associated with the underlying cytoskeleton. Lee et al. (1991) isolated tryptic peptides of this glycoprotein and, based on the amino acid sequence of one of the peptides and by using PCR, prepared a specific oligonucleotide to screen a lambda-gt10 human bone marrow cDNA library. One clone contained cDNA with an open reading frame for a predicted 83-kD protein. All known KEL amino acid sequences were present in the deduced sequence; moreover, rabbit antibody to a 30-amino acid peptide prepared from this sequence reacted on an immunoblot with authentic KEL protein. The KEL cDNA sequence predicted a 732-amino acid protein. A computer-based search showed that KEL has structural and sequence homology to a family of zinc metalloglycoproteins with neutral endopeptidase activity. Marsh (1992) reviewed the cloning of the KEL gene and its characterization. By Northern blot analysis of RNA from multiple tissues, Lee et al. (1993) demonstrated that the KEL gene is expressed only in erythroid tissues. Wagner et al. (2000) presented data indicating that KEL is expressed not only on erythroid blood cells but also on myeloid progenitor cells. By dot-blot analysis, Camara-Clayette et al. (2001) detected high levels of Kell expression in brain tissues, spleen, lymph node, bone marrow, and testis. Most tissues analyzed exhibited low levels of Kell transcripts. All fetal tissues showed Kell expression.

GENE STRUCTURE

Lee et al. (1995) determined that the KEL gene comprises 19 exons and spans 21.5 kb. The single membrane spanning region of the Kell protein is encoded in exon 3 and the putative zinc endopeptidase active site is in exon 16.

MAPPING

Despite its high level of polymorphism with a series of serologically distinct antigens (KEL1 to KEL24), the gene controlling KEL antigen expression (KEL) eluded chromosomal assignment until the mapping work of Zelinski et al. (1991). They succeeded in showing linkage with prolactin-inducible protein (PIP; 176720), which had been assigned to 7q32-q36. No evidence of recombination was found; maximum lod = 10.36 at theta = 0.00. The mapping of the Kell blood group to chromosome 7 means that PTC tasting (171200), the YT blood group (112100), and hyperreflexia (145290) are also located there. Purohit et al. (1992) demonstrated close linkage to cystic fibrosis (see CFTR; 602421); sex-specific estimates of recombination fractions were 0.013 in males and 0.219 in females, with a joint maximum lod score of 4.58. Lee et al. (1993) used genomic clones as probes to confirm the assignment of the gene to chromosome 7 by Southern analysis of human/hamster somatic cell hybrids; by in situ hybridization, they localized the KEL gene to 7q33. Using a biotinylated 1.1-kb DNA fragment containing the 3-prime half of the KEL cDNA for in situ hybridization, Murphy et al. (1993) likewise assigned the KEL gene to 7q33-q35. They suggested that since the in situ assignment agrees with the genetic localization using antigenic variation as the marker ... More on the omim web site

Subscribe to this protein entry history

July 2, 2021: Protein entry updated
Automatic update: OMIM entry 110900 was added.

July 2, 2021: Protein entry updated
Automatic update: OMIM entry 613883 was added.

April 11, 2021: Protein entry updated
Automatic update: OMIM entry 110900 was added.

April 11, 2021: Protein entry updated
Automatic update: OMIM entry 613883 was added.

Feb. 17, 2021: Protein entry updated
Automatic update: OMIM entry 110900 was added.

Feb. 17, 2021: Protein entry updated
Automatic update: OMIM entry 613883 was added.

Oct. 21, 2020: Protein entry updated
Automatic update: OMIM entry 110900 was added.

Oct. 21, 2020: Protein entry updated
Automatic update: OMIM entry 613883 was added.

Aug. 25, 2020: Protein entry updated
Automatic update: OMIM entry 110900 was added.

Aug. 25, 2020: Protein entry updated
Automatic update: OMIM entry 613883 was added.

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 110900 was added.

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 613883 was added.

April 26, 2020: Protein entry updated
Automatic update: OMIM entry 110900 was added.

April 26, 2020: Protein entry updated
Automatic update: OMIM entry 613883 was added.

March 4, 2020: Protein entry updated
Automatic update: OMIM entry 110900 was added.

March 4, 2020: Protein entry updated
Automatic update: OMIM entry 613883 was added.

Jan. 23, 2020: Protein entry updated
Automatic update: OMIM entry 110900 was added.

Jan. 23, 2020: Protein entry updated
Automatic update: OMIM entry 613883 was added.

Dec. 3, 2019: Protein entry updated
Automatic update: OMIM entry 110900 was added.

Dec. 3, 2019: Protein entry updated
Automatic update: OMIM entry 613883 was added.

Oct. 28, 2019: Protein entry updated
Automatic update: OMIM entry 110900 was added.

Oct. 28, 2019: Protein entry updated
Automatic update: OMIM entry 613883 was added.

Sept. 23, 2019: Protein entry updated
Automatic update: OMIM entry 110900 was added.

Sept. 23, 2019: Protein entry updated
Automatic update: OMIM entry 613883 was added.

Aug. 20, 2019: Protein entry updated
Automatic update: OMIM entry 110900 was added.

Aug. 20, 2019: Protein entry updated
Automatic update: OMIM entry 613883 was added.

July 5, 2019: Protein entry updated
Automatic update: OMIM entry 110900 was added.

July 5, 2019: Protein entry updated
Automatic update: OMIM entry 613883 was added.

June 7, 2019: Protein entry updated
Automatic update: OMIM entry 110900 was added.

June 7, 2019: Protein entry updated
Automatic update: OMIM entry 613883 was added.

May 12, 2019: Protein entry updated
Automatic update: OMIM entry 110900 was added.

May 12, 2019: Protein entry updated
Automatic update: OMIM entry 613883 was added.

Jan. 21, 2019: Protein entry updated
Automatic update: OMIM entry 110900 was added.

Jan. 21, 2019: Protein entry updated
Automatic update: OMIM entry 613883 was added.

Nov. 17, 2018: Protein entry updated
Automatic update: OMIM entry 110900 was added.

Nov. 17, 2018: Protein entry updated
Automatic update: OMIM entry 613883 was added.

Oct. 20, 2018: Protein entry updated
Automatic update: OMIM entry 110900 was added.

Oct. 20, 2018: Protein entry updated
Automatic update: OMIM entry 613883 was added.

Oct. 2, 2018: Protein entry updated
Automatic update: OMIM entry 110900 was added.

Oct. 2, 2018: Protein entry updated
Automatic update: OMIM entry 613883 was added.

July 7, 2018: Protein entry updated
Automatic update: OMIM entry 110900 was added.

July 7, 2018: Protein entry updated
Automatic update: OMIM entry 613883 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 110900 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 613883 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 110900 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 613883 was added.

July 4, 2018: Protein entry updated
Automatic update: OMIM entry 110900 was added.

July 4, 2018: Protein entry updated
Automatic update: OMIM entry 613883 was added.

July 3, 2018: Protein entry updated
Automatic update: OMIM entry 110900 was added.

July 3, 2018: Protein entry updated
Automatic update: OMIM entry 613883 was added.

May 27, 2018: Protein entry updated
Automatic update: OMIM entry 110900 was added.

May 27, 2018: Protein entry updated
Automatic update: OMIM entry 613883 was added.

April 27, 2018: Protein entry updated
Automatic update: OMIM entry 110900 was added.

April 27, 2018: Protein entry updated
Automatic update: OMIM entry 613883 was added.

Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated

Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated

Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated

March 16, 2016: Protein entry updated
Automatic update: OMIM entry 110900 was added.

Kell blood group glycoprotein (KEL)