Abstract
KELL is a member of the M13 family of type II neutral endopeptidases, which functions as a blood group antigen in human and animal populations. KELL amino acid sequences and structures and KEL gene locations were examined using bioinformatic data from several mammalian genome projects. Mammalian KELL sequences shared 55-99% identity, as compared with 21-31% sequence identities with other M13-like family members. Four predicted N-glycosylation sites were conserved among the mammalian KELL proteins examined. Sequence alignments, key amino acid residues and conserved predicted secondary and tertiary structures were also studied, including active site residues, predicted disulfide forming Cys residues, cytoplasmic, transmembrane and extracellular sequences and KELL C-terminus amino acid sequences. Mammalian KEL genes usually contained 18 or 19 coding exons on the direct strand. Transcription factor binding sites within the human KEL promoter may regulate transcription within erythroid cells. Phylogenetic analyses examined the relationships and potential evolutionary origins of the mammalian KEL gene with six other vertebrate neutral endopeptidase M13 family genes. These suggested that KEL originated in an ancestral marsupial genome from a gene duplication event of a neutral endopeptidase M13-like gene.
Highlights
Blood Group Glycoprotein (KELL) blood group glycoprotein (KELL, called CD antigen 238; EC 3.4.24.-) is one of at least seven members of the M13 family of neutral endopeptidases, which are zinc-containing type II transmembrane enzymes [1,2,3,4]
Other M13 neutral endopeptidases have been described: Membrane endopeptidase (MME) or neprilysin (NEP) inactivates signaling peptides involved in regulating blood pressure, the immune system and neuronal activity [12,13,14]; membrane metallo-endopeptidaselike 1 (MMEL1) or neprilysin-like protein 1 (NEPL1), reported as a susceptibility locus for multiple sclerosis, primary biliary cirrhosis and rheumatoid arthritis with a proposed sperm function role [15,16,17,18]; endothelin-converting enzyme 1 (ECE1, EC=3.4.24.71) [19,20], and endothelin-converting enzyme 2 (ECE2, EC=3.4.24.71) participate in regulatory peptide processing [21,22]; endothelin-converting enzymelike 1 (ECEL1) serves an essential role in the nervous control of respiration [23,24]; and phosphate-regulating neutral endopeptidase (PHEX), which is involved in bone mineralization, and has a proposed role in renal phosphate reabsorption [25,26]
This study suggests that mammalian KELL Blood Group Glycoproteins and Genes (KEL) genes and encoded KELL proteins represent a distinct gene and protein family of M13 Type II neutral endopeptidase-like proteins which share conserved sequences, and active site residues with those reported for other related M13 Type II endopeptidases, MME, MMEL1, ECE1, ECE2, ECEL1 and PHEX, previously studied [19,20,21,22,25,58]
Summary
KELL blood group glycoprotein (KELL, called CD antigen 238; EC 3.4.24.-) is one of at least seven members of the M13 family of neutral endopeptidases, which are zinc-containing type II transmembrane enzymes [1,2,3,4]. KELL is a single-pass transmembrane protein which is linked to the XY protein, found in red blood cell (RBC) membranes [8,9], and serves as an endothelinconverting enzyme, an endopeptidase which cleaves ‘big’ endothelin-3 to form an active vasoconstrictor peptide [10,11]. At least 30 KELL antigens are reported [27,30,31], including the highest frequency KEL polymorphism in human populations, designated as K1/ K2, due to a C→T substitution in exon 6 causing a 193Thr to 193Met substitution and disruption of an N-glycosylation site [32]. A ‘null’ human KEL phenotype (designated as K0), which abolishes KELL expression in erythroid tissues, resulting from a mutation at the splicing exon 3 donor site [33], while other K0 alleles have been reported in low frequency in a Chinese population [34]. Antibodies generated in the circulation system in response to KELL antigens are usually immunoglobulin G, which
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