Plasma membrane calcium-transporting ATPase 4 (ATP2B4)
The protein contains 1241 amino acids for an estimated molecular weight of 137920 Da.
Calcium/calmodulin-regulated and magnesium-dependent enzyme that catalyzes the hydrolysis of ATP coupled with the transport of calcium out of the cell (PubMed:8530416). By regulating sperm cell calcium homeostasis, may play a role in sperm motility (By similarity). (updated: Nov. 22, 2017)
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.
This protein is annotated as membranous in Gene Ontology, is annotated as membranous in UniProt, is predicted to be membranous by TOPCONS.
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Biological Process
Blood coagulation
Calcium ion export
Calcium ion homeostasis
Calcium ion import across plasma membrane
Calcium ion transmembrane import into cytosol
Calcium ion transmembrane transport
Cellular calcium ion homeostasis
Cellular response to acetylcholine
Cellular response to epinephrine stimulus
Flagellated sperm motility
Hippocampus development
Ion transmembrane transport
Negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway involved in heart process
Negative regulation of angiogenesis
Negative regulation of arginine catabolic process
Negative regulation of blood vessel endothelial cell migration
Negative regulation of calcineurin-NFAT signaling cascade
Negative regulation of cardiac muscle hypertrophy in response to stress
Negative regulation of cellular response to vascular endothelial growth factor stimulus
Negative regulation of citrulline biosynthetic process
Negative regulation of gene expression
Negative regulation of nitric oxide biosynthetic process
Negative regulation of nitric oxide mediated signal transduction
Negative regulation of nitric-oxide synthase activity
Negative regulation of peptidyl-cysteine S-nitrosylation
Negative regulation of the force of heart contraction
Neural retina development
Obsolete negative regulation of adrenergic receptor signaling pathway involved in heart process
Positive regulation of cAMP-dependent protein kinase activity
Positive regulation of peptidyl-serine phosphorylation
Positive regulation of protein localization to plasma membrane
Regulation of cardiac conduction
Regulation of cell cycle G1/S phase transition
Regulation of cytosolic calcium ion concentration
Regulation of sodium ion transmembrane transport
Regulation of transcription by RNA polymerase II
Response to hydrostatic pressure
Spermatogenesis
Transmembrane transport
Transport across blood-brain barrier
Urinary bladder smooth muscle contraction
Cellular Component
Basolateral plasma membrane
Caveola
Glutamatergic synapse
Integral component of plasma membrane
Integral component of presynaptic active zone membrane
Intracellular membrane-bounded organelle
Membrane
Membrane raft
Neuron projection
Obsolete cell
Plasma membrane
Protein complex
Protein-containing complex
Sperm flagellum
Sperm principal piece
T-tubule
Z disc
Molecular Function
ATP binding
ATPase-coupled cation transmembrane transporter activity
Calcium ion transmembrane transporter activity
Calcium-dependent protein binding
Calmodulin binding
Metal ion binding
Nitric-oxide synthase binding
Nitric-oxide synthase inhibitor activity
P-type calcium transporter activity
PDZ domain binding
Protein kinase binding
Protein phosphatase 2B binding
Scaffold protein binding
Sodium channel regulator activity
The reference OMIM entry for this protein is 108732
Atpase, ca(2+)-transporting, plasma membrane, 4; atp2b4
Plasma membrane ca(2+)-atpase, type 4; pmca4
Atp2b2, formerly
DESCRIPTION
The Ca(2+)-ATPases are a family of plasma membrane pumps encoded by at least 4 genes: ATP2B1 (108731) on chromosome 12q21; ATP2B2 (108733) on 3q26; ATP2B3 (300014) on Xq28; and ATP2B4.CLONING
By PCR, Brandt et al. (1992) detected expression of the PMCA4a variant in all tissues examined. They identified a second variant, PMCA4b, that was primarily expressed in skeletal muscle, small intestine, heart, spinal cord, and brain. Brandt et al. (1992) isolated the full-length PMCA4b cDNA from a fetal brain cDNA library. The deduced 473-amino acid protein lacks a large portion of the C terminus found in PMCA4a. By RT-PCR, Santiago-Garcia et al. (1996) found variable expression of the PMCA and SERCA (see 108730) genes during human fetal heart development. PMCA4 and PMCA1 were expressed in 8-, 12-, and 20-week fetal heart and in adult heart. Two PMCA4 splice variants were detected in heart tissue, whereas only 1 was detected in placenta. Okunade et al. (2004) examined Pmca1 and Pmca4 expression in mouse tissues. Pmca1 was expressed in all tissues examined, and Pmca4 was expressed in all tissues examined except liver. Pmca1 predominated in brain, intestine, kidney, lung, and stomach, whereas Pmca4 predominated in aorta, portal vein, bladder, diaphragm, seminal vesicles, and testis. Immunostaining localized Pmca4 to the principal piece of the sperm tail, the location of Catsper (606389), the major Ca(2+) channel required for sperm motility.MAPPING
Olson et al. (1991) mapped the PMCA4 gene to chromosome 1q25-q32 by Southern analysis of human-rodent somatic cell hybrids, in situ hybridization of human metaphase spreads, and genetic linkage analysis in the CEPH pedigrees. No evidence was obtained for multiple copies of the gene at this locus; however, a cross-hybridizing sequence was detected on Xq13-qter at low stringency.MOLECULAR GENETICS
- Associations Pending Confirmation For discussion of a possible association between variation in the ATP2B4 gene and resistance to severe malaria, see 611162.ANIMAL MODEL
Chen et al. (2004) expressed mouse Cd22 (107266) in mouse and chicken B-cell lines devoid of Cd22 and examined B cells from mice deficient in Cd22 or Pmca4. They identified an activation-dependent interaction between phosphorylated Cd22 and Pmca4 and found that Cd22 together with Shp1 (PTPN6; 176883) provided negative control of B-cell activation by enhancing Pmca4-mediated calcium efflux after B-cell receptor stimulation. Okunade et al. (2004) found that loss of both copies of the mouse Pmca4 gene resulted in no overt phenotype. Loss of Pmca4 impaired phasic contractions and caused apoptosis in portal vein smooth muscle in vitro, but this phenotype was dependent on the mouse strain employed. On a Black Swiss background, the phenotype was not expressed unless the mice also carried a null mutation in 1 copy of the Pmca1 gene. Pmca4 -/- male mice were infertile but had normal spermatogenesis and mating behavior. Pmca4 -/- sperm that had not undergone capacitation exhibited normal motility but did not achieve hyperactivated motility needed to traverse the female genital tract. Ultrastructure of the motility apparatus of mutant sperm tails showed mitochondrial condensation, indicating Ca(2+) overload. Okunade et al. (2004) concluded that PMCA4 expression in the principal piece of sperm tail is essential for hyperactivated motility and male fertility. ... More on the omim web site
Feb. 10, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
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 108732 was added.
Jan. 25, 2016: Protein entry updated
Automatic update: model status changed