The reference OMIM entry for this protein is 108730

Atpase, ca(2+)-transporting, fast-twitch 1; atp2a1
Sarcoplasmic reticulum ca(2+)-atpase 1; serca1 serca1 truncated isoform, included; s1t, included

CLONING

The function of calcium-transporting ATPase found in different membranes is to lower cytoplasmic Ca(2+) concentration by pumping Ca(2+) to luminal or extracellular spaces. Although there had long been evidence of differences between the Ca(2+) ATPase found in fast-twitch skeletal muscle fibers and those of slow-twitch/cardiac fibers, the differences were not clarified until cDNAs encoding the 2 forms were cloned and sequenced (Brandl et al., 1986). The proteins share 84% amino acid sequence identity and 76% nucleic acid sequence homology. Coding for these 2 proteins is clearly carried out by different genes which are presumably related to one another by an ancient gene duplication event. Zhang et al. (1995) isolated and characterized genomic DNA and cDNA encoding human ATP2A1. The deduced 994-amino acid protein has a calculated molecular mass of 109 kD and contains 10 putative transmembrane segments. Chami et al. (2001) stated that an adult SERCA1 variant, SERCA1A, has a stop codon in exon 22, whereas a fetal variant, SERCA1B, lacks exon 22 and has a stop codon in exon 23. By screening a liver cDNA library, they identified 2 additional splice variants, S1T+4 and S1T-4. Both S1T variants lack exon 11, but S1T-4 also lacks exon 4. Splicing of exon 11 in both variants leads to a frameshift that introduces a stop codon in exon 12, resulting in C-terminally truncated proteins that lack transmembrane segments 5 through 10, which include 6 of the 7 Ca(2+)-binding residues found in full-length SERCA1. The S1T proteins are therefore predicted to lack the ability to pump Ca(2+). RT-PCR analysis detected full-length SERCA1 in most adult and fetal tissues examined, including adult brain, but not fetal brain. S1T transcripts were detected in adult pancreas, liver, kidney, lung, and placenta and in fetal kidney, liver, brain, and thymus, but not in adult skeletal muscle, heart, and brain or in fetal skeletal muscle and heart. In brain, expression appeared to switch from S1T in the fetus to SERCA1 in the adult. Western blot analysis detected S1T and SERCA1 at 46 and 110 kD, respectively. S1T appeared to form homodimers and colocalized with SERCA2B (ATP2A2; 108740) in endoplasmic reticulum (ER) membranes.

GENE FUNCTION

Chami et al. (2001) found that overexpression of S1T proteins in several human cell lines induced apoptosis and reduced steady-state Ca (2+) levels in the ER and increased ER Ca(2+) leakage. In cotransfection experiments, S1T proteins consistently reduced the higher steady-state Ca(2+) level in ER following SERCA1 or SERCA2B overexpression. Chami et al. (2001) concluded that the S1T isoforms modulate full-length SERCA-dependent Ca(2+) accumulation into the ER and have a role in apoptosis. Chami et al. (2008) found that overexpression of S1T, but not full-length SERCA1, induced ER stress in HeLa cells and amplified ER stress through the PERK (EIF2AK3; 604032)-EIF2A (609234)-ATF4 (604064)-CHOP (DDIT3; 126337) pathway. S1T1 increased ER Ca(2+) leak, increased the number of contact sites between the ER and mitochondria, and inhibited mitochondria movements. These changes led to increased Ca(2+) transfer to mitochondria in both resting and stimulated cells and activated the mitochondrial apoptotic pathway. S1T knockdown prevented ER stress, mitochondrial Ca(2+) overload, and subsequent apoptosis.

GENE STRUCTURE

Zhang et al. (1995) determined that the human ATP2A1 gene is 26 kb long and contains 23 exon ... More on the omim web site

Subscribe to this protein entry history

May 11, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.

Oct. 20, 2018: Protein entry updated
Automatic update: OMIM entry 108730 was added.

Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).