Calreticulin is a multifunctional protein that acts as a major Ca(2+)-binding (storage) protein in the lumen of the endoplasmic
reticulum. It is also found in the nucleus, suggesting that it may have a role in transcription regulation. Calreticulin binds to the
synthetic peptide KLGFFKR, which is almost identical to an amino acid sequence in the DNA-binding domain of the superfamily
of nuclear receptors.
Membrane form of this protein binds to LRP and are important for apoptosis ("eat me" signal).
NCBI Summary:
Calreticulin is a multifunctional protein that acts as a major Ca(2+)-binding (storage) protein in the lumen of the endoplasmic reticulum. It is also found in the nucleus, suggesting that it may have a role in transcription regulation. Calreticulin binds to the synthetic peptide KLGFFKR, which is almost identical to an amino acid sequence in the DNA-binding domain of the superfamily of nuclear receptors. Calreticulin binds to antibodies in certain sera of systemic lupus and Sjogren patients which contain anti-Ro/SSA antibodies, it is highly conserved among species, and it is located in the endoplasmic and sarcoplasmic reticulum where it may bind calcium. The amino terminus of calreticulin interacts with the DNA-binding domain of the glucocorticoid receptor and prevents the receptor from binding to its specific glucocorticoid response element. Calreticulin can inhibit the binding of androgen receptor to its hormone-responsive DNA element and can inhibit androgen receptor and retinoic acid receptor transcriptional activities in vivo, as well as retinoic acid-induced neuronal differentiation. Thus, calreticulin can act as an important modulator of the regulation of gene transcription by nuclear hormone receptors. Systemic lupus erythematosus is associated with increased autoantibody titers against calreticulin but calreticulin is not a Ro/SS-A antigen. Earlier papers referred to calreticulin as an Ro/SS-A antigen but this was later disproven. Increased autoantibody titer against human calreticulin is found in infants with complete congenital heart block of both the IgG and IgM classes. [provided by RefSeq, Jul 2008]
General function
Protein metabolism and modification
Comment
Cellular localization
Nuclear, Endoplasmic reticulum
Comment
Ovarian function
Follicle development, Oocyte maturation
Comment
Involvement of ER-calreticulin-Ca(2+) signaling in the regulation of porcine oocyte meiotic maturation and maternal gene expression. Zhang DX et al. Calcium is one of the most ubiquitous signaling molecules, and controls a wide variety of cellular processes. It is mainly stored in the endoplasmic reticulum (ER), bound to lumenal proteins. Calreticulin is the major Ca(2+)-binding chaperone in oocytes, and is integral to numerous cellular functions. To better understand the role of the ER- calreticulin-Ca(2+) pathway in oocyte maturation and early embryogenesis, we characterized the porcine calreticulin gene and investigated its expression profile during oocyte maturation and early embryonic development. Calreticulin was widely expressed in pig tissues and its transcripts were downregulated during maturation, especially at 44 hr, and were undetectable at the blastocyst stage. We also investigated the effect of increased cytosolic Ca(2+) induced by the Ca(2+)-ATPase inhibitor, cyclopiazonic acid (CPA), on pig oocyte maturation and maternal gene expression. CPA at 10 microM did not inhibit germinal vesicle breakdown, but did result in the arrest of 38.6% oocytes at or before the MI stage. In addition, expression of the maternal genes C-mos, BMP15, GDF9, and Cyclin B1 was significantly increased in CPA-treated MII oocytes compared with control groups. These data were supported by the results of poly(A)-test PCR, which revealed that the cyclin B1 short isoform (CB-S), GDF9, and C-mos underwent more intensive polyadenylation modification in CPA-treated oocytes than control oocytes, suggesting that polyadenylation may influence Ca(2+)-modulated changes in gene expression. Furthermore, CPA treatment decreased the percentage of four-cell parthenotes that developed into blastocysts, suggesting the need for functional SR/ER Ca(2+)-ATPase pumps or Ca(2+) signals during early embryo development after zygotic genome activation. Together, these data indicate that ER-calreticulin-associated Ca(2+) homeostasis plays a role in oocyte and embryo development, and that alterations in maternal gene expression may contribute to the underlying molecular mechanism, at least partially, via polyadenylation. Mol. Reprod. Dev. 2010. (c) 2010 Wiley-Liss, Inc.
Expression regulated by
Comment
Ovarian localization
Oocyte, Cumulus, Granulosa
Comment
Balakier H, et al 2002 reported the expression of calcium-binding proteins and calcium-release channels in human
maturing oocytes, pronuclear zygotes and early preimplantation
embryos.
The study aim was to investigate the presence and localization of
Ca2+-binding proteins and Ca2+-release receptor channels in human maturing
oocytes, pronuclear zygotes and preimplantation embryos.
Immunocytochemical analysis, using specific antibodies against the proteins
being studied, followed with confocal laser microscopy, was performed on human
oocytes and embryos. Calreticulin and calsequestrin (the two major
calcium storage proteins of somatic cells), two types of calcium release
receptors, the inositol trisphosphate and ryanodine receptors (InsP(3)R-2,
RyRs-1,2,3), and the molecular chaperone, calnexin, were identified in all
investigated cell types. Calreticulin was predominant in the cell cortex and
in the nuclear envelope, while calsequestrin was distributed throughout the
entire cytoplasm. Generally, localization of the InsP(3)R-2 and RyRs was
similar to that of calreticulin and calsequestrin respectively. Both types of
receptor were enriched in the subplasmalemmal region of meiotic oocytes. In
addition, the InsP(3)R was detected in the nuclear structures of oocytes and
blastomeres. Calnexin distribution overlapped with that of calreticulin but
appeared to be present in distinct subcompartments. CONCLUSIONS: Human oocytes
and embryos express the calcium sequestration and release proteins in highly
organized and developmentally regulated patterns. Fine-tuning of these
proteins may play a crucial role in regulation of Ca2+ transience during
oocyte maturation, fertilization and early embryo development.
Follicle stages
Preovulatory
Comment
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: type: null mutation fertility: infertile - ovarian defect Comment: Calreticulin is required for development of the cumulus oocyte complex and female fertility. Tokuhiro K et al. (2015) Calnexin (CANX) and calreticulin (CALR) chaperones mediate nascent glycoprotein folding in the endoplasmic reticulum. Here we report that these chaperones have distinct roles in male and female fertility. Canx null mice are growth retarded but fertile. Calr null mice die during embryonic development, rendering indeterminate any effect on reproduction. Therefore, we conditionally ablated Calr in male and female germ cells using Stra8 (mcKO) and Zp3 (fcKO) promoter-driven Cre recombinase, respectively. Calr mcKO male mice were fertile, but fcKO female mice were sterile despite normal mating behavior. Strikingly, we found that Calr fcKO female mice had impaired folliculogenesis and decreased ovulatory rates due to defective proliferation of cuboidal granulosa cells. Oocyte-derived, TGF-beta family proteins play a major role in follicular development and molecular analysis revealed that the normal processing of GDF9 and BMP15 was defective in Calr fcKO oocytes. These findings highlight the importance of CALR in female reproduction and demonstrate that compromised CALR function leads to ovarian insufficiency and female infertility.//////////////////