Calreticulin 钙网蛋白, a Novel Secreted Calcium Binding Protein

是1974年命名的骨骼肌肌质网膜上的钙结合蛋白。该蛋白质在非肌肉组织中含量丰富，是内质网(ER)主要的钙结合蛋白之一。存在于高等生物除红细胞之外 的所有细胞中。结合钙的能力极强。分子中有三个结构和功能区，即N-末端区，P区和C-末端区。N-末端区包含180个氨基酸残基(1～180)，这一区 域的氨基酸序列是最保守的。P区(181～280氨基酸残基)富含脯氨酸，具有二组三序列重复。C-末端与肌质网的钙贮藏蛋白-集钙蛋白 (calsequestrin)相似，这一区域呈强酸性，有很高钙结合容量，但与钙亲和力低。C-末端含有作为内质网滞留信号的四肽(KDEL)。它通常 认为定位于内质网(包括核膜和滑面内质网)中。它主要有四种生物学功能：(1)作为内质网监护蛋白；(2)钙的贮藏和信号转导；(3)细胞黏附；(4)基 因表达的调控。

Calreticulin is a multifunctional protein that binds Ca2+ ions (a second messenger molecule in signal transduction), rendering it inactive. The Ca2+ is bound with low affinity, but high capacity, and can be released on a signal (see inositol triphosphate). Calreticulin is located in storage compartments associated with the endoplasmic reticulum.Calreticulin binds to misfolded proteins and prevents them from being exported from the Endoplasmic reticulum to the Golgi apparatus. Calreticulin can act as an important modulator of the regulation of gene transcription by nuclear hormone receptors.Calreticulin binds to antibodies in certain sera of systemic lupus and Sjogren patients which contain anti-Ro/SSA antibodies.

Calreticulin inhibits commitment to adipocyte differentiation

Calreticulin, an endoplasmic reticulum (ER) resident protein, affects many critical cellular functions, including protein folding and calcium homeostasis. Using embryonic stem cells and 3T3-L1 preadipocytes, we show that calreticulin modulates adipogenesis. We find that calreticulin-deficient cells show increased potency for adipogenesis when compared with wild-type or calreticulin-overexpressing cells. In the highly adipogenic crt–/– cells, the ER lumenal calcium concentration was reduced. Increasing the ER lumenal calcium concentration led to a decrease in adipogenesis. In calreticulin-deficient cells, the calmodulin–Ca2+/calmodulin-dependent protein kinase II (CaMKII) pathway was up-regulated, and inhibition of CaMKII reduced adipogenesis. Calreticulin inhibits adipogenesis via a negative feedback mechanism whereby the expression of calreticulin is initially up-regulated by peroxisome proliferator–activated receptor (PPAR). This abundance of calreticulin subsequently negatively regulates the expression of PPAR, lipoprotein lipase, CCAAT enhancer–binding protein , and aP2. Thus, calreticulin appears to function as a Ca2+-dependent molecular switch that regulates commitment to adipocyte differentiation by preventing the expression and transcriptional activation of critical proadipogenic transcription factors.

Szabo E., et al. The Journal of Cell Biology, Vol. 182, No. 1, 103-116

Calreticulin significantly reduces intimal hyperplasia after arterial injury, potentially acting as a vascular regulatory protein

Synonyms

• CALR
• CRTC

Human Calreticulin , 417 amino acids, MW 48142 Da MLLSVPLLLG LLGLAVAEPA VYFKEQFLDG DGWTSRWIES KHKSDFGKFV LSSGKFYGDE EKDKGLQTSQ DARFYALSAS FEPFSNKGQT LVVQFTVKHE QNIDCGGGYV KLFPNSLDQT DMHGDSEYNI MFGPDICGPG TKKVHVIFNY KGKNVLINKD IRCKDDEFTH LYTLIVRPDN TYEVKIDNSQ VESGSLEDDW DFLPPKKIKD PDASKPEDWD ERAKIDDPTD SKPEDWDKPE HIPDPDAKKP EDWDEEMDGE WEPPVIQNPE YKGEWKPRQI DNPDYKGTWI HPEIDNPEYS PDPSIYAYDN FGVLGLDLWQ VKSGTIFDNF LITNDEAYAE EFGNETWGVT KAAEKQMKDK QDEEQRLKEE EEDKKRKEEE EAEDKEDDED KDEDEEDEED KEEDEEEDVP GQAKDEL 417 Swiss-Prot entry P27797; N-domain (amino acid residues 1 to 182), the P-domain (amino acid residues 139 to 273), N and P-domain (amino acids 1 to 273), and the C-domain (amino acid residues 270 to 401)   Involvement of calreticulin in signal transduction pathways. Calreticulin is essential for integrin signaling and the dephosphorylation and nuclear translocation of NF-AT3. The size of the Ca2+ symbols reflects the differing concentrations in the extracellular space and the sarcoplasmic reticulum (10–3 M), as compared with the cytoplasm (10–5 M in systole and 10–7 M in diastole, with higher levels seen in Ca2+ sparks). J. Clin. Invest. Alexander Maass, et al. 107:1223 doi:10.1172/JCI13125 Hematoxylin and eosin–stained sections of the iliofemoral artery at sites of balloon injury and calreticulin, calsequestrin, and saline infusion, Studies 1 and 2. Magnification x260. (A) Near total arterial occlusion and associated hemosiderin-laden macrophage infiltration after balloon injury and saline control infusion. (B) Contralateral control artery in a saline-infused rat that was not injured by balloon angioplasty. No intimal hyperplasia is seen in this section. (C) Infusion of 0.1 mg of calreticulin with significant decrease in plaque development. (D) Infusion of 0.1 mg of calsequestrin showing circumferential plaque development. Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:2359-2368. Immunohistochemical analysis of balloon-injured arterial sections taken 24 hours and 4 weeks after injury and concomitant protein or peptide infusions demonstrating a reduction in macrophage invasion and an associated reduction in ICAM staining at both 24 hours and 4 weeks after balloon injury and calreticulin infusion. Magnification x400. (A) Saline control treated rat femoral artery section with increased macrophage staining at 24 hours after balloon injury. (B) Decreased macrophage invasion into the medial layer is seen at 24 hours after balloon injury and calreticulin infusion. (C) Increased ICAM staining at 24 hours in the media after balloon injury and saline infusion. (D) Decreased ICAM staining at 24 hours after balloon injury in calreticulin-treated rat femoral artery section. Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:2359-2368.

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Role of Calnexin and Calreticulin in protein folding in the ER

Calreticulin in human pregnancy and pre-eclampsia

Pre-eclampsia is a disorder of human pregnancy that involves pregnancy-induced maternal hypertension and proteinuria. Evidence indicates that pre-eclampsia involves widespread activation of maternal endothelial cells. Calreticulin is a ubiquitously expressed, multi-functional protein that has been shown to have both pro- and anti-inflammatory effects on cultured endothelial cells in vitro and in whole animals. In order to clarify the role of this protein in normal human pregnancy and in pre-eclampsia, this study has measured expression of calreticulin in maternal blood and in placenta in patients with pre-eclampsia and in control pregnancies. There was a significant increase (5-fold) in calreticulin in plasma in term pregnant women compared with women who were not pregnant. There was no difference, however, in calreticulin in plasma from women who were sampled at first trimester, second trimester and at term. In addition, there was a significant increase (50%) in calreticulin in plasma from pre-eclamptic women compared to controls. Calreticulin mRNA and protein expression in placenta were not changed between pre-eclampsia and control pregnancies. These novel results indicate that calreticulin is increased in peripheral maternal blood early in pregnancy and remains elevated throughout normal gestation and that there is a further increase in calreticulin in pre-eclampsia.

Gu V.Y., et al. Molecular Human Reproduction 2008 14(5):309-315; doi:10.1093/molehr/gan017