Structure of the Human Sarco/Endoplasmic Reticulum Ca2+-ATPase 3 Gene

Dode, Leonard; Greef, Christine De; Mountian, Irina; Attard, Marlene; Town, Margaret; Casteels, Rik; Wuytack, Frank

doi:10.1074/jbc.273.22.13982

Cited by 82 publications

(64 citation statements)

References 52 publications

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“…We have provided evidence for the existence of up to four distinct ATP2C1 splice variants in human keratinocytes, generated by alternative processing at the 3Ј-end of the ATP2C1 pre-mRNA. Similar to ATP2C1, internal 5Ј donor splice sites are involved in generating five alternatively spliced human ATP2A3 (SERCA3) transcripts (27,28) and four alternatively processed ATP2B1 (PMCA1) transcripts (29 -31) due to the alternative exclusion, inclusion, or partial inclusion of exons at the 3Ј-end of the gene. So far, no evidence has been provided for the existence of alternatively spliced transcripts in the S. cerevisiae or C. elegans SPCA orthologues.…”

Section: Discussionmentioning

confidence: 99%

Effect of Hailey-Hailey Disease Mutations on the Function of a New Variant of Human Secretory Pathway Ca2+/Mn2+-ATPase (hSPCA1)

Fairclough

Dode

Vanoevelen

et al. 2003

Journal of Biological Chemistry

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115

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ATP2C1, encoding the human secretory pathway Ca 2؉ /Mn 2؉ ATPase (hSPCA1), was recently identified as the defective gene in Hailey-Hailey Disease (HHD), an autosomal dominant skin disorder characterized by persistent blisters and erosions. To investigate the underlying cause of HHD, we have analyzed the changes in expression level and function of hSPCA1 caused by mutations found in HHD patients. Mutations were introduced into hSPCA1d, a novel splice variant expressed in keratinocytes, described here for the first time. Encoded by the full-length of optional exons 27 and 28, hSPCA1d was longer than previously identified splice variants. The protein competitively transported Ca 2؉ and Mn 2؉ with equally high affinity into the Golgi of COS-1 cells. Ca 2؉ -and Mn 2؉ -dependent phosphoenzyme intermediate formation in forward (ATP-fuelled) and reverse (P ifuelled) directions was also demonstrated. HHD mutant proteins L341P, C344Y, C411R, T570I, and G789R showed low levels of expression, despite normal levels of mRNA and correct targeting to the Golgi, suggesting instability or abnormal folding of the mutated hSPCA1 polypeptides. P201L had little effect on the enzymatic cycle, whereas I580V caused a block in the E 1 ϳP 3 E 2 -P conformational transition. D742Y and G309C were devoid of Ca 2؉ -and Mn 2؉ -dependent phosphoenzyme formation from ATP. The capacity to phosphorylate from P i was retained in these mutants but with a loss of sensitivity to both Ca 2؉ and Mn 2؉ in D742Y and a preferential loss of sensitivity to Mn 2؉ in G309C. These results highlight the crucial role played by Asp-742 in the architecture of the hSPCA1 ion-binding site and reveal a role for Gly-309 in Mn 2؉ transport selectivity.

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Section: Discussionmentioning

confidence: 99%

Effect of Hailey-Hailey Disease Mutations on the Function of a New Variant of Human Secretory Pathway Ca2+/Mn2+-ATPase (hSPCA1)

Fairclough

Dode

Vanoevelen

et al. 2003

Journal of Biological Chemistry

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115

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“…We have identified four rare missense mutations ± Gln 108 ®His, Val 648 ®Met, Arg 674 ®Cys Ile 753 ®Leu ± in Type II diabetic patients. These mutations affect residues that are conserved in human [5,6] SERCA3 and in the structurally related human [10] SERCA1 protein. Site-directed mutagenesis has been extensively used to explore relations of structure and function in SERCA1 [3].…”

Section: Discussionmentioning

confidence: 99%

Sequence variants of the sarco(endo)plasmic reticulum Ca 2+ -transport ATPase 3 gene (SERCA3) in Caucasian Type II diabetic patients (UK Prospective Diabetes Study 48)

et al. 1999

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Genetic factors play an important part in the pathogenesis of Type II (non-insulin-dependent) diabetes mellitus, a heterogeneous disorder characterised by defects in insulin action as well as insulin secretion [1]. Investigations of candidate genes for Type II diabetes have led to the identification of polymorphisms of several genes. Major genetic causes of this disease, however, remain elusive.Glucose-dependent sequestration of Ca 2+ into endoplasmic reticulum and its subsequent release play an important part in the control of intracellular Ca 2+ concentration, which regulates insulin secretion in pancreatic beta cells [2]. The active uptake of cytosolic Ca 2+ into endoplasmic reticulum is mediated by sarco(endo)plasmic reticulum Ca 2+ -transport ATPases (SERCAs) Abstract Aims/hypothesis. Type II (non-insulin-dependent) diabetes mellitus is a common heterogeneous metabolic disorder of largely unknown genetic aetiology. The sarco(endo)plasmic reticulum Ca 2+ -transport ATPase (SERCA) plays an important part in the glucose-activated beta-cell Ca 2+ signalling that regulates insulin secretion. Impaired function and expression of SERCA have been shown in islets of Langerhans from diabetic animal models and have also been associated with beta-cell apoptosis. Thus, the SERCA3 encoding gene is a plausible candidate for a primary pancreatic beta-cell defect. Methods. In this study, the entire coding and the promoter regions of SERCA3 gene were screened by single-strand conformation polymorphism analysis in white Caucasian Type II diabetic patients. Results. We found four rare missense mutations [Exon 4: Gln 108 ®His (CAG®CAT), Exon 14: Val 648 ®Met (GTG®ATG) and Arg 674 ®Cys (CGC® TGC), and Exon 15: Ile 753 ®Leu (ATC®CTC)]. The patients with Gln 108 ®His, Val 648 ®Met and Arg 674 ®Cys mutations, which may affect the E1P-E2P transition of SERCA3 during its enzyme cycle, had normal body weight with marked hyperglycaemia and beta-cell dysfunction. That is an unusual phenotype only found in 6 % of the Type II diabetic patients recruited for the UK Prospective Diabetes Study. In addition, five silent polymorphisms, six intron variants and two polymorphisms in the 3' untranslated region of exon 22 were found with similar frequency in diabetic and control subjects. Conclusion/interpretation. Our result suggests that in white Caucasians, the SERCA3 locus possibly contributes to the genetic susceptibility to Type II diabetes [Diabetologia (1999.

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“…Work done with rabbit SERCA2 revealed that transcriptional activation in C2C12 cells was dependent upon intact Sp1 and Sp1-like sites between Ϫ284 and ϩ1 (43). The human SERCA3 gene also contains seven Sp1 and Sp1-like sites in the same region that have been suggested as being critical to transcriptional activation (12). Thus, transcription of both SERCA2 and SERCA3 is dependent upon GC-rich regions in the proximal promoter.…”

Section: Discussionmentioning

confidence: 98%

“…The sarco(endo)plasmic reticulum Ca 2ϩ ATPase (SERCA) 1 proteins translocate Ca 2ϩ from the cytosol to the sarcoplasmic reticulum or endoplasmic reticulum lumen, thereby reducing intracellular Ca 2 and refilling the sarcoplasmic/endoplasmic reticulum Ca 2ϩ stores. The cloning, expression, and functional characterization of three SERCA genes and their splicing variants have been described (3)(4)(5)(6)(7)(8)(9)(10)(11)(12).…”

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confidence: 99%

Identification of Weight-bearing-responsive Elements in the Skeletal Muscle Sarco(endo)plasmic Reticulum Ca2+ ATPase (SERCA1) Gene

Mitchell-Felton

Hunter

Stevenson

et al. 2000

Journal of Biological Chemistry

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The skeletal muscle sarco(endo)plasmic reticulum calcium ATPase (SERCA1) gene is transactivated as early as 2 days after the removal of weight-bearing (Peters, D. G., Mitchell-Felton, H., and Kandarian, S. C. (1999) Am. J. Physiol. 276, C1218-C1225), but the transcriptional mechanisms are elusive. Here, the rat SERCA1 5 flank and promoter region (؊3636 to ؉172 base pairs) was comprehensively examined using in vivo somatic gene transfer into rat soleus muscles (n ‫؍‬ 804) to identify region(s) that are both necessary and sufficient for sensitivity to weight-bearing. In all, 40 different SERCA1 reporter plasmids were constructed and tested. Several different regions of the SERCA1 5 flank were sufficient to confer a transcriptional response to 7 days of muscle unloading when placed upstream of a heterologous promoter. Two of these regions were analyzed further because they were necessary for the unloading response of ؊3636 to ؉172, as demonstrated using internal deletion constructs. Deletion analysis of these regions (؊1373 to ؊1158 and ؊330 to ؉172) suggested that unloading responsiveness corresponded to CACC sites and E-boxes. Mutagenesis of cis-elements in the first region showed that a specific CACC box (؊1262) was involved in SERCA1 transactivation and a nearby E-box (؊1248) was also implicated. Constructs containing trimerized CACC sites and E-boxes showed that the presence of both elements is required to activate transcription. This is the first identification of specific ciselements required for the regulation of a Ca 2؉ handling gene by changes in muscle loading condition.The sarco(endo)plasmic reticulum is the major organelle that regulates the Ca 2ϩ signaling associated with a multitude of cellular processes (1, 2). The sarco(endo)plasmic reticulum Ca 2ϩ ATPase (SERCA) 1 proteins translocate Ca 2ϩ from the cytosol to the sarcoplasmic reticulum or endoplasmic reticulum lumen, thereby reducing intracellular Ca 2 and refilling the sarcoplasmic/endoplasmic reticulum Ca 2ϩ stores. The cloning, expression, and functional characterization of three SERCA genes and their splicing variants have been described (3-12).At least one of the SERCA gene products is expressed in every mammalian tissue studied, emphasizing the fundamental role of this protein in cellular function. Products of the SERCA1 gene are the predominant isoforms expressed in skeletal muscle (SERCA1a adult, SERCA1b neonatal) (4, 9), and one product of the SERCA2 gene is the predominant isoform expressed in cardiac myocytes (SERCA2a (3)). The alternative splicing product of SERCA2 (SERCA2b (3)) and the products of the SERCA3 gene (3, 11) are ubiquitously expressed in muscle and non-muscle tissue but in much lower levels. SERCA expression is much higher in striated muscle than in smooth muscle or non-muscle to accommodate the large calcium fluxes associated with excitation-contraction coupling.Contractile activity has a marked effect on SERCA expression in striated muscle. Increased contractile activity leads to decreases in SERCA1 and SERCA2a express...

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Structure of the Human Sarco/Endoplasmic Reticulum Ca2+-ATPase 3 Gene

Cited by 82 publications

References 52 publications

Effect of Hailey-Hailey Disease Mutations on the Function of a New Variant of Human Secretory Pathway Ca2+/Mn2+-ATPase (hSPCA1)

Effect of Hailey-Hailey Disease Mutations on the Function of a New Variant of Human Secretory Pathway Ca2+/Mn2+-ATPase (hSPCA1)

Sequence variants of the sarco(endo)plasmic reticulum Ca 2+ -transport ATPase 3 gene (SERCA3) in Caucasian Type II diabetic patients (UK Prospective Diabetes Study 48)

Identification of Weight-bearing-responsive Elements in the Skeletal Muscle Sarco(endo)plasmic Reticulum Ca2+ ATPase (SERCA1) Gene

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