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Calcium Pumps: Why So Many?

Marisa Brini, Tito Calì, Denis Ottolini, Ernesto Carafoli

10.1002/cphy.c110034

Source: Volume 2, Issue 2, April 2012

Published online: April 2012

Full Article on Wiley Online Library



Abstract

Ca2+‐ATPases (pumps) are key to the regulation of Ca2+ in eukaryotic cells: nine are known today, belonging to three multigene families. The three endo(sarco)plasmic reticulum (SERCA) and the four plasma membrane (PMCA) pumps have been known for decades, the two Secretory Pathway Ca2+ ATPase (SPCA) pumps have only become known recently. The number of pump isoforms is further increased by alternative splicing processes. The three pump types share the basic features of the catalytic mechanism, but differ in a number of properties related to tissue distribution, regulation, and role in the cellular homeostasis of Ca2+. The molecular understanding of the function of all pumps has received great impetus from the solution of the three‐dimensional (3D) structure of one of them, the SERCA pump. This landmark structural advance has been accompanied by the emergence and rapid expansion of the area of pump malfunction. Most of the pump defects described so far are genetic and produce subtler, often tissue and isoform specific, disturbances that affect individual components of the Ca2+‐controlling and/or processing machinery, compellingly indicating a specialized role for each Ca2+ pump type and/or isoform. © 2012 American Physiological Society. Compr Physiol 2:1045‐1060, 2012.

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Figure 1. Figure 1.

Phylogenetic tree of Ca2+‐transporting ATPases. Protein sequences of P‐type ATPases of different species were aligned using ClustalW software and a phylogenetic tree was generated using TreeView. The three different branches represent the three main Ca2+‐ATPase: SERCAs and SPCAs (type IIA) and PMCAs (type IIB).
Figure 2. Figure 2.

A simplified reaction scheme of the transport cycle of Ca2+‐ATPases. The pumps exist in two main conformational states: E1 binds Ca2+ with high affinity at the cytosolic site; E2 has a low affinity for Ca2+ and thus releases it to the opposite site of the membrane. The cycle has a number of other states which have been omitted for simplicity, but which are discussed in the text. ATP phosphorylates a highly conserved aspartic acid residue allowing the translocation of Ca2+.
Figure 3. Figure 3.

Three‐dimensional structure of the SERCA pump showing the open and closed conformation in the E1 2Ca2+ and E2 (thapsigargin) states. The amino terminus is shown in blue and the carboxy terminus in red. The purple spheres (circled and numbered as I and II) represent bound Ca2+. The three cytoplasmatic domain (A, N, and P), the a‐helices in the A domain (A1‐3) and those in the transmembrane domain (M1‐M10) are indicated. M1′ is an amphipathic part of the M1 helix. M2′ is the top part of M2 helix. Docked ATP and thapsigargin (TG), as several key residues are shown. Figure modified, with permission, from 137.
Figure 4. Figure 4.

Generation of multiple SERCA isoforms by alternative splicing of the human ATP2A1‐3 genes. Exons are represented by colored boxes, introns by the black line. Thin box represents untranslated pseudoexon. 5'D1, 5'D2, and 5'D3 indicate optional splice donor sites for SERCA2a, SERCA2b, and SERCA2c transcripts, respectively. Sa‐f indicate the position of the different stop codons for the corresponding protein isoforms. The size of the protein products is indicated on the left. The boxes are not in scale. Details of the different splicings are described in the text.
Figure 5. Figure 5.

Deduced structure of the SPCA pump (in white) superimposed on that of the SERCA pump (in red). The figure shows the ten transmembrane domains of the two pumps in the lower portion of the figure and the three cytosolic protruding domains, the N (nucleotide binding) domain on the left, the P (phosphorylation) domain in the center and the A (actuator) domain on the right. Naturally, the conclusions on the SPCA pump are only guess from molecular modeling work. The image is a kind gift of Dr. L. Raeymakers (Leuven, Belgium).
Figure 6. Figure 6.

Generation of multiple SPCA1 isoforms by alternative splicing of the human ATP2C1 gene. Exons are represented by filled gray boxes and introns by the black line. 5'D1 and 5'D2 indicate splice donor sites in exon 27 for SPCA1b and SPCA1d, respectively. Sa‐d indicate the position of the different stop codons in the a‐d variants. Details of the different splicings are described in the text. The relative sizes of each splice variant is on the left.
Figure 7. Figure 7.

Deduced structure of the PMCA pump (in blue) superimposed on that of the SERCA pump (in red). The long C‐terminal tail of PMCA pump (absent in the SERCA pump) is not included in the superimposition. See legend for Figure 5 for the explanation of the different pump domains. The image is a kind gift of Dr. S. Pantano (Montevideo, Uruguay).
Figure 8. Figure 8.

Alternative splicing of rat ATP2B1‐4 genes generating multiple PMCA isoforms. The scheme summarizes the splice variants at sites A (Panel A) and C (Panel B). Exons are represented by colored boxes and introns by the black line. Details on the different splicings are described in the text. The numbers in the boxes represent the nucleotides number of each rat exon. Human exons are slightly different in the number of nucleotides, but display essentially the same splice variants.


Figure 1.

Phylogenetic tree of Ca2+‐transporting ATPases. Protein sequences of P‐type ATPases of different species were aligned using ClustalW software and a phylogenetic tree was generated using TreeView. The three different branches represent the three main Ca2+‐ATPase: SERCAs and SPCAs (type IIA) and PMCAs (type IIB).



Figure 2.

A simplified reaction scheme of the transport cycle of Ca2+‐ATPases. The pumps exist in two main conformational states: E1 binds Ca2+ with high affinity at the cytosolic site; E2 has a low affinity for Ca2+ and thus releases it to the opposite site of the membrane. The cycle has a number of other states which have been omitted for simplicity, but which are discussed in the text. ATP phosphorylates a highly conserved aspartic acid residue allowing the translocation of Ca2+.



Figure 3.

Three‐dimensional structure of the SERCA pump showing the open and closed conformation in the E1 2Ca2+ and E2 (thapsigargin) states. The amino terminus is shown in blue and the carboxy terminus in red. The purple spheres (circled and numbered as I and II) represent bound Ca2+. The three cytoplasmatic domain (A, N, and P), the a‐helices in the A domain (A1‐3) and those in the transmembrane domain (M1‐M10) are indicated. M1′ is an amphipathic part of the M1 helix. M2′ is the top part of M2 helix. Docked ATP and thapsigargin (TG), as several key residues are shown. Figure modified, with permission, from 137.



Figure 4.

Generation of multiple SERCA isoforms by alternative splicing of the human ATP2A1‐3 genes. Exons are represented by colored boxes, introns by the black line. Thin box represents untranslated pseudoexon. 5'D1, 5'D2, and 5'D3 indicate optional splice donor sites for SERCA2a, SERCA2b, and SERCA2c transcripts, respectively. Sa‐f indicate the position of the different stop codons for the corresponding protein isoforms. The size of the protein products is indicated on the left. The boxes are not in scale. Details of the different splicings are described in the text.



Figure 5.

Deduced structure of the SPCA pump (in white) superimposed on that of the SERCA pump (in red). The figure shows the ten transmembrane domains of the two pumps in the lower portion of the figure and the three cytosolic protruding domains, the N (nucleotide binding) domain on the left, the P (phosphorylation) domain in the center and the A (actuator) domain on the right. Naturally, the conclusions on the SPCA pump are only guess from molecular modeling work. The image is a kind gift of Dr. L. Raeymakers (Leuven, Belgium).



Figure 6.

Generation of multiple SPCA1 isoforms by alternative splicing of the human ATP2C1 gene. Exons are represented by filled gray boxes and introns by the black line. 5'D1 and 5'D2 indicate splice donor sites in exon 27 for SPCA1b and SPCA1d, respectively. Sa‐d indicate the position of the different stop codons in the a‐d variants. Details of the different splicings are described in the text. The relative sizes of each splice variant is on the left.



Figure 7.

Deduced structure of the PMCA pump (in blue) superimposed on that of the SERCA pump (in red). The long C‐terminal tail of PMCA pump (absent in the SERCA pump) is not included in the superimposition. See legend for Figure 5 for the explanation of the different pump domains. The image is a kind gift of Dr. S. Pantano (Montevideo, Uruguay).



Figure 8.

Alternative splicing of rat ATP2B1‐4 genes generating multiple PMCA isoforms. The scheme summarizes the splice variants at sites A (Panel A) and C (Panel B). Exons are represented by colored boxes and introns by the black line. Details on the different splicings are described in the text. The numbers in the boxes represent the nucleotides number of each rat exon. Human exons are slightly different in the number of nucleotides, but display essentially the same splice variants.

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Further Reading
 1.Calcium Signalling and disease. Molecular Pathology of Calcium. In: Ernesto Carafoli, Marisa Brini, editors. Subcellular Biochemistry. New York: Springer Science + Business Media, 2007, Vol. 45.

Further Reading

Calcium Signalling and disease. Molecular Pathology of Calcium. Subcellular Biochemistry vol.45 Edited by Ernesto Carafoli and Marisa Brini. 2007 Springer


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Article Title: Calcium Pumps: Why So Many?
 

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Marisa Brini, Tito Calì, Denis Ottolini, Ernesto Carafoli. Calcium Pumps: Why So Many?. Compr Physiol 2012, 2: 1045-1060. doi: 10.1002/cphy.c110034