The Ca Pumps of the Endoplasmic Reticulum and Golgi Apparatus
Total Page：16
File Type：pdf, Size：1020Kb
Downloaded from http://cshperspectives.cshlp.org/ on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press The Ca2þ Pumps of the Endoplasmic Reticulum and Golgi Apparatus Ilse Vandecaetsbeek, Peter Vangheluwe, Luc Raeymaekers, Frank Wuytack, and Jo Vanoevelen Laboratory of Ca2þ-transport ATPases, Department of Molecular Cell Biology, K.U.Leuven, B-3000 Leuven, Belgium Correspondence: [email protected] The various splice variants of the three SERCA- and the two SPCA-pump genes in higher ver- tebrates encode P-type ATPases of the P2A group found respectively in the membranes of the endoplasmic reticulum and the secretory pathway.Of these, SERCA2b and SPCA1a represent the housekeeping isoforms. The SERCA2b form is characterized by a luminal carboxy termi- nus imposing a higher affinity for cytosolic Ca2þ compared to the other SERCAs. This is medi- ated by intramembrane and luminal interactions of this extension with the pump. Other known affinity modulators like phospholamban and sarcolipin decrease the affinity for Ca2þ. The number of proteins reported to interact with SERCA is rapidly growing. Here, we limit the discussion to those for which the interaction site with the ATPase is specified: HAX-1, calumenin, histidine-rich Ca2þ-binding protein, and indirectly calreticulin, cal- nexin, and ERp57. The role of the phylogenetically older and structurally simpler SPCAs as transporters of Ca2þ, but also of Mn2þ, is also addressed. ll cells invest a considerable part of their pumps can be discerned in Eumetazoa: the Atotal energy budget in active transport to SERCA-,theSPCA-,andthePMCA-type.Where- keep up transmembrane (TM) ion gradients as ancestral representatives of each type are (Rolfe and Brown 1997). Prokaryotes already recognized in some Eubacteria and Archaea, it evolved P-type ion-transport ATPases/ion is also remarkable that some Eukaryotes have pumps to that aim (Axelsen and Palmgren apparently lost either SERCA or SPCA pumps. 1998). The name P-type refers to the transient Yeast for instance lacks SERCA pumps whereas transfer of the g-phosphate group of ATP to a plants thrive well without SPCAs (Mills et al. highly conserved aspartate group in the enzyme 2008). The SERCA pumps, which are found in forming a phospho-intermediate. This auto- the endoplasmic reticulum (ER) or in the sar- phosphorylation is an important step in the coplasmic reticulum (SR) of eukaryotic cells pump’s catalytic cycle (Kuhlbrandt 2004). and the evolutionary older secretory pathway Based on amino-acid sequence comparisons ATPases (SPCA) found in the Golgi apparatus, and on the exon/intron layout of the corre- are closely related to each other and together 2þ sponding genes, three types of P-type Ca belong to the P2A subfamily. They form the Editors: Martin D. Bootman, Michael J. Berridge, James W. Putney, and H. Llewelyn Roderick Additional Perspectives on Calcium Signaling available at www.cshperspectives.org Copyright # 2011 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a004184 Cite this article as Cold Spring Harb Perspect Biol 2011;3:a004184 1 Downloaded from http://cshperspectives.cshlp.org/ on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press I. Vandecaetsbeek et al. topic of this review. The plasma-membrane 500 mM) luminal ER Ca2þ concentration. The Ca2þ-pumps (PMCA), on the other hand, ER not only serves as a useful Ca2þ store for appear to be phylogenetically the oldest of the the release of Ca2þ that activates an impressive three and form the P2B-subfamily branch. number of cellular activities (e.g., contraction, PMCAs are addressed in an article by Brini fertilization, insulin release, etc.) but it also and Carafoli (2009). Some further information creates the luminal environment necessary for on the evolution of the three types of ATPases almost all local enzyme activities (such as was recently reviewed by Palmgren and Axelsen protein folding and synthesis of lipids and ste- (1998) and Vangheluwe et al. (2009). Of the roids) and that controls cell fate (proliferation, three families, only SERCA pumps translocate apoptosis, growth, or differentiation) (Wuytack two Ca2þ ions and hydrolyze one ATP for each et al. 2002). catalytic turnover. They possess two Ca2þ- The muscle variant SERCA2a removes the transport sites: site I and site II; the numbers Ca2þ stimulus for contraction by pumping specify the sequence of filling of the respective myoplasmic Ca2þ into the SR and thereby sites. The single Ca2þ-binding site of the SPCA determines the Ca2þ load of the SR, which in and PMCA pumps structurally corresponds to turn determines the amount of Ca2þ that can site II of SERCA (Toyoshima 2009). be released for the next contraction. Together, SERCA2a is a major determinant of the speed and force of cardiac contraction and relaxation 2þ THE UBIQUITOUS SERCA2 Ca PUMP (Periasamy and Huke 2001). SERCA2 expres- SERCA2 Splicing Variants sion is reduced in end-stage heart failure, contributing to an impaired contractility of Vertebrates generate multiple SERCA isoforms the heart (Hasenfuss et al. 1994). as a result of alternative processing of the Ablation in mice of the two Atp2a2 alleles is transcripts of three paralogous SERCA genes incompatible with life (Periasamy et al. 1999). (ATP2A1-3) (Brini and Carafoli 2009). Inverte- But in light of the central role SERCA2a exerts brates typically have only a single SERCA gene in the heart, it is quite surprising that in an that is orthologous to the vertebrate housekeep- inducible cardiac-specific knock-out mouse ing SERCA2. The two major vertebrate SERCA2 model at 4 weeks following Atp2a2 gene dele- protein isoforms are the housekeeping SER- tion, cardiac function remained near normal CA2b and the more specialized SERCA2a in spite of the drop of the myocardial SERCA2 isoform. The latter is found in slow skeletal levels below 5% of controls (Andersson et al. muscle and cardiac muscle, but is also expressed 2009). However, end-stage heart failure devel- in lower amounts in smooth muscle and in oped at 7 weeks. These results show the remark- neuronal cells (Vandecaetsbeek et al. 2009a). able power of a compensatory (albeit ultimately Recently novel SERCA2c (Dally et al. 2006) failing) response to such a major acute re- and SERCA2d (Kimura et al. 2005) isoforms duction in SERCA2 function (Andersson et al. were discovered in the heart, but are expressed 2009). The effect of heterozygous knock-out at low levels and their physiological meaning of Atp2a2 in mice is also paralleled by com- remains to be further explored. pensatory responses, with only slight impact on cardiac contractility and relaxation without eliciting cardiac disease (Periasamy et al. 1999; Physiological Role of SERCA2 Ji et al. 2000). With age, these heterozygotes The housekeeping SERCA2b Ca2þ pump serves are prone to develop squamous cell tumors, a dual role. By translocating Ca2þ from the which supports the notion that altered Ca2þ cytosol into the lumen of the ER, it restores homeostasis plays a significant role in cancer the cytosolic Ca2þ concentration to its low (Liu et al. 2001; Prasad et al. 2005). Likewise, resting level (circa 100 nM). At the same time, humans lacking one functional ATP2A2 allele SERCA2b maintains a sufficiently high (circa do not develop cardiomyopathy (Tavadia et al. 2 Cite this article as Cold Spring Harb Perspect Biol 2011;3:a004184 Downloaded from http://cshperspectives.cshlp.org/ on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press Intracellular Ca2þ Pumps 2001), but the effect of reduced Ca2þ uptake even if the overall sequence similarity is low activity is manifested in keratinocytes, where it (Fig. 1). Three cytosolic domains can be recog- triggers the onset of the skin disorder of Darier nized in the P-type ATPases: a nucleotide- (Sakuntabhai et al. 1999). binding (N), phosphorylation (P), and actuator Whereas previous studies suggest that (A) domain (Fig. 1). ATP binds on the N- changes in SERCA2 expression levels are rea- domain, whereas the P-domain drives ATP sonably well tolerated in the heart (Ji et al. hydrolysis leading to phosphorylation of a 2000; Tavadia et al. 2001), other studies point highly conserved aspartate in the P-domain. to a more critical regulation of the apparent The A-domain then contains a conserved gluta- affinity of the Ca2þ pump for cytosolic Ca2þ mate that catalyzes the dephosphorylation of ions (MacLennan and Kranias 2003; Vande- the P-domain (Kuhlbrandt 2004; Vangheluwe caetsbeek et al. 2009a; Sipido and Vangheluwe et al. 2009). The large headpiece is intimately 2010). For normal cardiac function, the affinity connected with and partially embedded in the of SERCA2a in the cardiac SR needs to be con- TM region that contains the ion-binding sites. trolled within a tight window (Vangheluwe et al. This connection assures tight coupling between 2005a; Vandecaetsbeek et al. 2009a). Genetic ATPhydrolysis in the cytosolic domains and ion manipulations in mouse that lead to the expres- transport across the membrane. Surprisingly, sion of the high Ca2þ-affinity variant SERCA2b the overall structure of the TM region is also in the cardiomyocyte instead of the normal highly conserved with only subtle differences SERCA2a, triggers cardiac hypertrophy and accounting for ion specificity (Gadsby 2007). heart failure (Ver Heyen et al. 2001; Vangheluwe The accessibility of the TM Ca2þ-binding sites et al. 2006b). Likewise, in humans (Haghighi in SERCA1a is controlled by both a cytosolic et al. 2003), but not in mice (Luo et al. 1994), and a luminal gate, which are under control of the increased Ca2þ affinity resulting from the the phosphorylation and dephosphorylation absence of phospholamban (PLN, i.e., an affin- events, respectively, in the headpiece (Moller ity modulator of the pump, discussed below) et al. 2005; Toyoshima 2008; Toyoshima 2009). triggers heart failure (Haghighi et al. 2003). Moreover, a feedback mechanism associated On the contrary, a chronic reduction in the with ion binding guarantees that ATPhydrolysis Ca2þ affinity triggered by a higher activity of can only occur when ions are bound.