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Volume 272, Number 46, Issue of November 14, 1997 pp. 28815-28818
§,¶ and
From the 
Banting and Best Department of Medical
Research, C. H. Best Institute, University of Toronto, Toronto,
Ontario M5G 1L6, Canada and the 
National Institute for Medical
Research, The Ridgeway, Mill Hill, London NW71AA, United Kingdom
Function
Structure
Structure/Function Relationships
Mechanism of Ca2+ Transport
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
Function Ca2+ pumps, together with Ca2+
release channels, form ubiquitous Ca2+ regulatory systems
in muscle and non-muscle cells. The sarco(endo)plasmic reticulum
Ca2+-ATPases
(SERCA)1 and the plasma
membrane Ca2+-ATPases have the highest affinity for
Ca2+ removal from the cytoplasm and, together, set resting
cytoplasmic Ca2+ concentrations. Three differentially
expressed genes encode SERCA proteins (1). SERCA1a and -1b are
expressed in fast-twitch skeletal muscle, but loss of SERCA1 function
in Brody disease is sufficiently compensated to preserve life (2).
SERCA2a is the cardiac/slow-twitch isoform, whereas SERCA2b, with a
C-terminal extension, is expressed in smooth muscle and non-muscle
tissues. It is almost certainly an essential gene. SERCA3 is expressed in a limited set of non-muscle tissues, including endothelial, epithelial, and lymphocytic cells and platelets, and its knockout is
not lethal (3).
SERCA enzymes are typical of the class of P-type ATPases, which form a
phosphoprotein intermediate and undergo conformational changes during
the course of ATP hydrolysis (4, 5). Some of the conformational states
can be stabilized, either by adjustment of reaction conditions or
through mutagenesis, and characterized as intermediates in the overall
reaction cycle (Fig. 1A). The phosphorylated intermediate,
E1P(Ca)2, can phosphorylate ADP, whereas E2P can only react with water. The
formation of E1P requires that two high affinity
Ca2+ binding sites be occupied. The enzyme is then
phosphorylated by ATP and, concomitantly, the two Ca2+ ions
are occluded and can no longer exchange with cytoplasmic Ca2+. The rate-limiting transition to
E2P is accompanied by loss of Ca2+
into the lumen, the affinity having fallen by 3 orders of magnitude. Hydrolysis of E2P and regeneration of the high
affinity Ca2+ binding sites
(E1(Ca)2) complete the reversible
cycle. High lumenal Ca2+ drives the formation of
E1P from phosphate (Pi), and its
effect on the level of E1P led Jencks (5, 6) to
postulate a second set of Ca2+ binding sites on the lumenal
surface. Proton countertransport, involving the exchange of one
H+ per Ca2+, has been shown during the reaction
cycle (7), emphasizing the similarity between Ca/H- and Na/K- or
H/K-ATPases.
[View Larger Version of this Image (38K GIF file)]
Structure Two-dimensional arrays and helical tubes of SERCA1a were first
produced by treatment of native membranes with decavanadate, and in a
negative stain, these yielded a three-dimensional structure with a
resolution of 25 Å (8). At high Ca2+ concentration, thin
plates were obtained, which have given a 6-Å projection map (8, 9).
Thapsigargin, a SERCA-specific inhibitor (10) that appears to bind to
the M3 transmembrane sequence (11), stabilizes the
E2 state of the pump and promotes formation of
helical tubes (12). These are also compatible with bound nucleotides,
but they are disrupted by low Ca2+. In contrast, the thin
plates, probably corresponding to
E1(Ca)2, are disrupted by
thapsigargin and by nucleotides.
Current modeling is based on a 14-Å structure (Fig. 1B)
obtained by cryoelectron microscopy of decavanadate tubes (13). A large
cytoplasmic head is linked to the membrane by a narrow stalk. The
protein within the membrane is divided into two major densities,
A1 and A2, lying beneath the stalk, and two minor
densities, B and C, to one side. A recent
structure for the CrATP-bound complex (14) locates the nucleotide
binding site in the groove on the underside of the head (Fig.
1B).
[View Larger Version of this Image (77K GIF file)]
Two main segments of sequence (Fig. 2) form the cytoplasmic head and
stalk (Fig. 1B) (15). The segment of about 130 residues following the M1/M2 hairpin, likely to form a 7-8-membered The bulk of the central domain is predicted to be a mixture of
The C terminus of the nucleotide binding domain, close to the top of
the stalk, is highly conserved and may form a subdomain, which by
analogy with some kinases could form a hinge between phosphorylation
and nucleotide binding domains. Several sites in this hinge region are
labeled by The sequences of all P-type ion pumps, except for the shorter ones
mostly specific for copper or cadmium, show a common pattern of
hydrophobicity (21). A 10-transmembrane helix model for SERCA1a and
SERCA2a (Fig. 3) was proposed on the
basis of analysis of hydrophobicity (15). It has received growing
support (16, 20) from well controlled experiments with proteases,
antibodies, and sulfhydryl labels, which showed the N and C termini to
be cytoplasmic and the M7/M8 loop to be lumenal, and from proteolysis of intact vesicles with trypsin, which led to the isolation of hydrophobic fragments corresponding to M1/M2, M3/M4, M5/M6, and M7/M8
(22). Evidence for the M9/M10 hairpin comes from experiments involving
in vitro insertion of this hairpin into membranes using eukaryotic expression vectors encoding a series of membrane inserts (23). The volume of the transmembrane domain, as deduced from a 14-Å
structure (21), will accommodate 10-transmembrane helices.
[View Larger Version of this Image (39K GIF file)]
Tentative assignments of the 10-transmembrane helices (Fig. 3) to the
four transmembrane regions, A1, A2, B, and C (Fig. 1B), have
been made (13, 21) but will be subject to refinement. M2, M3, M4, and
M5, which underlie the stalk, must occupy part of A1, but differing
slopes of helices below the stalk would permit crossover to other
regions. Since M4, M5, and M6 must cluster to form the Ca2+
binding sites (see below), M6 must lie close, making it a strong candidate for A2. This places the entrance to the Ca2+
binding sites to one side of the stalk on the boundary between A1 and
A2. The small lumenal domain joins the A2 region to the B region. Since
the only long loop (38 residues) on that side of the membrane joins M7
to M8, the M7/M8 hairpin can be associated with both A2 and B. Cytoplasmic densities near the membrane surface, above the A1 and C
regions, could represent N and C termini, respectively. If so, M9 and
M10 might occupy the C region, whereas M1 might be located in A1. A
second approach to helix arrangement involves analysis of conserved
(internal) and variable (lipid-exposed) sites in the transmembrane
sequences of diverse Ca2+ pumps (21).
Structure/Function Relationships Mutagenesis
Site-directed mutagenesis has provided key insights into
structure/function relationships in SERCA1 and SERCA2 (24, 25). In
these experiments, mutated cDNA is expressed transiently in heterologous cell culture, microsomal vesicles are isolated, and overall and partial reactions of ATP-dependent
Ca2+ transport are assayed. In Fig. 3, loss of function,
reduced function, and unaltered function mutants in SERCA1 or SERCA2
are located relative to predicted structural domains.
Two principles were key to
the characterization of two Ca2+ binding sites through
mutagenesis. These were: (i) that binding of Ca2+ to the
first site (site I), presumably the more distal from the cytoplasm,
leads to cooperative binding to the second, presumably more proximal
site (site II) (6, 26); and (ii) occupation of both Ca2+
binding sites I and II is required for "forward" phosphorylation from ATP, whereas occupation of site I alone is sufficient to convert
Pi-reactive E2 conformations to
non-reactive E1, thereby depleting the substrate
for "reverse" phosphorylation from Pi (25, 27) (Fig.
1).
The initial mutagenic screen identified Glu309 in M4,
Glu771 in M5, Asn796, Thr799, and
Asn800 in M6, and Glu908 in M8 as potential
Ca2+ binding ligands (28). Mutants were Ca2+
transport negative and not phosphorylated by ATP plus Ca2+;
for all but N796A, high Ca2+ did not prevent reverse
phosphorylation, suggesting that mutation of any of these residues
would lead to the loss of at least one Ca2+ binding site.
The first measurements of reverse phosphorylation were carried out at
pH 6.4, but later measurements, carried out at neutral pH, showed
normal Ca2+ inhibition of phosphorylation from
Pi for mutants E309Q as well as for N796A (29, 30). These
results are consistent with retention of Ca2+ binding site
I, implying that both Glu309 and Asn796
contribute to site II. This conclusion was supported by the direct demonstration that mutant E309Q retains a single Ca2+
binding site and that, at pH 6.4, Ca2+ can gain access to
the site (presumably from the lumenal side) in detergent-disrupted
membranes but not in intact vesicles (31).
By contrast, mutants E771Q, T799A, and E908A showed similar, very low
Ca2+ affinity in both forward and reverse phosphorylation
assays, implying that site I was disrupted (29, 30). Mutant D800N showed reduced Ca2+ affinity in both assays but to
different extents, suggesting that Asp800 was contributing
to both sites. In the plasma membrane Ca2+-ATPases, which
transport only a single Ca2+, the residues homologous to
Glu771, Thr799, and Glu908, all
assigned to site I, are replaced by Ala, Met, and Gln, respectively (32).
Mutants E309N, E771Q, N796A, T799A, D800N, as well as G310P and G801V
(but not G770A) lost the ability to occlude Ca2+ in the
presence of CrATP (25, 30, 33). By contrast, E908Q retained full
function (mutants E309Q, E771Q, and D800N are non-functional), and the
mutant E908A retained Ca2+ occlusion and transport with low
affinity (25). These observations, together with the fact that
Glu908 is the only mutation-sensitive residue in all of M8
(34), suggest, at best, a peripheral role in Ca2+ binding
and transport for Glu908 and for helix M8.
The location of Ca2+ ligands on separate helices means that
correct helix orientation will be crucial for the formation of high affinity Ca2+ binding sites and that reorientation coupled
to movements of the cytoplasmic domains could cause occlusion and
changes in Ca2+ affinity. The packing of these helices is
being studied by introduction of pairs of cysteines into selected
positions and assay of the expressed products for cross-linking (35).
Cross-links observed at different tiers of helices M4 and M6
(A305C/L793C, E309C/N796C, T317C/A804C) are in relative positions
i, i + 4, i + 12, favoring packing of
M4 and M6 as a right-handed supercoil at an angle of about 40°. It
would normally be difficult to maintain such a large angle over several
turns of helix, but the presence of four prolines and three glycines
could permit sufficient curvature.
Insights from cross-linking data provide a possible solution to a
problem raised by the assignment of Ca2+ ligands to two
sites in a model with the two sites stacked one above the other (Fig.
3A) (25, 26). Stacking leads to the placement of
Asn796 in the more cytoplasmic site (site II), even though
it is the most lumenal ligand. Andersen (25) suggested that this might be resolved if M6 were not fully helical. However, if M4 and M6 are
oriented to optimize cross-links between them, as indicated in Fig.
3B (cross-section), then Glu309,
Asn796, and Asp800 would be positioned near the
M4/M6 contact, whereas Thr799 would lie to the right of
this contact. If M5 is placed so that Glu771 is apposed to
Thr799 in M6, then the ligands between M4 and M6 are those
assigned to site II (Glu309, Asn796), whereas
the ligands between M5 and M6 are those assigned to site I
(Glu771, Thr799). Asp800 in M6
would be in a position to contribute to both sites. This new
"side-by-side sites" model has the advantage that
Asn796, which lies below Asp800 in the helix
(Fig. 3B, oblique view), can contribute to site II without
distortion of the M5/M6 helices. Positioning of M8 so that
Glu908 would be apposed to site I would permit its
peripheral contribution to that site.
The side-by-side sites model would mean that the pathway of
Ca2+ translocation would follow an angular course (Fig.
3B, schematic, large arrows) rather
than a direct pathway (Fig. 3A, schematic). In
both schemes, occupation of site I by Ca2+ initiates
cooperative binding to site II, locking in Ca2+ at site I,
but in the side-by-side sites model Ca2+ entry to site II
could be through an independent pathway (small arrows).
Randomization could follow when links are weakened following occlusion,
and exit could be independent or through a single pathway (small or large arrows). There is, however,
evidence for interaction during exit, since occupation of the more
lumenal site (presumably site I) prevents dissociation from the more
cytoplasmic site, the inverse of the behavior at the cytoplasmic
surface (6).
Scanning mutagenesis revealed that relatively small residues lying
within discrete patches on the helix surfaces in the three turns
surrounding the five Ca2+ ligands in M4, M5, and M6 (Fig.
2), when mutated, block pump activity at a variety of different steps
in the reaction cycle (34). By contrast, only a few of the residues in
the top and bottom two turns of M4, M5, and M6 are sensitive to
mutation and, overall, are much larger, especially in M5. This
concentration of small residues in the middle of the membrane could
provide a polar cavity with the larger surface residues controlling
access to it. In M5 the replacement of the bulky
Tyr763, above Glu771 and near the top of
M5, by the tiny Gly gives an uncoupled mutant (36) in which
Ca2+ escapes to the cytoplasm before it can be translocated
(Fig. 1). At the bottom of M4, the mutation-sensitive
Lys297 (28, 37) has a suitable charge, size, and position
to function as a gating residue for release of Ca2+ to the
lumen.
A double mutant, D813A/D818A, in the M6/M7 loop causes loss of
Ca2+-ATPase activity and loss of the ability of Ca2+ to
prevent phosphorylation from Pi (38). This loop could form part
of the entry portal to Ca2+ binding sites I and II or be part
of the gate operating during occlusion.
A motif in the mutation-sensitive regions of M4 and M6, (E/D)GLPA(V/T),
suggests a sequence duplication (34). A sequence in the same region of
M5 (SSNVGE) is related when reversed. However, since there is no
symmetry in the ligands contributed by M4, M5, and M6 to the
Ca2+ binding and transport site, the significance of the
similarity in this triad of binding sequences is not clear.
Mutagenesis of highly conserved sequences
in the large cytoplasmic domain between M4 and M5 showed that many
mutants did not form phosphoenzyme intermediates from either ATP or
Pi, consistent with, but not proving, their involvement in
ATP binding (39, 40). Measurement of ATP binding affinity through
competitive inhibition of [ The crucial labile intermediate
E1P(Ca)2 normally loses its ADP
sensitivity and its Ca2+ within a few hundred milliseconds,
but the intermediate can be stabilized. A number of site-directed
mutations in all the major domains block this step (24, 25), showing
that the conformational effects accompanying E1P
Chemical and Physical Probes of Conformational Changes
The wide separation of phosphorylation sites and Ca2+
sites within the ATPase molecule implies long distance transmission of conformational effects, whereas the rigid domains and long helices provide a plausible medium for their transmission. Although the nature
and extent of conformational changes cannot be defined without a
detailed structure, a variety of chemical and physical methods have
been employed to detect conformational changes and, in some cases, to
follow their kinetics. Cross-linking of the hinge domain to the N
terminus of the nucleotide binding domain blocks
E1P Mechanism of Ca2+ Transport A basic mechanism for a P-type pump, illustrated in Fig.
4, takes into account the characteristics
of the transport process and the structure of the pump (24). The
Ca2+ binding and translocation sites are in a cavity
between M4, M5, and M6, where they are formed by the precise
juxtaposition of Ca2+ binding residues located in these
three helices. Access to the cavity is controlled by interactions
between the larger residues near the cytoplasmic ends of the helices.
The phosphorylation-induced domain movements that close off cytoplasmic
access to the cavity will initiate occlusion. If such movements
involved M4, M5, or M6, they might also be expected to disrupt the
precise placement of the ligands required to form high affinity sites,
so that, after occlusion, the two Ca2+ ions would be less
firmly bound and capable of exchanging their positions, consistent with
kinetic observations (49). Further long range, phosphorylation-induced
domain movements will open the exit gate, permitting release of weakly
bound Ca2+ to the lumen. Later conformational
changes will result in dephosphorylation of E2P
and reformation of E1(Ca)2,
completing the Ca2+ transport cycle.
[View Larger Version of this Image (77K GIF file)]
Fig. 1.
A, reaction cycle for
Ca2+ transport by SERCA pumps, illustrating points where
mutations either block Ca2+ transport at different stages
(1, Ca2+ binding or affinity; 2, ATP
binding; 3, phosphorylation; 4,
E1P 
E2P;
5, E2P dephosphorylation) or release
occluded Ca2+ to the cytoplasmic surface (6,
uncoupling). Parentheses around Ca2+ or
H+ indicate occlusion. B, a model of SERCA1a
structure in the absence of ATP and Ca2+. The surfaces of
the bilayer are indicated by the two shadow planes.
(Reprinted with permission from Nature (13), copyright 1993, MacMillan Magazines Ltd.)
Fig. 2.
A planar illustration of the structure of
SERCA1a in which the amino acid sequence is laid out in accordance with
assigned domains and probable secondary structure (15) (stacked
sequences of three or four residues represent 
-helices, zigzag
alternations represent 
-strands, and linear sections represent
loops). Mutated residues are color coded as follows:
red, loss of function; yellow, partial loss of
function; green, retention of function. Many of the
mutations in the sequence between residues 365 and 412 were carried out
with SERCA2a.
-strand domain, is linked by long, amphipathic helices, S2 and S3, to M2 and
M3. A central segment of about 440 residues forms the main head region.
It includes the phosphorylation site at Asp351 and widely
separated residues such as Lys492, Lys515,
Cys674, Lys684, Asp703, and
Asp707, which are affinity labeled by various nucleotide
analogues in either Ca2+ or homologous Na/K-ATPases (16).
The N and C termini of the central domain form stalk helices S4 and S5,
which link M4 to the phosphorylation site and M5 to the hinge
region.
-helices and -strands, which alternate fairly regularly in the
C-terminal half, a characteristic associated with nucleotide binding,
but less regularly in the N-terminal half, referred to as the
phosphorylation domain. The phosphorylation domain extends to the
variable sequence preceding Lys492, which is labeled by
8-azido-TNP-ATP (17), and is likely to be part of the nucleotide
binding domain. On the basis of a 20-residue Walker B region and an
overall -- pattern of secondary structure, kinase-related
folds in the nucleotide binding region were proposed (18). However, the
inclusion of Lys492 implicated an extra antiparallel
-strand in this domain, which together with immunological evidence
for an exposed epitope on the central strand of the -sheet (19, 20)
suggests that this region has a new fold specific to P-type pumps.
-phosphate-linked affinity labels, suggesting that it is
close to the phosphorylation site (16).
Fig. 3.
Alternative models of the location of the two
Ca2+ binding sites within transmembrane helices M4, M5, and
M6. A, assignment of ligands to "stacked"
Ca2+ binding sites (27, 29, 30). B, different
views (schematic, cross-section, and oblique) of a "side-by-side"
placing of Ca2+ binding sites, consistent with
cross-linking results and with a helical structure for M6 (35).
E4, Glu309 in M4;
E5, Glu771 in M5;
N6, Asn796 in M6;
T6, Thr799 in M6;
D6, Asp800 in M6;
E8, Glu908 in M8. Ca2+
binding ligands are indicated in red, whereas
Ca2+ is indicated in yellow. In the schematic
view of the side-by-side model, the possibility of additional or
alternative entry and exit sites is indicated by gray
arrows. The oblique view consists of a series of tilted discs
representing the seven tiers of the helical nets illustrated in Fig. 2.
This view clarifies the proposed geometry of the sites but does not
show the proposed right-handed coiling of the helices.
Thr799 in M6 is partially obscured.
-32P]8-azido-TNP-ATP
photolabeling is a promising recent assay (41). With this assay,
mutants of Phe487, Arg489, and
Lys492 were found to have altered ATP dependence of ATPase
activity in low, intermediate, and high ATP concentration ranges,
showing their involvement in both catalytic and regulatory ATP binding. Mutants in Phe487 also failed to show
CrATP-dependent Ca2+ occlusion.
E2P involve all of these domains. Mutants that affect hydrolysis of E2P have so far been
found only in M4, M5, and M6, implying that a limited, long range
interaction between cytoplasmic and transmembrane sites controls this
step.
E2P (42),
providing evidence for essential domain movements. Analysis of x-ray
diffraction following the photolysis of caged ATP (43) or comparisons
of structural features of the enzyme crystallized in two different
conformations (44) provide evidence for large global changes consistent
with domain movements. Large domain movements, however, are not
reflected in changes in CD (45), in intrinsic fluorescence, or in
excitation energy transfer between bound dyes (46). FTIR difference
spectra in which absorption bands can be assigned to specific bond
types (8, 47, 48) show that 10-15 residues may be involved and that
the observed kinetic constants are independent of the absorption band
used. FTIR results provide direct evidence for small conformational changes accompanying Ca2+ binding, ATP binding,
E1P E2P, and
hydrolysis of E2P.
Fig. 4.
Model illustrating the mechanism of
Ca2+ transport by SERCA1. A, the structural
model (Fig. 1B) is skeletonized to reveal some of the
interacting domains. M4, S4, and the phosphorylation domain are
blue; the nucleotide binding/hinge domain, S5, and M5 are
pink; M6 is yellow; ATP is green;
Ca2+ is red. B, the transmembrane
domain is simplified by removal of all helices but M4 and M5 so that
the essential contribution of M6 to the Ca2+ binding sites
must be imagined. In the E1 conformation, high affinity
Ca2+ binding sites located near the center of helices M4,
M5, and M6 are accessible to cytoplasmic Ca2+ but not to
lumenal Ca2+. C, phosphorylation from ATP,
following the occupation of both sites by Ca2+, leads to
linked movements of both cytoplasmic and transmembrane domains,
resulting in occlusion through closure of the entry gate. Ca2+ is now contained in a polar cavity formed near the
center of the transmembrane domain by relatively small amino acids and
blocked from exit by the juxtaposition of relatively large residues at both ends of the transmembrane helices. D, further
conformational changes open the gate allowing exit of the two
Ca2+ ions to the lumen. In this conformation
Ca2+ affinity is very low. This conformation also activates
dephosphorylation and returns the pump to the high Ca2+
affinity form, completing the cycle. (Copyright 1997, Alice Y. Chen.)
FOOTNOTES
(3)-O-(2,4,6-trinitrophenyl)adenosine 5-triphosphate; FTIR, Fourier-transform infrared spectroscopy.
ACKNOWLEDGEMENTS
We thank Dr. David L. Stokes for discussion, critical reading of the manuscript, and sharing of recent structural information and Alice Y. Chen for illustrations in Fig. 4.
REFERENCES
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M. Jidenko, R. C. Nielsen, T. L.-M. Sorensen, J. V. Moller, M. le Maire, P. Nissen, and C. Jaxel Crystallization of a mammalian membrane protein overexpressed in Saccharomyces cerevisiae PNAS, August 16, 2005; 102(33): 11687 - 11691. [Abstract] [Full Text] [PDF]
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G. Wang, K. Yamasaki, T. Daiho, and H. Suzuki Critical Hydrophobic Interactions between Phosphorylation and Actuator Domains of Ca2+-ATPase for Hydrolysis of Phosphorylated Intermediate J. Biol. Chem., July 15, 2005; 280(28): 26508 - 26516. [Abstract] [Full Text] [PDF]
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J. D. Clausen and J. P. Andersen Functional Consequences of Alterations to Thr247, Pro248, Glu340, Asp813, Arg819, and Arg822 at the Interfaces between Domain P, M3, and L6-7 of Sarcoplasmic Reticulum Ca2+-ATPase: ROLES IN Ca2+ INTERACTION AND PHOSPHOENZYME PROCESSING J. Biol. Chem., December 24, 2004; 279(52): 54426 - 54437. [Abstract] [Full Text] [PDF]
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R. A. Christensen, A. Shtifman, P. D. Allen, J. R. Lopez, and H. W. Querfurth Calcium Dyshomeostasis in {beta}-Amyloid and Tau-bearing Skeletal Myotubes J. Biol. Chem., December 17, 2004; 279(51): 53524 - 53532. [Abstract] [Full Text] [PDF]
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A. R. Tupling, A. O. Gramolini, T. A. Duhamel, H. Kondo, M. Asahi, S. C. Tsuchiya, M. J. Borrelli, J. R. Lepock, K. Otsu, M. Hori, et al. HSP70 Binds to the Fast-twitch Skeletal Muscle Sarco(endo)plasmic Reticulum Ca2+-ATPase (SERCA1a) and Prevents Thermal Inactivation J. Biol. Chem., December 10, 2004; 279(50): 52382 - 52389. [Abstract] [Full Text] [PDF]
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Y. Li, M. Ge, L. Ciani, G. Kuriakose, E. J. Westover, M. Dura, D. F. Covey, J. H. Freed, F. R. Maxfield, J. Lytton, et al. Enrichment of Endoplasmic Reticulum with Cholesterol Inhibits Sarcoplasmic-Endoplasmic Reticulum Calcium ATPase-2b Activity in Parallel with Increased Order of Membrane Lipids: IMPLICATIONS FOR DEPLETION OF ENDOPLASMIC RETICULUM CALCIUM STORES AND APOPTOSIS IN CHOLESTEROL-LOADED MACROPHAGES J. Biol. Chem., August 27, 2004; 279(35): 37030 - 37039. [Abstract] [Full Text] [PDF]
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K. Sato, K. Yamasaki, T. Daiho, Y. Miyauchi, H. Takahashi, A. Ishida-Yamamoto, S. Nakamura, H. Iizuka, and H. Suzuki Distinct Types of Abnormality in Kinetic Properties of Three Darier Disease-causing Sarco(endo)plasmic Reticulum Ca2+-ATPase Mutants That Exhibit Normal Expression and High Ca2+ Transport Activity J. Biol. Chem., August 20, 2004; 279(34): 35595 - 35603. |
