1 Department of Molecular
Biology and Genetics, Biological membranes exist in many forms, one of
which is known as tubular myelin (TM). This pulmonary surfactant
membranous structure contains elongated tubes that form square
lattices. To understand the interaction of surfactant protein (SP) A
and various lipids commonly found in TM, we undertook a series of transmission-electron-microscopic studies using purified SP-A and lipid
vesicles made in vitro and also native surfactant from bovine lung.
Specimens from in vitro experiments were negatively stained with 2%
uranyl acetate, whereas fixed native surfactant was delipidated,
embedded, and sectioned. We found that
dipalmitoylphosphatidylcholine-egg phosphatidylcholine (1:1
wt/wt) bilayers formed corrugations, folds, and predominantly
47-nm-square latticelike structures. SP-A specifically interacted with
these lipid bilayers and folds. We visualized other proteolipid
structures that could act as intermediates for reorganizing lipids and
SP-As. Such a reorganization could lead to the localization of SP-A in
the lattice corners and could explain, in part, the formation of
TM-like structures in vivo.
tubular myelin; surfactant protein A-tubular myelin interaction; pulmonary surfactant; dipalmitoylphosphatidylcholine; phosphatidylcholine
PULMONARY SURFACTANT is essential for lowering surface
tension at the air-liquid interface of the alveolus, thereby ensuring proper breathing and enabling gas exchange (16, 25). Surfactant is
composed of several lipids (~90%) and proteins (~10%) (16, 33).
The lipid component of pulmonary surfactant exists as a monolayer at
the air-liquid interface and as a bilayer and possibly other forms in
the alveolar hypophase (5, 28). Lipid bilayers are secreted as lamellar
bodies (LBs) and are thought to pass through the tubular
myelin (TM) intermediate before reaching the surface to become
monolayers (5). Surfactant protein (SP) A, SP-B, and SP-C are present
in the LBs, although SP-A is also secreted directly into the aqueous
hypophase (3, 12, 30). LBs appear to interact with the secreted SP-A
and calcium to form TM (27, 32). TM contains membranes as square
lattices in cross sections and as tubules in longitudinal sections (1,
25, 28, 29). SP-A appears to be located near the corners of the square
membrane lattices of TM (1, 8, 17, 27-29).
SP-A, a glycoprotein member of the C-type (calcium-binding) collectin
(collagen-like lectin) family, is involved in various biological
processes including recognition of microbes for macrophage-mediated immunity and in surfactant processing (10, 31). SP-A is an inherent
component of TM (25, 30), and transgenic mouse models show that TM is
absent in SP-A null mutants (9). In addition, in vitro experiments show
that SP-A is essential for the formation of TM structures (17, 24).
These in vitro experiments further identified
dipalmitoylphosphatidylcholine (DPPC), phosphatidylglycerol, SP-B, and
calcium as the other components necessary for the formation of TM structures.
Recently, Palaniyar et al. (15) elaborated the structure
of bovine SP-A and its abilities to form specific filaments using transmission electron microscopy (TEM). Palaniyar and colleagues (13,
15) and Ridsdale et al. (19) also showed that calcium and other metal
cations altered SP-A quaternary structure and that the supraquaternary
filamentous structure of SP-A was influenced by the presence of metal
ions and protein concentration. These studies determined that both
SP-A-SP-A interactions and SP-A-lipid interactions were affected by the
types of lipids used. Therefore, the parameters such as protein
concentration, cations, and type of lipid could directly affect the
formation of TM and the interaction of SP-A with TM.
Although many studies have investigated the structural organization of
TM, the manner in which these structures are formed is not clearly
understood. Here, we show that DPPC-egg phosphatidylcholine (PC)
bilayers spontaneously form lattice structures ~50 nm on each side.
These structures specifically interact with SP-A in the presence of
calcium. These lattice structures share certain similarities with TM
structures found in thin sections of native surfactant. Our experiments
also provided images of several structures that could act as
intermediates of this latticelike lipid structure. Using this new
information as well as previously published data by Palaniyar and
colleagues (13-15) and Ridsdale et al. (19), we propose a model
for the formation of TM. This model emphasizes the fact that the lipids
are not passive structures but instead can play an important role in
determining the three-dimensional organization of TM. Lipids may also
play a similar role in the organization of specialized structures in
other biological membranes.
All experiments were performed literally as described in the companion
paper (13). Briefly, SP-A was purified from bovine lung lavage with
standard procedures involving delipidation by organic solvents and
column chromatography (3). Lipids were purchased from Avanti Polar
Lipids (Alabaster, AL) and dissolved in chloroform-hexane (1:1), and
vesicles of heterogeneous sizes were made as previously described (22).
Freshly prepared lipid vesicles were mixed with buffer containing SP-A
and incubated at 37°C for 10-20 min. Control reactions
involved buffer without SP-A. After time was allowed for the protein to
associate with lipids, CaCl2 was
added to each tube, and the incubation was continued. Control tubes
received double-distilled H2O in
place of CaCl2. Considering the
time of CaCl2 addition as the
beginning, samples were withdrawn at various times of incubation for
TEM analysis. Generally, a 30- to 60-min incubation time sufficed to
produce the structures that we present here. The SP-A-lipid vesicle
samples were negatively stained before examination with TEM (22).
Fourier transform analysis of native TM
structures. Image analysis was performed with the
IMAGIC program system (26). Briefly, micrographs of native TM
structures were scanned with a charge-coupled device camera and Winview
software (Princeton Instruments, EMPIX, Mississauga, ON). The image was
filtered to enhance the contrast, and a circular mask was placed at the
center of the image. The diffraction pattern of this image was obtained
by allowing the repeating information to pass through the filter. This
information was used to reconstruct the final image.
Purified SP-A preparations do not contain detectable
amounts of SP-B. To ascertain the purity of the SP-A
preparations, we size fractionated the purified protein preparation on
14.5% polyacrylamide gels with SDS-PAGE (Fig.
1). Because SP-B is extremely
hydrophobic, the addition of urea to this gel system was necessary.
Loading of even 2-3 µg of the protein and subsequent sensitive
silver staining did not show any protein band comparable to SP-B.
Instead, the preparations showed the typical protein profile expected
for SP-A (2). Because the detection limit of protein by silver staining
is roughly 10 ng, SP-B can constitute no more than 0.5% of the total
protein, if it is at all present. Therefore, the SP-A preparations used
in our study are devoid of detectable and significant amounts of SP-B.
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Fig. 1.
Polyacrylamide gel showing purity of surfactant protein (SP) A
preparation. Approximately 2 µg of protein from SP-A and SP-B
preparations were size fractionated via SDS-PAGE on a 14.5%
polyacrylamide gel in presence of 2 M urea. Gel was subsequently
stained with silver. Lanes 1 and
4, molecular-mass markers (nos. on
right); lane 2, SP-A
preparation; lane 3, SP-B preparation.
SP-A preparation did not contain any detectable amounts of SP-B
(<0.5% of total protein).
Fusion of small vesicles leads to the formation of
large, striated bilayers. To study the interaction of
SP-A with lipid bilayers, we incubated SP-A with DPPC-egg PC vesicles
in calcium-containing buffer, negatively stained the preparations, and
analyzed them with TEM. This lipid combination generated some vesicles
with corrugated surfaces (Fig.
2A). At
lower magnification, it could be seen that SP-A-containing lipid
preparations showed a high degree of vesicle aggregation (Fig.
2B). In some cases, large vesicles
that interacted with many small vesicles and other lipid structures
could be identified. These large complexes were up to 100 µm in
length. However, most of the isolated vesicles were <1 µm in size.
Often, small vesicles interacted with large vesicles composed of
striated sheets (Fig. 2). Small vesicles were coaggregated in these
complexes. To obtain details of the process involved, we analyzed the
lipid and associated lipid structures in detail. Clearer information
was obtained from the images where SP-A-lipid interactions were
detectable. These images showed that the DPPC-egg PC mixture was
capable of generating different types of bilayers, which appeared as
either "smooth" or "striated" vesicles (Fig. 3A)
(13). Although both of these types of vesicles were seen in the same
fields of view, the predominant type had a smooth surface. Accurate
quantitation of different types of vesicles was not feasible because of
the presence of aggregates that were common in these types of
experiments.
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SP-As were most frequently associated with the striated vesicles compared with smooth-surfaced vesicles (Fig. 3B). But even in the absence of SP-A, some lipid vesicles contained striations (Fig. 2), showing that the formation of striated surfaces was not entirely dependent on SP-A. However, in the presence of SP-A, many of these small vesicles were aggregated (Figs. 2 and 3), and some small vesicles apparently fused to form large sheets of bilayers that often contained striated surfaces (Fig. 3A). Some of these areas were sparsely populated by SP-A, whereas others were completely devoid of it (Fig. 3). A detailed description of the association between the SP-A filaments or octadecamers and the corrugated surfaces of the lipid bilayers can be found in the companion paper (13).
These results allowed two conclusions to be made regarding the formation of lipid structures. First, because control vesicles also formed striated surfaces, the DPPC-egg PC lipid mixture was inherently capable of forming striated vesicles. Second, the presence of SP-A appeared to enhance but was not essential for the formation of striated vesicles.
Large corrugated sheets fold to form lattice
structures. Another group of TEM images showed that the
large lipid bilayer sheets could fold onto themselves in a U-turn
manner (Fig. 4). The folding of these
striated vesicles often occurred at 90° to the direction of the
striations (Fig. 4, A and
B), with corresponding square lattice arrangements. Roughly one-fourth of the vesicles folded at
non-90° angles to the direction of the striations and showed an
altered spacing on the surfaces of the folded vesicles (Fig. 4,
C and
D). Folded vesicles also contained a
mixture of lattice structures and striations (Fig.
4A). These vesicles often contained apparently intact vesicles associated with their folds (Fig. 4). Irregular folding, furthermore, created unequal spacings in the lattice
structures (Fig. 4D). In some cases,
multiple U-turns appeared to occur on the same bilayer, leading to the
multiple layers of folded vesicles (Fig.
4D). Recently, Siegel and Epand (21)
observed very similar structures of different lipid vesicles undergoing
fusion. They performed cryo-TEM of vesicles embedded in vitreous ice
and thereby trapped in their native hydrated state. The congruence with
our work here supports the observation that the structures that we
observed were not merely drying artifacts.
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These results (Fig. 4) revealed two features of vesicle folding. First, the large striated vesicles formed folds, and the folding occurred more frequently in the presence of SP-A. Second, the folding occurred via a U-turn, often at 90° to the direction of the striations. These folded structures generated square lattice structures in two-dimensional projection.
SP-A specifically interacts with junctions of the
lattice structures. When we examined the interaction
between SP-A and the folded lipid vesicles, we found that many of these
vesicles contained SP-A at specific locations on the surface, mainly at
the junctions of square lattice structures (Fig.
5). Some of the clearer
examples shown in Fig. 5A showed that
the SP-As were reorganized on the lipid surface created by vesicle
folds. SP-A molecules on these completely folded structures did not
exist as filaments as seen on corrugated vesicles (Fig.
3B) (13). To determine the
relationship between the lattice structures and SP-A molecules,
spacings of regularly arranged lattice structures and spacings between
SP-A molecules were measured. The lengths (48.4 ± 7.5 nm;
n = 28 measurements) and widths
(45.3 ± 6.0 nm; n = 28 measurements) of individual lattice structures were not significantly
different from each other (P < 0.05). Hence the lattices existed predominantly as square structures
with a mean side dimension of 46.9 nm (Figs. 4,
A and
B, and
5C). The spacings between clearly
spaced SP-A octadecamers were also measured (Fig. 5,
B and
C) and found to average 47.4 ± 6.7 nm (n = 64 measurements). The mean
lattice spacings and the SP-A spacings were not significantly different (P < 0.05).
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These results (Fig. 5) illustrate two parameters regarding the interaction of SP-A and the folded vesicles. First, SP-As were preferentially located in the junctions of the square lattices. Second, the spacings between the SP-A molecules and the spacings between the square lattices were the same, reflecting a strong association of SP-A with the corners of the square lattice structures.
TM structures found in the native surfactant
preparations. To compare the results of the in vitro
lipid vesicle-SP-A experiments with native structures, we studied
native surfactant materials from bovine lungs. These were fixed
(involving the use of absolute alcohol), acetone treated, embedded in
resin, sectioned, and analyzed with TEM. Because our method generated
very clear images of square lattice structures (Fig.
6,
A-F),
we performed Fourier transform analysis as for two-dimensional crystals
(26). The results clearly demonstrated the regularity of the spacings
of the lattice structures (45 ± 3.2 nm;
n = 80 measurements; Fig. 6,
E and
F). Furthermore, "X"-shaped
electron-dense materials were clearly identified (Fig. 6,
E and
F). These stained preparations were
probed with SP-A-specific antibodies, and the locations of these
complexes were identified by gold particles. Many of the gold particles
were located near the corners of the lattice structures (Fig.
6G). The average distance between
the closest lattice corner and the gold particle was 8.7 ± 4.1 nm
(n = 158 measurements),
whereas the average distance between the centers of the square lattices
and the gold particles was 15.6 ± 5.9 nm
(n = 148 measurements). These results
showed that SP-A antibodies bound to SP-As near the corners of the
lattice structure (Fig. 6G).
Interestingly, gold particles were not detected in the centers of the
lattices with the X-shaped structures. When these native
lattice structures were compared with the lattice structures seen in
the in vitro experiments (Figs. 4 and 5 vs. Fig. 6), the spacings were
not significantly different from one another
(P < 0.05).
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The results from these experiments showed parallels between the in vitro system and the native surfactant system. First, the spacings of the native square lattice structures were identical to the square lattice spacings of the TM-like structures found in the in vitro experiments. Second, SP-As were primarily located near the corners of the native TM lattice structures, and the SP-As were found in the same location in the TM-like lattice structures seen in the in vitro experiments.
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DISCUSSION |
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Lipid membranes of TM and TM-like structures are unusual in their organization, and it is evident that SPs and lipid composition play critical roles in their formation (24, 30). To study TM and/or surfactant functions, researchers have previously used different combinations of lipids: DPPC, egg PC, and phosphatidylglycerol in different proportions (17, 24, 30). Because unsaturated PC (25-30%) and DPPC (35-45%) are the major phospholipid components of pulmonary surfactant (16, 33), we used these lipids in the ratio of 1:1 (wt/wt). Interestingly, either DPPC alone or this simple lipid combination was capable of forming corrugations (Figs. 2 and 3) (13), and some of the folded bilayers formed lattice structures with certain similarities to the native TM (Figs. 4-6). SP-A preferred to interact with such folded structures (Figs. 2 and 3). Although these structures were not the major types in the lipid vesicle-SP-A preparations, these intermediates could explain several key steps in the interconversion of LBs to TM. Note that detailed characterization of different surfactant lipid components (5) shows that TM contains only <5-10% of the total surfactant lipids.
The structures detected in our in vitro experiments (Figs. 4 and 5) show similarities in appearance to reconstituted native TM (Fig. 6) and to structures found in sections of fixed lung tissues (1, 28) and so could reflect the nature of pulmonary surfactant material in vivo. The TM structures detected in the native preparations did not always portray a perfectly square lattice; instead, various sizes and shapes were observed (Fig. 6) (8, 27-29). We also found similar structural variations in the in vitro system (Fig. 4). However, these lipid structures formed predominantly square lattices of 45-47 nm in size for each side and smaller and larger variants from this norm. The variants could be explained by the folding of bilayers at non-90° angles in relation to the striations (Fig. 4, C and D). A careful reconstruction of TM and LBs with serial sections and electron microscopy revealed that TM did, indeed, contain U-turns and that the lipid bilayers connected the LBs and TM (32). Sections of surfactant materials also revealed the presence of folded bilayers in vivo (23). Formation of such striated surfaces on the lipid bilayer from native surfactant has also been previously detected (20). These authors considered different lipid arrangements at the molecular level and suggested that the formation of striations was possible under a variety of conditions.
Many reports (17, 24, 30) envisaged the presence of SP-B as an essential component for the formation of TM structures in vitro. Our results showed that SP-A alone was capable of inducing the reorganization of phospholipid membranes into latticelike structures that, in part, resembled TM. To confirm that there was no SP-B in our SP-A preparations, we examined them by SDS-PAGE followed by silver staining and found no detectable amounts (Fig. 1). Furthermore, lipid vesicles made without any protein were also able to generate these latticelike structures (Fig. 2A). These observations are evidence that SP-B is not essential for the formation of latticelike structures, at least in the initial stages. SP-B probably plays a more important role in lipid mixing and/or fusion in the terminal stages of TM formation (17, 18). Because our in vitro preparations were thin and did not need to be examined with the sectioning procedure, the structures that we observed clearly represented an intermediate and not the true final TM product. Hence this approach greatly facilitated the detection and interpretation of intermediate structures during the formation of TM.
In previous publications, Palaniyar and colleagues (13-15) elaborated the interaction of SP-A octadecamers or filaments with various lipid surfaces. These studies showed that SP-A interacted with lipid bilayers via the head or neck region. In addition, we also showed that most or all of the SP-A headgroups could interact with depressions in the lipid bilayer. SP-As in the filamentous arrangements also appeared to interact with the lipid bilayers via the SP-A headgroups. Curiously, when SP-A interacted with striated vesicles, formation of extensive SP-A filamentous networks was prevented. Instead, SP-A formed filaments in a single direction. This observation suggested that when most or all of the headgroups in the lateral positions were interacting with lipids, the remaining headgroups were available to interact with other headgroups on adjacent SP-As to form elongated filaments. It may be that when lipid bilayers fold to create a "pocket" or a corner, all of the headgroups interact with the lipid surfaces and the continuity of the protein filaments is broken (Fig. 5). When the lipid structure becomes a complete tubular structure, with the four corners forming long tubes, then the preferred arrangement could be to arrange the SP-As in all of the corners of the tube as illustrated in Fig. 6 and previously reported by others (1, 27, 29).
Our system of native surfactant processing for microscopy greatly facilitated detection of X-shaped structures in the center of the lattice structures that had previously been reported by some workers (1, 28). The improvement presumably resulted from the acetone treatment to remove lipid components and the use of LR White resin. In addition, Fourier transform-filtered images clearly showed the presence of electron-dense materials observed as X-shaped structures, but the antibody labeling was exclusively found only near the corners (Fig. 6). Because the carbohydrate moiety at the head of the SP-A molecules is responsible for immunoreactivity (22), it is probable that SP-A heads interact near the lattice corners. This conclusion agrees with previous findings by Palaniyar and colleagues (13, 14) that SP-A can interact with corrugations or depressions on DPPC-egg PC lipid bilayers.
Model for the formation of TM.
Considering all the different types of images that were observed under
different conditions in this and the companion paper (13), we propose
the following model to explain the formation of TM (Fig.
7). The lipid bilayers required for the
formation of TM exist in different forms, primarily vesicular forms
such as LBs. Smaller vesicles, possibly with different amounts of SPs,
could fuse to form larger vesicles, especially in the presence of
calcium. TM formation could also begin from the preformed bilayers of
LBs. LBs are potentially a rich source of calcium because they have a
fivefold higher calcium concentration than the surrounding alveolar
environment (4). Outer layers of the LBs are more accessible to the
alveolar environment and can act as targets for changes in the
concentration of calcium and other ions and also for constitutively
secreted SP-A. Lateral phase separation of phospholipids, especially
DPPC in these bilayers, could lead to the alteration in the lipid
surface structures. Such a phase separation or alteration of surfaces
may occur by different mechanisms such as preferential binding of
calcium to certain phospholipids or the formation of gel-liquid
interfaces to generate corrugations. SP-A octadecamers or filaments
specifically interact with these lipid structures, possibly at the
gel-liquid interface. Folding of striated vesicles containing SP-A at
90° to form U-turns could lead to further specific SP-A-lipid
bilayer interactions. Repeated lipid bilayer folding could generate
multiple layers of TM-like lattice structures (Fig. 7). Presumably, the hydrophobic SP-B plays a role in lipid mixing and membrane-membrane fusion at this step (18), resulting in the formation of the complete
tubular structures seen in native TM.
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This model for the formation of TM structures could explain many of the present findings satisfactorily (Fig. 7) and also accommodates the findings from previous experiments by Palaniyar and colleagues (13-15). Furthermore, the presence of calcium in this system would favor the formation of compact forms of SP-A molecules with clearly identifiable stems (14, 19). This could explain the differences in the detection of linear arrays of particles at the TM corners (1, 7, 29). Our results contradict one proposed arrangement for SP-A in TM structures where the stems of the SP-A octadecamers interact with TM lattice corners (1, 6) but are in agreement with many recent biochemical studies (10, 11, 34) that suggest that the carbohydrate recognition domain is responsible for SP-A-lipid interactions.
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ACKNOWLEDGEMENTS |
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We thank Bob Harris for technical assistance in electron microscopy and Dianne Moyles for sectioning native surfactant materials.
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FOOTNOTES |
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This work was supported in part by the Ontario Thoracic Society (G. Harauz), the Natural Sciences and Engineering Research Council of Canada (G. Harauz), and the Medical Research Council of Canada (F. Possmayer).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: G. Harauz, Dept. of Molecular Biology and Genetics, University of Guelph, Guelph, Ontario, Canada N1G 2W1 (E-mail: gharauz{at}uoguelph.ca).
Received 13 August 1998; accepted in final form 14 January 1999.
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