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Blood, Vol. 92 No. 5 (September 1), 1998:
pp. 1814-1819
The Plasmodium falciparum-CD36 Interaction Is Modified by a
Single Amino Acid Substitution in CD36
By
Lena Serghides,
Ian Crandall,
Eric Hull, and
Kevin C. Kain
From the Institute of Medical Science, Department of Medicine,
University of Toronto; and the Tropical Disease Unit, The Toronto
Hospital, Toronto, Canada.
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ABSTRACT |
CD36 is an 88-kD glycoprotein involved in the cytoadherence of
Plasmodium falciparum-parasitized erythrocytes (PE) to
endothelial cells. The molecular mechanisms involved in CD36-dependent
cytoadherence were examined by expressing three CD36 homologues (human,
murine, and rat) in COS-7 cells and observing their PE-binding
characteristics over a pH range of 6.0 to 7.4 and following iodination
of these receptors. PE binding to human CD36 was pH dependent, with
peak binding at pH 6.8 to 7.0, and binding was unaffected by
iodination. In contrast, PE adherence to murine and rat CD36 was
insensitive to changes in pH, and iodination significantly reduced
binding. We further show that the differences observed in the binding
phenotype of human and rodent CD36 can be attributed to a single
residue. Site-directed mutagenesis of the histidine at position 242 of human CD36 to tyrosine (found in rodent CD36) conferred the binding phenotype of rodent CD36 onto human CD36. Furthermore, substitution of
the tyrosine at position 242 of rat CD36 for histidine conferred the
binding phenotype of human CD36 onto rat CD36. These findings suggest
that residue 242 is part of, or important to the conformation of, the
PE-binding domain of CD36.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
PLASMODIUM FALCIPARUM malaria is
the world's most important parasitic infection accounting for an
estimated 300 million cases and 1.5 to 2.7 million deaths
annually.1 The central pathophysiologic event in
falciparum malaria is the sequestration of parasitized erythrocytes (PE) in the microvascular beds of vital organs resulting in the disruption of local circulation and the manifestations of severe
malaria.2 Sequestration of infected erythrocytes is
mediated by specific ligand-receptor interactions. A number of
endothelial cell receptors have been implicated in this interaction, including intercellular cell adhesion molecule-1 (ICAM-1),3 vascular cell adhesion molecule (VCAM),4
E-selectin,4,5 chondroitin sulphate A,6,7
thrombospondin,8 and CD36.9 Although the
interaction of wild isolates of P falciparum with many of the
implicated endothelial cell receptors is variable, almost all natural
populations preferentially bind to CD36,10 even under
conditions of shear stress.11
CD36 is an 88-kD cell surface glycoprotein that is expressed on
monocytes, macrophages, endothelial cells, platelets, erythroid precursors, and breast epithelium.12,13 CD36 together with lysosomal integral membrane protein II (LIMP II), CD36 and LIMP II
analogous-1 (CLA-1),14 class B scavenger receptor
1(SR-B1),15 and epithelial membrane protein
(EMP)16 constitute a novel gene family. CD36 is composed of
a single polypeptide chain and, based on hydropathy
analysis,17,18 is predicted to contain transmembrane domains at both the carboxyl and amino termini with evidence of palmitoylation of the cysteine residues at both termini.19
Although little is definitively known about the structure and function of CD36, many roles have been ascribed to it, including an endothelial cell and macrophage receptor for P falciparum-infected
erythrocytes20; a receptor for collagen type I and IV or
thrombospondin21; an interaction with platelet
agglutinating protein p3722; a receptor for the uptake of
the oxidatively modified low-density lipoprotein23; a
receptor for neutrophils undergoing apoptosis24; a cell
marker in endothelial cancer25; and a receptor that
participates in signaling via a physical association with the
src family of tyrosine kinases.26
Although it is known that the CD36 receptor family binds a variety of
ligands, the molecular mechanisms underlying these various interactions
are poorly understood. The objective of this study was to characterize
the molecular basis for the interaction of PEs with CD36. We examined
the binding of human PEs to CD36 from human (hCD36),27
murine (mCD36),28 and rat (rCD36),18 which share over 90% sequence homology at the amino acid level. mCD36 has
previously been shown to participate in the binding and uptake of
oxidized low-density lipoprotein (ox LDL),28 and rCD36 (or FAT) has been shown to mediate the transport of long-chain fatty acids.18,29 Both mCD36 and rCD36 are not recognized by
OKM5, a cytoadherence inhibiting monoclonal antibody.30
However, we have recently shown that both mCD36 and rCD36 support PE
binding. Human, murine, and rat CD36 possess six conserved cysteine
residues located in a 90 amino acid cysteine-rich region (residues
243-333). Cysteine replacement mutagenesis studies in our laboratory
have shown that five of these six cysteine residues are essential for avid cytoadherence, suggesting that this cysteine-rich region represents a discrete domain important for CD36-mediated adhesion of
PEs (unpublished data).
In this study, we show that PE binding to human CD36 is pH dependent
but unaffected by iodination of the receptor. In contrast, PE binding
to murine and rat CD36 is pH-independent but inhibited by iodination.
We examined the amino acid sequences of the homologues to determine
which divergent residues may be responsible for the different binding
characteristics observed. We then show that a single amino acid
substitution within the previously identified cysteine-rich domain can
confer the binding phenotype of murine or rat CD36 onto human CD36 and
the binding phenotype of human CD36 onto rat CD36.
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MATERIALS AND METHODS |
Chemicals and antibodies.
RPMI 1640 and fetal bovine serum were from Life Technologies
(Mississauga, Ontario, Canada). COS-7 cells were purchased from ATCC
(Rockville, MA). pGEM7 was from Promega (Madison, WI). pcDNAI/amp was
from Invitrogen (San Diego, CA). DEAE-dextran, chloroquine, dimethylsulfoxide (DMSO), and fluorescein
isothiocyanate (FITC)-conjugated goat anti-mouse IgG were from Sigma
(St Louis, MO). Iodobeads were from Pierce (Rockford, IL). Anti-CD36
monoclonal antibodies no. 25, no. 30, and no. 32 were the kind gift of
Dr C. Ockenhouse (WRAIR, Washington, DC). cDNAs were the kind gifts of
Dr B. Seed (hCD36; Harvard University, Cambridge, MA), Dr G. Endemann
(mCD36; Scios Nova Inc, Mountain View, CA), and Dr N. Abumrad (rCD36; SUNY, Syracuse, NY).
Cultures.
P falciparum cultures of the ITG clone were grown in A+ blood
and serum obtained by venupunture of volunteers. Cultures were maintained by the method of Trager and Jensen31 using RPMI
1640 supplemented with 10% human serum and 50 µmol/L hypoxanthine.
Site-directed mutagenesis.
Segments of hCD36 DNA containing nucleotides  210 to 549 and 550 to 1872, and the complete rCD36 cDNA were subcloned into pGEM7, and
single-stranded template was generated by the method of
Kunkel.32 The codon for the histidine residue at position 242 and the codon for phenylalanine at position 97 of hCD36 were mutagenized to a codon for tyrosine, and the tyrosine residue at
position 242 of rCD36 was mutagenized to a codon for histidine, using
the appropriate templates. The presence of the mutations was verified
via the dideoxy chain termination method using the Sequenase PCR
product sequencing kit (United States Biochemical Corporation,
Cleveland, OH). The mutated hCD36 fragment was then subcloned back into
pcDNAI/amp such that the entire 5 to 3 untranslated sequence was restored. The mutated rCD36 cDNA was also subcloned back
into pcDNAI/amp.
Transient transfection.
Plasmid DNA for transfection was prepared using Qiagen columns
(Qiagen, CA) according to manufacturer's instructions. COS-7 cells
were plated at 30% confluency in 12-well culture plates and incubated
at 37°C in 5% CO2 overnight. The cells were then transiently transfected using DNA (1 µg/mL) in RPMI plus DEAE-dextran (0.2 mg/mL) and 100 µmol/L chloroquine for 2 hours at 37°C in 5%
CO2, followed by exposure to 10% DMSO in RPMI for 3 minutes.32 The DMSO solution was removed, and RPMI with
10% fetal bovine serum was added. Cell surface expression was
confirmed, 72 hours post transfection, by immunofluoresence using a
pool of monoclonal antibodies (no. 25, no. 30, and no. 32) to human
CD36 that recognize hCD36, rCD36, and the human and rat CD36 mutants.
Expression of murine CD36, which is not recognized by the pool of
monoclonal antibodies, was inferred by ability to cytoadhere. The level
of cell surface expression of human and rat CD36 and all CD36 mutants was quantitated by use of confocal microscopy and
fluorescence-activated cell sorter (FACS) analysis.
Cytoadherence assays.
Seventy-two hours after transfection, COS-7 cells were fixed with 4%
formalin in phosphate buffer saline (PBS) for 10 minutes and were then
rinsed three times with Bis Tris saline (BTS; 25 mmol/L Bis Tris, 135 mmol/L NaCl, pH 6.8). P falciparum-infected erythrocytes were
pelleted, resuspended in BTS and diluted to 5% hematocrit and 5%
parasitemia in a total volume of 300 µL of BTS per well. The sample
was kept in suspension by continuous agitation using a 3D Rotator (Lab
Line, Melrose Park, IL) and was incubated with the target cells for 90 minutes. Nonadherent cells were removed by aspiration, the well was
rinsed with 400 µL aliquots of BTS with agitation, and the process
was repeated until no erythrocytes were present between COS-7 cells.
Adherence was quantitated by direct microscopic observation of COS-7
cells. The number of adherent erythrocytes per transfected cell
(defined as supporting the adherence of at least 3 PEs) was counted for at least 40 representative COS-7 cells per well. Transfection efficiency of COS-7 cells was between 40% and 60%. Transfected COS-7
cells did not support adherence of uninfected red cells. All
cytoadherence assays were performed in triplicate and repeated at least
three times. The results are presented as the mean with standard
deviation of a typical experiment performed in triplicate.
In cytoadherence assays to determine the optimum pH binding, the pH of
BTS was adjusted using concentrated NaOH or HCl. The iodination studies
were done at pH 6.833 using fixed cells. The transfected
COS-7 cells were fixed with 4% formalin and then subjected to either
no additions; the addition of 10 mmol/L NaI in phosphate-buffered
saline (PBS); the addition of an iodobead in PBS; or the addition of
both 10 mmol/L NaI and a single iodobead in PBS. After a 5-minute
incubation at room temperature with gentle agitation, the bead was
removed and the wells were thoroughly washed three times with BTS
before use in the adhesion assays.
Statistical analysis.
Analysis of variance (ANOVA) was used to determine whether pH is a
factor in PE cytoadherence to CD36 (Fig 1A
and B). t-Test analysis was performed to examine differences in
cytoadherence levels between homologues, mutants, and between control
and treated wells in the iodination experiments (Figs 1 and
2).
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| Fig 1.
Effect of pH on the cytoadherence of PEs to hCD36, mCD36,
rCD36, H242Y, and Y242H. Adhesion assays were performed using
transiently transfected COS-7 cells expressing human CD36, murine CD36,
rat CD36, H242Y (human CD36 with residue 242 altered to tyrosine), or
Y242H (rat CD36 with residue 242 altered to histidine). Infected blood
suspended in BTS (pH adjusted by HCl or NaOH) to a 5% hematocrit and
5% parasitemia was added and incubated under continuous agitation for
90 minutes. After washing, adherence was quantitated microscopically by
counting the number of adherent erythrocytes per transfected COS cell
for at least 40 representative COS-7 cells per data point. Values
indicated are for (A) human CD36 ( ), rat CD36 ( ), and H242Y ( )
and for (B) human CD36 (), rat CD36 (),mouse CD36 ( ), and
Y242H (). The values are mean values with standard deviations
represented by error bars. Similar results were obtained in three
independent experiments. Cytoadherence to human CD36 and Y242H is
significantly pH dependent (P < .005, by ANOVA).
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| Fig 2.
Effect of CD36 iodination on the cytoadherence of PEs.
Adhesion assay was as in Fig 1 with all assays performed at pH 6.8. Iodination was performed by subjecting the transfected COS-7 cells to
no additions (a); addition of 10 mmol/L NaI in PBS (b); addition of an
iodobead (c); or the addition of both 10 mmol/L NaI and an iodobead in
PBS (d). Results represent the mean with standard deviation indicated
by error bars. Similar results were obtained in three independent
experiments. Values indicated are for (A) human CD36 and F97Y (human
CD36 with residue 97 substitute for tyrosine) and for (B) human CD36,
murine CD36, rat CD36, H242Y (human CD36 with residue 242 substituted
for tyrosine), and Y242H (rat CD36 with residue 242 substituted for
histidine). Iodination significantly reduces the level of cytoadherence
to murine CD36, rat CD36, and H242Y (P < .01, t-test).
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RESULTS |
Altering pH.
It has been observed that the interaction of human PEs with target
cells bearing a mixed population of receptors has a notable pH
dependence,34 and studies using CHO cell lines transfected with human CD36 or ICAM-1 suggest that it is the CD36 contribution to
cytoadherence that is pH dependent.33 To determine whether the CD36 homologues, mCD36 and rCD36, also show this pH dependency, we
tested the level of cytoadherence to all three homologues over a pH
range of 6.0 to 7.4. hCD36 showed pH-dependent binding (P < .001, by ANOVA), with peak binding at pH 6.8 to 7.0. In contrast, no pH
optimum was observed for mCD36 and rCD36 (Fig 1A and B).
Iodination of CD36.
Tyrosine residues are converted to di-iodotyrosine in the presence of
iodide and an oxidizing agent (iodogen). To test whether iodination of
tyrosines present in CD36 has an effect on cytoadherence of PEs, human,
murine, and rat CD36 were iodinated before their interaction with PEs.
Iodination did not affect cytoadherence of PEs to hCD36 (Fig 2A and B),
but this procedure significantly reduced binding of PEs to murine and
rat CD36 (P < .01, by t-test; Fig 2B).
Mutagenesis of hCD36 and rCD36.
The pH and iodination results suggested that one or more histidines
might be involved in the human CD36-PE interaction, whereas one or more
tyrosines might be involved in the murine and rat CD36-PE interaction.
A comparison of the aligned sequences of the three homologues
(Fig 3; GenBank M24795, L23108, L19658) indicated that tyrosines at position 97 and 242 in the murine and rat
CD36 are replaced by phenylalanine and histidine, respectively, in the
human sequence. The histidine at position 242 is the only histidine in
hCD36 that is not conserved in mCD36 and rCD36. To determine if these
residues are participating in the CD36-PE interaction, site-directed
mutagenesis of hCD36 and rCD36 was performed to change the
phenylalanine at position 97 in hCD36 to a tyrosine (to produce mutant
F97Y), the histidine at position 242 of hCD36 to a tyrosine (to produce
mutant H242Y), and the tyrosine at position 242 of rCD36 to a histidine
(to produce mutant Y242H).
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| Fig 3.
Predicted amino acid sequences of human, murine,
and rat CD36. Tyrosine residues found in rodent CD36 that are not
present in human CD36 are indicated in enlarged and bolded script, and
conserved tyrosine residues are in bolded italicized script. GenBank
accession numbers are M24795 (hCD36),27 L23108
(mCD36),28 L19658 (rCD36).18
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Cell surface expression of the three mutants was equal to that of human
and rat CD36 as determined by confocal microscopy and FACS analysis
(data not shown). All three mutants supported avid cytoadherence of
PEs. As was observed in the case of native hCD36, PE binding to F97Y
was not reduced following iodination of this mutant (Fig 2A). In
contrast, cytoadherence of PEs to H242Y was significantly reduced upon
iodination (P < .01, by t-test; Fig 2B).
Cytoadherence to native rCD36 is reduced following iodination; however,
PE binding to the mutant Y242H was not affected by iodination (Fig 2B).
The ability of PEs to bind to H242Y and Y242H over a pH range was
determined. Although H242Y is only a single residue different from
hCD36, PE binding to H242Y was pH-independent, similar to rodent CD36
(Fig 1A). Binding of PEs to Y242H, which differs from rCD36 also by a
single residue, became pH dependent (P < .005, by ANOVA; Fig
1B) resembling hCD36. At the pH optimum of 7.0, binding to hCD36 was
significantly greater than to rCD36 (P < .001, t-test) or to the human mutant, H242Y (P < .001, t-test) but was not significantly different from the rat mutant
Y242H. At the same pH optimum, binding to rCD36 was equivalent to H242Y but was significantly less than to Y242H (P < .001, t-test).
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DISCUSSION |
Human, murine, and rat CD36 show over 90% identity at the amino acid
level. However, these homologues display different binding characteristics to P falciparum-infected erythrocytes under
varying pH conditions and following iodination. These observations
suggest that minor sequence differences might account for the observed binding disparities. The iodination process primarily affects tyrosines; therefore, we looked for sites in the homologues sequences where murine and rat CD36 had tyrosine-related substitutions. This only
occurred in two sites, residues 97 and 242. We mutagenized residue 97 in hCD36 from a phenylalanine to a tyrosine but observed no decrease in
PE cytoadherence upon iodination. This suggests that residue 97 is not
responsible for the iodination sensitivity observed in rodent CD36.
The rodent sequences have a tyrosine at position 242, which is
substituted by a histidine in hCD36. This is the only histidine present
in the human sequence that is not conserved in rodent CD36. To
determine if the presence of this histidine affected the CD36-PE
interaction, we replaced the histidine at position 242 in hCD36 with
the tyrosine found in rodent CD36. This substitution conferred
iodination sensitivity to hCD36, indicating that the tyrosine at
position 242 is responsible for the decrease in cytoadherence observed
upon iodination of rodent CD36. When the same mutant was tested for PE
cytoadherence over a pH range of 6.0 to 7.4, the pH-dependent binding
observed with native hCD36 was absent. Thus, a single residue
substitution at position 242 conferred the binding characteristics of
rodent CD36, iodination sensitivity, and pH insensitivity onto human
CD36.
To confirm the importance of residue 242 in the CD36-PE binding
interaction, we replaced the tyrosine found in position 242 of rCD36 to
the histidine found in hCD36. This single residue change to rCD36 (to
produce mutant Y242H) conferred pH sensitivity to Y242H, with a pH
optimum similar to hCD36. In addition, in contrast to native rCD36, PE
binding to Y242H was unaffected by iodination. Thus, the reciprocal
substitution at residue 242 of rCD36 (to the hCD36 equivalent),
conferred the human CD36-binding phenotype onto rat CD36.
The process of iodination converts a tyrosine residue to a
di-iodotyrosine. Iodine atoms are a sizable electronegative addition to
the residue that might sterically interfere with the approach of the PE
ligand and thus potentially reduce binding. Although steric
interference might result in the complete loss of PE binding, the
results seen in both rodent CD36 and the mutant H242Y may be due to
incomplete iodination of all CD36 receptors present on the COS cells,
allowing for some binding to occur. It may also suggest that if residue
242 is a contact residue it is not the only residue involved in binding
the PE ligand and that preventing the interaction of the ligand with
residue 242 reduces the efficiency but does not completely abrogate
binding.
Previous studies have shown that cytoadherence to hCD36 is a
pH-dependent process. Cytoadherence to C32 amelanotic melanoma cells
(which express CD36) and to CHO-CD36 cells have pH optimums of 6.9 and
6.6 to 6.8, respectively.33,34 We have shown that PE
adherence to hCD36 expressed on COS-7 cells also displays pH dependence, with optimum adherence occurring at pH 6.8 to 7.0, similar
to optimums previously reported. Substitutions at position 242 of hCD36
or rCD36 modify the effect of pH on binding, indicating that histidine
242 is responsible for the pH effect. The observation that
cytoadherence to hCD36 shows a significant increase around pH 6.8 to
7.0 is of interest given that human erythrocytes infected with late
trophozoites/schizonts sequester preferentially in postcapillary venules of malaria patients where the surrounding microenvironment is
of lower than physiological pH due to higher CO2 and
lactate levels.2
Although all three CD36 homologues support avid cytoadherence of PEs,
we have observed that murine and rat CD36 consistently bind lower
levels of PEs compared with hCD36 using standard assay conditions.
Using FACS and confocal microscopy analysis we determined that the
lower binding avidity of rodent CD36, as compared with human CD36,
cannot be attributed to differences in cell surface expression.
Cytoadherence assays in our lab are generally performed at pH 6.8 where
the hCD36 binding pH optimum is observed; thus, the pH sensitivity of
hCD36 may be responsible for the binding avidity differences observed
between human and rodent CD36. It is of note that the binding
efficiency of rCD36 is increased to that of hCD36 levels when the
tyrosine at position 242 is substituted for a histidine. Conversely,
the binding efficiency of hCD36 is decreased to rCD36 levels when
residue 242 is changed from a histidine to a tyrosine. Because altering
residue 242 eliminates the pH effect observed in hCD36, the avidity
difference between human and rodent CD36 can be attributed to residue
242.
Previous studies have used epitope mapping of cytoadherence-inhibiting
monoclonal antibodies and recombinant CD36 fragments to define domains
that may participate in cytoadherence.21,30 It has been
suggested that the CD36 epitope of the cytoadherence inhibiting
monoclonal antibody OKM5 and the CD36-ligand binding domain
overlap.30 We have observed that OKM5's recognition of the
hCD36 mutant H242Y does not differ from that of native hCD36, under
control conditions and after iodination of both proteins as determined
by FACS analysis (data not shown). These observations suggest that the
OKM5 epitope and the PE-binding domain on CD36 are distinct, because
iodination of H242Y reduces PE binding but not OKM5 binding. The
cytoadherence inhibitory properties of OKM5 may be due to steric
interference of the approaching PE ligand rather than direct
competition for the binding domain. The present study examined CD36
homologues and mutants in the context of the cell membrane and examined
the effect of subtle amino acid substitutions on a cell-cell
interaction. We believe that this system represents a more direct and
physiologically relevant assessment of cytoadherence and one that more
closely reflects the in vivo situation. Our findings do not directly
refute previously implicated domains but suggest that the domain
involved in cytoadherence may be discontinuous.
In summary, we present evidence that a single amino acid substitution
at position 242 of CD36 can modify the characteristics of the P
falciparum-infected erythrocyte-CD36 interaction, suggesting that
the P falciparum binding domain includes or is influenced by
this residue. These findings are directly supported by cysteine replacement mutagenesis studies in our laboratory that indicate that
this residue lies within a discrete cysteine-rich domain of CD36,
region 243 to 333, which is essential for PE cytoadherence (unpublished
data, January 1998). Ultimately these observations may
facilitate the rational design of interventions to prevent or reverse
sequestration. Further study to assess whether CD36 mutants still
support other receptor functions such as the binding and uptake of
oxLDL and apoptotic neutrophils may help to determine whether these
ligands share or have unique binding sites on CD36.
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FOOTNOTES |
Submitted February 19, 1998;
accepted May 6, 1998.
Supported by the Medical Research Council of Canada (MT-13721), The
World Health Organization TDR program (TDR 920223), and the Heart and
Stroke Foundation of Canada (NA-3391). K.C.K. was supported in part by
a Career Scientist Award from the Ontario Ministry of Health.
Address reprint requests to Kevin C. Kain, MD, Tropical
Disease Unit, EN G-224, The Toronto Hospital, 200 Elizabeth St,
Toronto, Canada, M5G 2C4; e-mail: kkain{at}torhosp.toronto.on.ca.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
CD36 clones were kindly provided by Dr B. Seed (human), Dr G. Endemann
(mouse), and Dr N. Abumrad (rat).
| |
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Abstract
Introduction
Abstract