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2 Subunit I Domain in Regulation of Integrin 
L2 (LFA-1)1
*
Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037; and
Leukocyte Adhesion Laboratory, Imperial Cancer Research Fund, London, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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L I (inserted or interactive) domain of
integrin L
2 undergoes conformational
changes upon activation. Recent studies show that the isolated,
activated L I domain is sufficient for strong ligand
binding, suggesting the 2 subunit to be only indirectly
involved. It has been unclear whether the activity of the
L I domain is regulated by the 2 subunit.
In this study, we demonstrate that swapping the disulfide-linked
CPNKEKEC sequence (residues 169–176) in the 2 I domain
with a corresponding 3 sequence, or mutating
Lys174 to Thr, constitutively activates
L2 binding to ICAM-1. These mutants do
not require Mn2+ for ICAM-1 binding and are insensitive to
the inhibitory effect of Ca2+. We have also localized a
component of the mAb 24 epitope (a reporter of 2
integrin activation) in the CPNKEKEC sequence. Glu173 and
Glu175 of the 2 I domain are identified as
critical for mAb 24 binding. Because the epitope is highly expressed
upon 2 integrin activation, it is likely that the
CPNKEKEC sequence is exposed or undergoes conformational changes upon
activation. Deletion of the L I domain did not eliminate
the mAb 24 epitope. This confirms that the L I domain is
not critical for mAb 24 binding, and indicates that mAb 24 detects a
change expressed in part in the 2 subunit I domain.
These results suggest that the CPNKEKEC sequence of the
2 I domain is involved in regulating the
L I domain. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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L2 (LFA-1,
CD11a/CD18) is an heterodimeric receptor of the
2 integrin family.
L2 is expressed on
all leukocytes, is crucial to the inflammatory process, and mediates
adhesion to ligands ICAM-1, ICAM-2, and ICAM-3 (reviewed in Refs.
1, 2, 3, 4). The adhesiveness of
L2 can be dynamically
regulated by intracellular signals (inside-out signaling)
(5). Activation from the outside of the cell with
Mg2+ and EGTA results in the formation of a
high-affinity form of
L2, as shown by an
increased ability to bind to soluble ICAM-1, and in the expression of
an activation reporter epitope recognized by mAb 24 (2, 6, 7). mAb 24 was originally proposed to recognize an epitope
common to all 2 integrin subunits
(L, M,
X) (6, 7, 8, 9).
The L subunit has an I (inserted or
interactive)3 domain
of 
200 amino acid residues that is critically involved in ligand
binding. The I domain consists of a central sheet, surrounded by
seven helices, which is folded as a globular domain
(Rossmann-fold). At the top of the globular domain, the I domain has a
metal ion-dependent adhesive site (MIDAS) that is involved in
coordinating cations Mg2+ or
Mn2+ and in binding ligands (10).
The I domain of the integrin subunits undergoes conformational
changes on activation. The two different conformations of the integrin
subunit I domain (open and closed) have recently been defined, and
it has been proposed that these two structures represent the
high-affinity and low-affinity conformations, respectively
(11, 12, 13). Recently, Kallen et al. (14) found
that a chemical, lovastatin, binds to the L I
domain and blocks
L2-ligand
interaction. It is likely that lovastatin blocks the conformational
change that occurs when the closed (inactive) form alters to the open
(active) form. The M and
L I domain, with an open and closed
conformation, has been generated by site-directed mutagenesis
(15, 16). The isolated L I domain
with locked open conformation is sufficient for ligand binding,
suggesting that the 2 subunit may be only
indirectly involved in ligand binding (17).
It has been proposed that the integrin subunit also has an I domain
structure within the N-terminal region, which has been validated in the
recent v3 crystal
structure (11, 18). It is unclear how and whether the
2 subunit I domain is involved in the
conformational changes that
L2 undergoes upon
activation. We have reported that the disulfide-linked predicted loop
of the integrin 3 I domain (the CYDMKTTC
sequence) is critically involved in the ligand binding and specificity
of the non-I domain integrin
v3 (19).
Also, it has been proposed that the loop is localized within the
putative ligand-binding pocket in the non-I domain integrin
IIb3
(20). The recent
v3 crystal structure
shows that the CYDMKTTC sequence is actually exposed to the surface in
the headpiece of the 3 subunit
(18) (Fig. 1
). In the
present study, we designed mutagenesis experiments to determine the
potential function of the disulfide-linked CPNKEKEC sequence in the
2 subunit I domain. We show that mutation of
the CPNKEKEC sequence constitutively activates
L2. We propose that
this sequence in the 2 I domain is critically
involved in regulating the L subunit I domain.
We found that the CPNKEKEC sequence of 2 is
part of the mAb 24 epitope, indicating that mAb 24 detects a change in
the 2 I domain and/or in interdomain
interaction on activation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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mAb 24 was generated as previously described (6).
mAbs IB-4 (anti-2) (21) and
TS 1/22 (anti-L) (22) were
obtained from American Type Culture Collection (ATCC, Manassas, VA).
mAbs MEM-48 (anti-2) and MEM-83
(anti-L) (23) were provided
by V. Horejsi (Institute of Molecular Genetics, Academy of Sciences of
the Czech Republic, Prague, Czech Republic). ICAM-1/mouse C
fusion
protein was obtained from G. Weitz (Novartis, Basel, Switzerland). Rat
anti-mouse 2 mAb (C71/16) was purchased
from BD PharMingen (San Diego, CA). Mouse 2
cDNA was obtained from ATCC.
cDNA construct and expression of L2
Human L, human
2, and mouse 2 cDNAs
were subcloned into pBJ-1 (24), and site-directed
mutagenesis was conducted using unique restriction site elimination
(25). The presence of mutations was confirmed by DNA
sequencing. L and 2
cDNAs in the pBJ-1 vector were transfected into Chinese hamster ovary
(CHO) cells by electroporation. Flow cytometry was conducted as
described (26). In some experiments, 0.5 mM
Mn2+ was added to induce mAb 24 binding.
Adhesion assays
Adhesion of CHO and K562 cells expressing
L2 to ICAM-1 was
assayed as described (27). Briefly, wells of 96-well
Immulon-2 plates were coated with goat anti-mouse C chain
polyclonal Ab (Caltag Laboratories, South San Francisco, CA; 0.4
µg/well in 100 µl of PBS), and then with ICAM-1/mouse C fusion
protein (8 µg/ml), unless otherwise specified. Unoccupied protein
binding sites were blocked by incubating the wells with 1%
heat-denatured BSA. Cells (105/well) were added
and incubated for 1 h at 37°C in 100 µl of Tyrode/5 mM HEPES
buffer, pH 7.4, in the presence of 0.1% BSA and 2 mM
MgCl2 or 0.1 mM Mn2+. In
some experiments, Ca2+ was added at indicated
concentrations. Bound cells were quantified by assaying endogenous
phosphatase activity (27). Data are shown as means ±
SD of triplicate experiments.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2 I
domain on mAb 24 epitope, a reporter for 2
integrin activation, on ICAM-1 binding
It has been reported that mutating Asp112,
Ser114, Asp209, and
Glu212 residues in 2
significantly blocks ligand binding (28, 29). Also, it has
been reported that mutating Asp209 of
2 affects binding of mAb 24 (29).
Several residues (which correspond to Asp112,
Ser114, Asn207,
Asp209, Asp216,
Asp250, and Asp278 in
2) in the I domain of the
1 subunit are critical for fibronectin binding
to non-I domain integrin
51 (30, 31). It has not been established, however, whether these
residues that are critical for ligand binding relate to the
conformational alteration of the I domain during activation. To address
this question, we tested whether the conserved residues in the
2 subunit I domain are critical for both
exposure of the mAb 24 epitope and binding of ICAM-1 on activation. We
mutated several amino acid residues of the 2
subunit that are conserved among integrin subunits to Ala and
tested their ability to bind to ICAM-1 and mAb 24 using CHO cells
transiently expressing
L2 mutants. We found
that mutating several conserved residues (Asp112,
Ser114, Ser116,
Asp120, Asp151,
Asp207, Asp209,
Glu212, Asp216,
Asp250, and Asp278) blocks
ICAM-1 binding (Fig. 1
A). Interestingly, we
found that all of these mutations block the exposure of the mAb 24
epitope on activation (Fig. 1B). These results suggest that
there is a correlation between the 2 residues
that are critical for binding to ICAM-1 and those allowing exposure of
the mAb 24 epitope.
Effect of mutating the CPNKEKEC B-C loop sequence in the
2 subunit on ICAM-1 binding to
L2
To study the potential role of the 2
subunit I domain in regulation of
L2, we generated
another 2 subunit mutant, in which we replaced
the B-C disulfide-linked loop sequence, CPNKEKEC (residues
169–176), of the 2 subunit with the
corresponding sequence of the 3 subunit
(designated the 2-3-2 mutant). The
corresponding sequence of the 3 subunit
dictates ligand binding and specificity in
v3 and
IIb3 (19, 20) and is exposed to the surface at the top of the I domain
in v3
(18) (Fig. 2). We
transiently expressed the 2-3-2 mutant into
K562 cells together with wild-type L and
tested its ability to bind to ICAM-1 (Fig. 3A). We found that the
2-3-2 mutant showed activation of
L2. We introduced
point mutations within residues 170–175, in which the
2 residues are changed to the corresponding
3 residues, and studied their ability to bind
to ICAM-1. We found that the Lys174 to Thr
(K174T) mutant also activated
L2, but none of the
other mutants affected ICAM-1 binding to
L2.
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2-3-2 and the
K174T mutants in CHO cells together with wild-type
L and further sorted the cells to obtain high
expressers (designated
L2-3-2-CHO and the
L2K174T-CHO cells,
respectively). Wild-type
L2 and the
L2-3-2 and
L2K174T mutants were
expressed in CHO cells at comparable levels (Fig. 3B). The
divalent cation Mg2+ is required for the
adhesiveness of L2,
and Ca2+ bound to
L2 may serve to
maintain an inactive state (7). We determined the capacity
of L2-3-2- and
L2K174T-CHO cells to
adhere to a range of ICAM-1 concentrations in the presence of
Mg2+ to activate
L2 (Fig. 3C). We found that the
L2-3-2 and
L2K174T showed much
higher adhesion to ICAM-1 than wild-type
L2. These results
suggest that the 2-3-2 and K174T mutations
constitutively activated
L2. We next tested
whether Ca2+ was able to suppress the activating
effects of the 2-3-2 and the K174T mutation on
ligand binding, because Ca2+ has an inhibitory
effect on L2-ICAM-1
interaction (7). Although Ca2+ has
an inhibitory effect on wild-type
L2, it did not show
any inhibitory effect on the two mutants (Fig. 3D).
The epitope for mAb 24 is located in the B-C disulfide-linked
loop sequence of the 2 subunit
Expression of the mAb 24 epitope is associated with
2 integrin activation (2, 6, 7).
The L2-3-2 mutant was
tested for its reactivity with
anti-L2 Abs by
flow cytometry. We found that replacement of the
2 subunit I domain B-C disulfide-linked
loop with the homologous loop from the 3
subunit eliminates reactivity with mAb 24 (Fig. 4). This result suggests that this
mutation may have destroyed the mAb 24 epitope. To test this
possibility, we examined the reactivity of the
2-to-3 mutants with
mAb 24. We found that the E173K and E175T mutations block mAb 24
binding (Fig. 3). We also introduced human-to-mouse mutations within
the swapped region of 2. There is only one
residue difference between human and mouse 2
at position 175 (Glu in human and Ala in mouse) within the loop
170–175. We found that the Glu175 to Ala
mutation (E175A) obliterated the binding of mAb 24, indicating that
Glu175 is critical for mAb 24 binding. These
results indicate that Glu173 and
Glu175 are critically involved in mAb 24 binding.
We also found that the 2-3-2, E173K, E175T,
and E175A mutations similarly blocked binding of
anti-2 mAb IB-4 to
L2. This suggests
that the IB-4 and mAb 24 epitopes overlap within the predicted loop
170–175.
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2 subunit and tested whether this
mutation generates the mAb 24 epitope in mouse
2. We expressed the A175E mouse
2 mutant on CHO cells together with wild-type
human L. We found that the human
L/mouse 2(A175E)
bound to mAb IB-4 but did not bind to mAb 24 (data not shown). These
results suggest that the A175E mutation is enough for generating the
IB-4 epitope but is not enough for generating the mAb 24 epitope in the
mouse 2 subunit.
It has been reported previously that mAb 24 recognizes an epitope
common to several 2 integrin subunits
(6, 7, 8, 9). We tested whether the L I
domain is required for mAb 24 binding. We found that deletion of the
whole I domain did not block mAb 24 binding (Fig. 5). Several residues in the MIDAS of the
L I domain (Asp137,
Thr206, and Asp239) have
been reported to be critical for
L2-ICAM interaction
(26, 32). We found that mutating these MIDAS residues in
the L I domain had only a minimal effect on
mAb 24 binding (Thr208 was used as a control).
These results suggest that mAb 24 binding does not require the L I
domain. This confirms previous findings showing that mAb 24 does not
recognize the isolated I domain (33) and is still
expressed by L2 when
the I domain is deleted in Jurkat cell
L2 transfectants
(34).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2 may be involved in the regulation of
L2 ligand-binding
activity. We have shown that the 2-3-2 or the
K174T mutation within the CPNKEKEC sequence constitutively activates
L2. This is the first
study to show that the L I domain can be
activated by mutation of the 2 I domain. This
observation is consistent with the idea that the
2 I domain can indirectly regulate the
L I domain. It is interesting to speculate
that the CPNKEKEC sequence of the 2 subunit
may make direct contact with the L subunit
(the I domain or the -propeller) and that this interaction would
keep the I domain in an inactive conformation. When
L2 is activated, the
sequence would be detached from the L subunit
and the mAb 24 epitope would be expressed. It has been reported that an
L peptide (residues 238–254 of
L) blocks the appearance of the mAb 24 epitope
even when L2 is
activated (35). Because this peptide sequence is exposed
on the surface of the L subunit, this sequence
may be a potential contact site for the CPNKEKEC sequence. As the K174T
mutation also causes constitutive activation of LFA-1, as described in
this study, it may be particularly important in maintaining the
"off" contact of the CPNKEKEC loop. This mutation has been found as
a missense mutation in a leukocyte adhesion deficiency-1 patient
(36).
Another possible mechanism of the constitutive activation of the
L I domain by the
2-3-2 and K174T mutations is that these
mutations change the divalent cation-binding properties of
L2. It has been
proposed that extracellular Ca2+ can regulate the
function of integrins, including
L2. To date two
distinct classes of Ca2+ binding sites that
differ in their affinity for the metal ion have been characterized
(reviewed in Ref. 37). It has been proposed that a
high-affinity Ca2+ binding site promotes
binding to ligands and that a low-affinity site appears to compete with
a Mg2+ occupied site (37, 38, 39). The
homologous 3 I domain contains the
high-affinity Ca2+ binding site that promotes
ligand binding and the low-affinity Ca2+ binding
site that is inhibitory for ligand binding (37, 40). It
has been reported that mutations in the MIDAS residues in the
3 I domain, which affect
Mg2+/Mn2+ binding, leave
the inhibitory Ca2+ binding site intact
(41), suggesting that the inhibitory low-affinity
Ca2+ binding site is distinct from the MIDAS-like
motif. The recent v3
crystal structure shows that there is an additional cation-binding site
within the 3 I domain adjacent to MIDAS
(designated ADMIDAS) (20). The
Ca2+-binding affinity of the ADMIDAS is unclear.
In the present study, the 2-3-2 and the K174T
mutations make L2
insensitive to the inhibitory effect of Ca2+. One
possible explanation is that these mutations block access of
Ca2+ to the low-affinity
Ca2+ site of the 2 I
domain. The CPNKEKEC sequence and the ADMIDAS-like motif in the
2 subunit are both in the upper face of the
2 I domain and in close proximity to each
other (20). It is interesting to
speculate that removal of Ca2+ from this site and
corresponding addition of Mg2+ to the MIDAS site
may be the basis of the Mg2+/EGTA-induced
activation of LFA-1 (which also correlates with mAb 24 expression
(7)). A dynamic relationship between the B-C loop
sequence CPNKEKEC and ADMIDAS may be an essential part of the
allosteric control of LFA-1, leading to conformational change
associated with increased ICAM-1 binding.
The present study establishes that the CPNKEKEC sequence of the
2 subunit is a part of the mAb 24 epitope (a
reporter for 2 integrin activation) and that,
within this sequence, Glu173 and
Glu175 are particularly critical. These findings
are consistent with a recent report by Lu et al. (16) and
clearly indicate that exposure of the mAb 24 epitope upon
L2 activation
reflects conformational change of the 2 I
domain. In the I domain (20), the CPNKEKEC sequence is
in the loop protruding from the upper face of the globular domain. We
propose that the mAb 24 epitope may be located at the boundary between
the L and 2 subunits.
However, it is unclear whether the exposure of the mAb 24 epitope is
due to changes in the domain-domain interaction or due to
conformational changes in the 2 I domain. It
is possible that the 2 I domain undergoes
conformational changes on activation. We have previously reported that
activating and inhibiting mAbs against the homologous integrin
1 subunit recognize overlapping epitopes
within residues 207–218 of the 1 I domain
(42). These anti-1 mAbs
induce conformational changes in the 1 I
domain that either activate or inactivate the
1 integrins. Thus, changes in domain-domain
interaction and in the conformation of the 2 I
domain may also occur simultaneously on
L2 activation.
The present study establishes that a number of conserved residues in
the 2 I domain are critical for ICAM-1 binding
to L2 and the
exposure of the mAb 24 epitope on activation of
L2. These residues
include several that have not been tested in other subunits
(Ser116, Asp120, and
Asp151 in 2).
Interestingly, all of the critical 2 residues
are clustered in the 2 I domain in a recent
I domain structure (20). If the
2 subunit I domain is indirectly involved in
ICAM-1 binding (43), these 2
residues may contribute to ligand binding through possible
domain-domain interaction, a possible conformational change, and/or
cation binding in the 2 I domain, rather than
direct interaction with ICAM-1. Further studies will be required to
determine how the conformation of the subunit I domain is regulated
by the subunit I domain on activation.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Yoshikazu Takada, Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. E-mail address: takada{at}scripps.edu, or Dr. Tetsuji Kamata at the current address: Department of Anatomy, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160, Japan. E-mail address: kamata{at}sc.itc.keio.ac.jp
3 Abbreviations used in this paper: I, inserted or interactive; CHO, Chinese hamster ovary; MIDAS, metal ion-dependent adhesive site.
Received for publication June 20, 2001. Accepted for publication December 13, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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subunits. EMBO J. 8:3759.[Medline]
L2) integrin. Proc. Natl. Acad. Sci. USA 92:10277. subunit of integrin CR3 (CD11b/CD18). Cell 80:631.[Medline]
21. Cell 101:47.[Medline]
L2 I domain with disulfide bonds reveals functional relationships among integrin domains. Proc. Natl. Acad. Sci. USA 98:2393.L2 is sufficient for strong adhesive function when locked in the open conformation with a disulfide bond. Proc. Natl. Acad. Sci. USA 98:2387.v3. Science 294:339.v1 and v3 integrins by swapping a short diverse sequence of the subunit. J. Biol. Chem. 272:19794.IIb3. J. Biol. Chem. 275:7795.2 integrins for interactions with ICAM-1 and C3bi. J. Biol. Chem. 270:12531.2 (CD18) mutations abolish ligand recognition by I domain integrins LFA-1 (L2, CD11a/CD18) and MAC-1 (M2, CD11b/CD18). J. Biol. Chem. 270:94.2 (CD18) subunit required for L2 and M2 ligand interactions. J. Biol. Chem. 271:23729.1 subunit blocks binding of 51 to fibronectin and invasin but not recruitment to adhesion plaques. J. Cell Biol. 119:913.1 subunit. J. Biol. Chem. 271:20438.2 integrin lymphocyte function associated antigen-1 contains a binding site for ligand intercellular adhesion molecule-1. J. Biol. Chem. 269:12395.2 integrin lymphocyte function-associated antigen-1. Mol. Biol. Cell 11:677. subunit (CD18) in a patient with leukocyte adhesion molecule (Leu-CAM) deficiency. J. Clin. Invest. 85:977.
21 in human platelets. J. Biol. Chem. 275:24560.IIb3 and elicit different functional responses. J. Biol. Chem. 274:16923.3 and 5 subunits contain a metal ion-dependent adhesion site-like motif but lack an I domain. J. Biol. Chem. 272:14236.1 subunit using activating and inhibiting antibodies. J. Biol. Chem. 268:17597.2 subunit: a model for the I-domain. J. Biol. Chem. 275:21514.This article has been cited by other articles:
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Y. Xia, G. Borland, J. Huang, I. F. Mizukami, H. R. Petty, R. F. Todd III, and G |
