Leukocyte Adhesion Laboratory, Imperial Cancer Research Fund, London, England
Correspondence: Dr. N. Hogg, Leukocyte Adhesion Laboratory, Imperial Cancer Research Fund, Lincoln’s Inn Fields, London WC2A 3PX, England. E-mail: hogg{at}icrf.icnet.uk
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I-LFA-1) cannot bind ligand, it is able to signal constitutively
into the cell. One measure of this signaling activity is the ability of
I-LFA-1 to activate ß1 integrins on the same T lymphocyte.
Leukocytes use LFA-1 to migrate across the endothelium. Active ß1
integrins may be required subsequently to bind the matrix proteins
encountered by leukocytes as they continue their voyage into the tissue
interior.
Key Words: integrin structure • integrin activation • I domain
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subunits and 8 ß
subunits combine to form 25 different integrins [1
].
These integrins are expressed in different combinations and in a
cell-type-specific manner. For example, the CD11/CD18 family consists
of four integrins, lymphocyte function-associated antigen-1 (LFA-1),
Mac-1, p150,95, and dß2, which share a common ß2 subunit and are
restricted to leukocytes [2
].
Over the past few years, much structural information about integrins
has become available. Electron microscopy studies show the N-terminal
portions of both subunits to contribute to a globular "head"
domain, connected to the cell membrane by two stalks, which correspond
to the C-terminal portions of the extracellular domains
[3
, 4
] (Fig. 1
). At the N-terminus of all integrin subunits are 7 homologous,
60 amino-acid repeats, which have been predicted to fold into a
ß-propeller structure with seven "blades" formed by ß-sheets
that are named W1-7 [8
]. In addition to this
ß-propeller domain, a subset of nine subunits incorporates an
independently folding domain of approximately 200 amino acids, which is
termed the I (inserted) domain (reviewed in [9
]). The I
domain is the only integrin domain for which detailed, structural
information is available currently. The crystal structures of I domains
from four integrins are known and reveal a dinucleotide-binding fold
composed of a central ß-sheet surrounded by seven helices
(Fig. 2
). The subunit I domain is predicted to sit on "top" of the
putative ß-propeller domain, inserted into a loop between ß-sheets
2 and 3 (W2,3) [8
].
 View larger version (42K): [in a new window] |
Figure 1. Schematic diagram of integrin domain structure and hypothetical model
of integrin allostery adapted from Emsley et al.
[5
]. All integrin subunits contain a sevenfold
repeat region at their N-terminus, which has been modeled as a
ß-propeller fold (shown in red, numbers refer to the repeats W1-7).
In those integrins that contain an I domain, this domain is inserted
between repeats 2 and 3, facing the "top" of the putative
ß-propeller (-I, orange; the C-terminal 7 helix is shown in
yellow). In integrin ß subunits (blue), the N-terminal PSI
domain (aqua) is so named because of homology between plexins,
semaphorins, and integrins [6
]. The ßI-like domain is
predicted to adopt a fold similar to the I domain. In this model,
the integrin is in equilibrium between two quaternary conformations,
one of low affinity and one of high affinity. In the low-affinity
state, the I domain is held in the closed conformation by its
contacts with the ß-propeller domain and potentially by contacts with
the ßI-like domain, which is predicted to contact the ß-propeller
domain near repeat W3. Ligand binding (collagen peptide, green) may
induce conformational changes in the I domain, altering the position of
the C-terminal helix 7, which, in turn, could break the contacts
with the ß-propeller and the ßI-like domains. The conformational
changes of the integrin ectodomains are likely to be propagated across
the membrane, leading to signal transduction. Integrins can also be
activated to bind ligand by signaling from inside the cell. In this
case, a change in the conformation or configuration of the cytoplasmic
tails could be propagated across the membrane, altering the relative
orientation of the ß-propeller and the ßI-like domain. This would
release the intersubunit restraints on the I domain, allowing the
movement of the C-terminal helix 7 and the change in metal
coordination, thus creating the open conformation that binds ligand
with higher affinity. (This figure is reproduced with permission from
[7
].)
|
 View larger version (43K): [in a new window] |
Figure 2. The crystal structure of the I domain from the integrin M subunit
[10
]. The I domain consists of a dinucleotide-binding
fold with a central ß sheet surrounded by seven helices. The C
terminal 7 helix undergoes a major shift in position between the
"open" or ligand-bound conformation of the I domain, which is
represented here, and the "closed" or inactive form. The direction
of this movement is indicated by the open arrow. A specialized,
metal-binding MIDAS motif binds a Mg2+ or
Mn2+ ion. Ligand is considered to bind at the
top of the domain with the metal ion of the MIDAS forming the center of
the binding site [5
].
|
I domain and is known as the
ßI-like domain [10
, 11
]. The ßI-like
domain is predicted to contact the ß-propeller domain of the
subunit at the boundary between repeats 2 and 3 (W2,3)
[12
, 13
]. Thus, I and I-like domains
associate with the ß-propeller domain at a similar location: The I
domain loops out from the top of the ß-propeller, whereas the
ßI-like domain meets the side of the ß-propeller. Therefore, both I
domains are associated closely, with the bottom of the I domain in
contact potentially with the top of the ßI-like domain.
There are at least two types of divalent cation-binding motifs in all
integrins. The subunit I domain contains a unique, metal-binding
site termed the metal ion-dependent adhesion site (MIDAS), which
coordinates Mg2+ and
Mn2+ binding to the integrin. The conserved,
I-like domain of the ß subunit also contains a MIDAS-like motif for
which the divalent cation specificity has yet to be established. In
addition, the putative ß-propeller domain of the subunit contains
three (for I domain-containing integrins) or four (for non-I
domain-containing integrins) cation-binding motifs, which are deemed to
bind Ca2+. Thus, for each type of integrin,
there are five individual, divalent cation-binding sites. All
integrin-ligand interactions are dependent on divalent cations, and the
role of Mg2+/Mn2+ bound
to the I domain is understood best (see below).
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However, in other circumstances, signaling causes integrins to undergo
conformational changes leading to higher affinity forms. For integrins
such as IIbß3 on platelets and a second ß3 integrin, vß3,
agonists delivering inside-out signals appear to cause an affinity
alteration in these integrins. The conformational change undergone by
vß3 has been detected by the increased binding of WOW, a useful
monoclonal antibody (mAb), which incorporates the RGD (Arg, Gly, Asp)
motif that integrins recognize in many matrix-binding proteins
[18
, 19
]. Recently, the first evidence has
been published that LFA-1 might also undergo agonist-induced,
inside-out affinity regulation. Thus, the chemokines, SLC, ELC, and
SDF-1, can cause a transient increase in LFA-1 affinity as
well as inducing clustering [20
]. The most detailed
information about the nature of the conformational change that causes
the increase in the affinity of ligand binding comes from the analysis
of the I domains.
|
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7 helix. In the first Mac-1 I domain structure,
the octahedral coordination of the Mg2+ ion was
completed by a Glu side-chain from a neighboring I domain molecule in
the crystal. This observation led to the speculation that this first
Mac-1 I domain structure mimicked a ligand-receptor complex and that
natural ligands, most of which possess short, acidic peptides as
binding motifs, would coordinate the I domain via the MIDAS motif
[21
]. A major breakthrough last year was the crystal
structure of the I domain from 2ß1 in complex with ligand in the
form of a collagen tripeptide [5
] (reviewed in
[7
, 22
]). This structure confirmed the
predictions of Liddington and colleagues [21
]. The
conformation of the 2 I domain bound to the collagen peptide was the
same as that of the first Mac-1 I domain structure where the MIDAS
metal ion was coordinated by a Glu residue from a neighboring I domain.
Secondly, as expected, the metal ion in the 2 I domain-ligand
complex was coordinated by a Glu residue, which, in this situation, was
from the collagen peptide. In addition, the I domain-collagen peptide
structure provided definite evidence for a central and direct
structural role for the metal ion in ligand binding.
Three biochemical studies have linked the two crystallographically
defined conformations (termed "closed" and "open") of the I
domain to low- and high-affinity states, respectively. Arnaout and
colleagues [23
] introduced two mutations into the Mac-1
I domain that are predicted on structural grounds to destabilize the
closed conformation. The resulting proteins exhibited increased
affinity for some Mac-1 ligands. Using a theoretical approach,
Springer and colleagues [24
] have designed
computationally Mac-1 I domains stabilized in the open or closed
conformation. The computational approach focused on hydrophobic core
residues, which were allowed to mutate. The resulting I domains had
many of the predicted features in terms of ligand binding. Those
stabilized in the open conformation showed improved ligand binding,
both as isolated domains as well as within intact, heterodimeric
Mac-1. More recently, Arnaout and colleagues [25
] have
concentrated on the role of the N and C termini of the Mac-1 I domain
in determining ligand-binding affinity. By deleting an N-terminal
extension, a form of the I domain was created, which showed low
affinity for physiological ligands and crystallized in the closed
conformation. Conversely, deletion or substitution of an invariable
C-terminal Ile (I316) resulted in a high-affinity Mac-1 I
domain, which crystallized in the open conformation. In the closed I
domain conformation, the critical Ile residue in the C terminal 7
helix slots into a hydrophobic pocket and is displaced from it in the
open structure. The working model is that this Ile
(I316)-based switch controls conformation allosterically
and therefore ligand-binding affinity by interacting with sequences N
terminal to the I domain. Taken together, these three
biochemical studies are convincing proof of the importance of
conformational alterations in the I domain in the regulation of the
ligand-binding activity of integrins.
|
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7 helix (see previous section). Thus,
structural transitions propagate from the "top" of the domain,
where ligand binds, to the opposite pole near where the I domain
interfaces with the rest of the subunit/ß-propeller. Similar
conformational alterations on ligand binding were found recently in a
nuclear magnetic resonance (NMR) study using the LFA-1 I domain and its
ligand intercellular adhesion molecule-1 (ICAM-1) [26
].
Other evidence indicates the lower surface of the conformationally
pliable I domain to be important for ligand binding. Mutations that
lead to constitutive activation of Mac-1 map to this lower surface
[27
], and the crystal structure of the LFA-1 I domain in
complex with the inhibitor lovastatin shows the inhibitor to bind in a
hydrophobic pocket at the bottom of the domain near the C-terminal
helix [28
]. Taken together, these results implicate the
bottom of the I domain as a region for allosteric control of ligand
binding. Obviously, the I domain operates within the context of the intact integrin, but the current lack of structural information about the rest of the heterodimer precludes detailed knowledge about further structural changes that occur upon ligand binding. For LFA-1, there is evidence that, upon integrin activation, the I domain undergoes quaternary alteration with respect to the rest of the integrin [29 ]. Activation is also associated with epitope changes that map to a cysteine-rich region of the ß subunit [30 , 31 ], suggesting movement throughout a conformationally flexible receptor.
What happens to integrins that do not have an subunit I domain? For
IIbß3 or 5ß1, ligand binds to the upper surface of the
putative ß-propeller and also to the I-like domain of the ß
subunit. Electron microscopic studies show that binding of the RGD
ligand mimetic to the ßI-like domain of IIbß3 causes the and
ß subunits to spring apart [4
] (see Fig.1
). In fact,
the ligand-binding areas of the higher affinity and ß subunits
become separated by a distance of 7 nm. Thus, ligand binding by
integrins might occur by the correct positioning of sites that then
allow access to two appropriate motifs within the ligand. More
information about how integrins bind their ligands awaits completion of
the next big challenge of the crystallization of a complete integrin or
at least the globular head, which contains the essential ligand-binding
sites.
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and
ß subunits, suggesting a "springing of a hinge"-type model. A
third possibility is that the high- and low-affinity forms of integrins
are in equilibrium with one another with the low-affinity form
dominating. The presence of clustered integrin with multiple
low-affinity interactions with integrin would provide the forum for
capture and stabilization of the low-abundance, high-affinity forms. If
this scenario is correct, then an adhesion contact point would be
expected to build up the component of high-affinity integrin over time
and, by so doing, increase the strength of adhesion. In fact, if
integrins are truly versatile, bidirectional receptors, then all three
of the situations discussed above may be relevant. |
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L subunit [35
] and the ß2 subunit
[36
, 37
], and obviously, non-, I
domain-containing integrins also bind ligand.
To address some of these issues, we have removed recently the I domain
from LFA-1 and investigated the properties of this I domain minus
(I) integrin [38
]. The first observation was that the
I domain of LFA-1 is essential for ligand binding, because I-LFA-1
showed no detectable ligand-binding activity to ICAM-1 or ICAM-3. This
finding does not exclude the possibility of additional binding site(s)
for an integrin like LFA-1 but indicates that the I domain must be in
place for any other site to be operational. It may be that putative
additional sites, although participating in ligand binding in intact
LFA-1, are not sufficiently independent to sustain ligand
binding in the absence of the I domain and must cooperate with it for
stable interaction with ligand. The removal of the I domain from LFA-1
has been repeated in a second study with similar findings of abrogation
of ligand binding [39
]. For a second integrin, Mac-1,
removal of the I domain eliminated binding to its ligands fibrinogen
and bovine serum albumin (BSA), but some binding activity remained to
ligands iC3b and factor X [39
]. These results hint at
the possibility that the ligand-binding features of I
domain-containing integrins can extend beyond their I domains.
Although I-LFA-1 had lost its capacity to bind ligand, a significant
feature was the enhanced expression of seven mAb epitopes, which are
associated with active LFA-1 [38
]. No other tested mAb
epitopes (outside the I domain) were altered significantly in
expression on I-LFA-1. This result suggested that the removal of the
I domain had converted an inactive integrin to a constitutively active
one, which was, however, unable to bind ligand having lost its major
ligand-binding site. The epitopes for four of these "activation"
markers have been mapped to the cysteine-rich region of the ß2
subunit [30
, 40
]. The conjecture is that
the quaternary change, which the I domain undergoes normally during
activation of LFA-1, is mimicked here by complete removal of the I
domain. The expression of the activation epitopes, including several
located in the ß2 subunit stalk, implies that I-LFA-1 resembles
the high-affinity form of this integrin.
Although I-LFA-1 could no longer bind ligand, it was of interest to
know whether the "active" conformation of I-LFA-1 was correlated
with any signal transduction into the cell. The signaling capabilities
of LFA-1 have been tested frequently by analyzing LFA-1 as a
costimulator in conjunction with other membrane receptors. This has
made it difficult to resolve whether LFA-1 can signal independently of
other cell-membrane receptors. However, when LFA-1 is targeted
directly, with anti-LFA-1 mAbs or with its ligand ICAM-1, it does
transmit signals and influences the activity of ß1 integrins on the
same leukocyte surface, an activity termed "cross talk"
[41
]. We found that the I-LFA-1-expressing cells had
enhanced constitutive ß1 integrin activity because of signaling by
I-LFA-1 [38
]. Where might this cross-talk activity be
important? During leukocyte movement from the circulation into sites of
inflammation, LFA-1 is used by lymphocytes in their transmigration
across the vascular endothelium, and the switching on of ß1 integrin
function by LFA-1 might be essential for leukocyte migration within the
subendothelial matrix. How integrins cross talk to other integrins has
not been fully defined yet in molecular terms. So far, only two
signaling proteins have been implicated in integrin cross talk: protein
kinase C (PKC) in cross talk from 5ß1 to 2ß1
[42
] and calmodulin-dependent kinase II in cross talk
from vß3 to 5ß1 [43
]. Presently, it is not
known whether these kinases are relevant to LFA-1-mediated cross talk.
In the case of LFA-1, cross talk does not produce an affinity increase
in ß1 integrins [38
]. Instead, ß1 integrins on
I-LFA-1-expressing cells are expressed constitutively in a highly
clustered state. That cytochalasin D blocked the enhanced ß1 integrin
activity of I-LFA-1-expressing cells implies that the cytoskeleton
or processes dependent on the cytoskeleton are targets of
I-LFA-1-mediated signaling. These findings suggest that active LFA-1
might reorganize the cytoskeleton in a manner that instructs other
integrins to link into it, a process that is thought to happen during
migration of fibroblasts (reviewed in [44
]). Another
possibility is that active LFA-1, through competition for
cytoskeletal-associated proteins, might cause other integrins to become
untethered from the cytoskeleton, making them more mobile in the plane
of the membrane and leading to an increase in clustering.
Alternatively, the absence of the I domain on LFA-1 might alter the
association with other membrane proteins that could control the
clustering of ß1 integrins. The phenomenon of integrin cross talk
shows that integrins do not function in isolation on the leukocyte cell
membrane and that their signaling activity can affect other types of
integrin on the same cell. It is also possible that these down-stream
activities of integrins have an impact on other classes of proteins.
This last option remains to be explored.
Received December 27, 2000; revised February 21, 2001; accepted February 22, 2001.
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IIbß3 integrin conformation and oligomerization Biochemistry 38,14461-14474[Medline]2ß1 Cell 101,47-56[Medline]-subunits into a ß-propeller domain Proc. Natl. Acad. Sci. USA 94,65-72 subunit of integrin CR3 (CD11b/CD18) Cell 80,631-638[Medline]4 integrin clustering by immobilized chemokines stimulates leukocyte tethering and rolling on endothelial vascular cell adhesion molecule 1 under flow conditions J. Exp. Med. 192,495-506IIbß3 J. Cell Biol. 141,1685-1695Mß2 J. Biol. Chem. 271,29953-29957Lß2, CD11a/CD18) heterodimer formation and ligand binding FEBS Lett 440,414-418[Medline] IIb-subunit Proc. Natl. Acad. Sci. USA 97,1450-1455 subunit contains an ICAM-1 binding site in domains V and VI EMBO J 13,1790-1798[Medline]Lß2 and Mß2 ligand interactions J. Biol. Chem. 271,23729-23736Mß2 ligand recognition J. Leukoc. Biol. 64,767-773[Abstract] subunit Proc. Natl. Acad. Sci. USA 94,3156-31614ß1- and 5ß1-mediated function J. Cell Biol. 138,1437-14475ß1 integrin activates the 2ß1 receptor via the 5 subunit cytoplasmic domain and protein kinase C J. Immunol. 153,2222-2233[Abstract]vß3 suppression of calcium/calmodulin-dependent protein kinase II regulates 5ß1 function J. Cell Biol. 145,889-897This article has been cited by other articles:
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