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(Journal of Leukocyte Biology. 2001;69:893-898.)
© 2001 by Society for Leukocyte Biology

Shape and shift changes related to the function of leukocyte integrins LFA-1 and Mac-1

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

	ABSTRACT

TOP ABSTRACT GENERAL INFORMATION ABOUT... HOW INTEGRINS ON LEUKOCYTES... CONFORMATIONAL CHANGE IN THE... WHAT CONFORMATIONAL CHANGES... THE UNRESOLVED MATTER OF... THE I DOMAIN AND... REFERENCES

 
Integrin activity on leukocytes is controlled tightly, ensuring that ligand binding occurs only when leukocytes are in contact with their targets. For an integrinlike LFA-1, this ligand-binding activity comes about as a result of increased integrin clustering. Affinity regulation of integrins also plays a role, but the conformational changes giving rise to increased affinity appear to be secondary to clustering. Conformationally altered LFA-1 can be created artificially by deletion of the I domain, which is the key domain involved in ligand binding for many but not all integrins. Although I domain-deleted LFA-1 (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

	GENERAL INFORMATION ABOUT INTEGRINS

TOP ABSTRACT GENERAL INFORMATION ABOUT... HOW INTEGRINS ON LEUKOCYTES... CONFORMATIONAL CHANGE IN THE... WHAT CONFORMATIONAL CHANGES... THE UNRESOLVED MATTER OF... THE I DOMAIN AND... REFERENCES

 
The integrins are a family of adhesion receptors found on the majority of cells in the body including the cells of the immune system. They recognize multiple protein ligands, of which many are components of the extracellular matrix or cell-surface proteins such as members of the immunoglobulin superfamily. The integrins expressed by epithelial cells or keratinocytes, which recognize matrix proteins, bind their ligands in what appears to be a stable manner over time. However the integrins expressed by leukocytes are tightly negatively regulated and do not bind their ligands unless signaled specifically to do so. In this way, leukocytes do not make undesirable adhesive contacts while in the circulation. The integrins are a large family of heterodimeric, transmembrane receptors: The 19 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 this window] [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 this window] [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 ].

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).

	HOW INTEGRINS ON LEUKOCYTES BECOME ABLE TO BIND LIGAND

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Many integrins on resting cells (particularly leukocytes) do not bind ligand particularly avidly, but are activated rapidly and reversibly by diverse cellular agonists. Integrin activation has been the subject of much debate as well as investigation. Basically, there is general agreement that changes that give rise to an active integrin are of two kinds: increased integrin clustering and conformational change. However, there is a lack of agreement as to the order in which these events occur. For example, when T lymphocytes are stimulated, the ensuing inside-out signaling causes the lateral association of integrins on the cell membrane into clusters, thereby increasing the avidity of integrin interaction with ligand [^{14 15 16 17} ]. Clustering is a consequence of signaling by receptors, such as chemokine receptors or the T-cell receptor, and appears to be the initial step in regulation of integrins such as LFA-1 on T lymphocytes.

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.

	CONFORMATIONAL CHANGE IN THE I DOMAIN

TOP ABSTRACT GENERAL INFORMATION ABOUT... HOW INTEGRINS ON LEUKOCYTES... CONFORMATIONAL CHANGE IN THE... WHAT CONFORMATIONAL CHANGES... THE UNRESOLVED MATTER OF... THE I DOMAIN AND... REFERENCES

 
The first crystal structure of an integrin I domain was the Mg²⁺-occupied form of the Mac-1 I domain [¹⁰ ] (Fig. 2) . The Mg²⁺ ion was located at the top of the fold with its octahedral coordination supplied by residues from three different loops that formed the novel MIDAS motif. Subsequently, several other crystal structures of I domains were solved, which contained Mg²⁺ or Mn²⁺ as the metal ion, or were metal-ion-free. All of these new structures differed from the first by altered coordination of the metal ion and by a major shift in the positioning of the C-terminal 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.

	WHAT CONFORMATIONAL CHANGES OCCUR WHEN AN INTEGRIN IS "ACTIVATED"?

TOP ABSTRACT GENERAL INFORMATION ABOUT... HOW INTEGRINS ON LEUKOCYTES... CONFORMATIONAL CHANGE IN THE... WHAT CONFORMATIONAL CHANGES... THE UNRESOLVED MATTER OF... THE I DOMAIN AND... REFERENCES

 
Comparison of the ligand-occupied and -unoccupied I domain structures can give some insight into the structural changes that occur when integrins are "activated" and bound to ligand (Figs. 1 and 2) . There is a reorganization of the MIDAS metal-coordinating residues such that a direct metal bond to an Asp residue is lost, and a direct bond to a Thr is gained. The subtle changes in metal coordination are linked to more extensive secondary and tertiary changes, most notably to a 10 Å swing of the C-terminal 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.

	THE UNRESOLVED MATTER OF AFFINITY REGULATION—THREE OPTIONS

TOP ABSTRACT GENERAL INFORMATION ABOUT... HOW INTEGRINS ON LEUKOCYTES... CONFORMATIONAL CHANGE IN THE... WHAT CONFORMATIONAL CHANGES... THE UNRESOLVED MATTER OF... THE I DOMAIN AND... REFERENCES

 
It remains uncertain how the changes in integrin conformation that are outlined above are actually regulated. One option is that weak binding by ligand to the MIDAS motif might induce the rearrangement of metal-binding coordination, which then has a "knock on" effect, forcing the other conformational changes in the ectodomain of the integrin. These changes would then be mediated across the membrane as happens for other types of receptors. A second option is that affinity changes arise from within the cell and act through the short, cytoplasmic tails of integrins. Control of the binding of cytoplasmic adaptor proteins (reviewed in [³² ]) could cause structural alterations in the short, cytoplasmic tails of integrins [³³ ], having impact on the extracellular integrin domains. Such a change might involve altered spacing between 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.

	THE I DOMAIN AND THE EFFECT OF ITS REMOVAL

TOP ABSTRACT GENERAL INFORMATION ABOUT... HOW INTEGRINS ON LEUKOCYTES... CONFORMATIONAL CHANGE IN THE... WHAT CONFORMATIONAL CHANGES... THE UNRESOLVED MATTER OF... THE I DOMAIN AND... REFERENCES

 
The preceding discussion about integrins and their ligand-binding activities has highlighted the importance of the I domains in integrin function. As indicated, information about these integrin domains in terms of their structure and ligand-binding functions is more advanced than that for any other integrin domain. For an integrin such as LFA-1, the isolated I domain replicates the ICAM-1-binding activity of the intact receptor [³⁴ ]. However, there has been evidence that ligand binding might also involve regions of integrins other than the I domain. Sites contributing to ligand binding have been predicted in the 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.

	ACKNOWLEDGEMENTS

 
B. L. was supported by Celltech Chiroscience plc. We are grateful to David Ferguson for his help with the preparation and Kiki Tanousis for his careful reading of this manuscript.

Received December 27, 2000; revised February 21, 2001; accepted February 22, 2001.

	REFERENCES

TOP ABSTRACT GENERAL INFORMATION ABOUT... HOW INTEGRINS ON LEUKOCYTES... CONFORMATIONAL CHANGE IN THE... WHAT CONFORMATIONAL CHANGES... THE UNRESOLVED MATTER OF... THE I DOMAIN AND... REFERENCES

 

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