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Figure 1 Integrin activation states. This schematic representation shows bent (a), extended (b) andligand-bound (c) forms of an integrin protein, inserted into the plasma membrane of a cell. Theconformational equilibria between each state are regulated either by the binding of cytoskeletal orsignalling factors to the intracellular domains (below the membrane) or by ligand binding (bluerectangles). a, In the bent form, the head region points inwards towards the cell surface, and has lowaffinity for other molecules. b, In the extended form, the head region points away from the surface,allowing it to engage other molecules; the different domains that make up the head region also alter its shape (not shown), increasing the affinity of ligand binding. c, Ligand engagement stabilizes anoutward swing of the �-subunit (right-hand leg) and potentially allows variable leg separation.

of the head are apparent compared with the�v�3 structure, and the likely effect of thesechanges on the overall shape of the intactmolecule can be inferred.

So, what do we learn? The most obviousdifference between the inactive �v�3 andactive �IIb�3 structures is a large outwardswing of a module in the �-subunit known asthe hybrid domain. This domain, which islocated at the ‘neck’ of the integrin, under-goes a reorientation of some 60° relative tothe ligand-binding �I-domain. The �-sub-unit’s PSI domain is observed to lie below thehybrid domain and to act as a rigid connect-ing rod that translates the swing of the hybriddomain into a separation of the leg regions.Thus, the integrin knees are not wobbly butare instead precise articulation points.

These findings strongly suggest that theinactive form of an integrin is bent and thefully active form is unbent, with an alteredarrangement of the head domains. Such amodel fits well with the extended forms ofintegrins observed by electron microscopy7,and with the exposure of particular sites(detected by various antibodies) on the

NATURE | VOL 432 | 4 NOVEMBER 2004 | www.nature.com/nature 27

Cell biology

Adhesion articulatedA. Paul Mould and Martin J. Humphries

A new structure of the ‘head’ region of an integrin protein explains theremarkable vertical extension that enables these molecules to rise tothe task of mediating cell adhesion.

If they are to survive and move, cells mustbe able to stick to their surroundings.Integrin proteins enable a bidirectional

control of cell adhesiveness, by dynamicallycoupling the matrix of molecules found out-side the cell to the cell’s internal ‘skeleton’.All24 members of the integrin family have twosubunits, one from the �-subfamily and onefrom the �-subfamily; each subunit is com-posed of large extracellular and short intra-cellular regions.Integrins work by conveyingshape changes through these subunits —from the intracellular domains, through thecell membrane, to the extracellular region,and vice versa1,2. As adhesion needs to bestrictly controlled to avoid inappropriate cellaggregation or migration, integrins require a highly responsive structure that can exist inlow-affinity (inactive),high-affinity (primed)or ligand-bound (activated) states.

On page 59 of this issue, Xiao et al.3

explain the structural basis of intramolecu-lar signal transduction for one particularintegrin, termed �IIb�3, which is found onplatelets and binds to the blood protein fibrinogen. In doing so, the authors revealthe core mechanism that controls cellularadhesiveness.

The first integrin crystal structure (of theextracellular domains of integrin �v�3, areceptor for the extracellular-matrix proteinvitronectin) revealed an anthropomorphicmolecule composed of a ligand-binding

‘head’ and two long ‘legs’4. Each subunit (�and �) contributed one of the legs, and bothsubunits combined to form the head. Inter-estingly, the legs were highly bent at theirknees,such that the head was very close to thelower legs (Fig. 1a). In this structure, some ofthe modules making up the knee regionswere unresolved (including the so-called PSIdomain), suggesting that these regions werehighly flexible.

Although a huge advance for the field,these findings presented a conundrum: howcan shape changes be transduced from anintegrin’s head to its legs, or from its legs to itshead, particularly given that the knees arewobbly-looking? A controversy immediatelyarose as to whether the bent structure wasphysiologically relevant, and if so whether itrepresented a low-affinity or a high-affinitystate5. Subsequently, several studies showedthat the bent form can undergo a dramaticstraightening to an extended form (Fig.1b)6–8.

Now Xiao et al.3 have crystallized a frag-ment of the head region of integrin �IIb�3 incomplex with an antibody fragment andwith one of three different compounds thatmimic its natural ligand (fibrinogen), two ofwhich are used in the clinic for treating clot-ting in the coronary artery. These peptide-bound structures (which look very similar)represent the ligand-activated state (Fig. 1c).Although these structures lack most of theleg regions,major alterations in the structure

Thigh

Propeller

Cap

Ligand

βl-domain

Hybrid

PSIdomain

LM A

R G D

Figure 2 The complex between a macromolecularligand and the integrin head domains. The cap, propeller, �I, hybrid and PSI domains arepresent in the structure described by Xiao et al.3.The position of the thigh can be inferred from a previous structure4. Ligand binds across bothsubunits (� on the left; � on the right), with the RGD (arginine–glycine–aspartate) sequencewithin the ligand binding at the junction betweenthe �- and �-subunits. This sequence alsocoordinates the cation present in the site knownas MIDAS (metal-ion-dependent adhesion site;M) of the integrin. Secondary sites in the ligandcontact the �-subunit cap region. Sites in theintegrin that are known as ADMIDAS (adjacentto MIDAS, A) and LIMBS (ligand-induced metal-binding site, L) also bind cations and control the protein’s activation state. Ligand bindingstabilizes an outward swing (arrow) of therigidly connected hybrid and PSI domains, andthereby separates the integrin legs (not shown).

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Seemingly unprecedented events inhuman lifetimes can be business-as-usual when viewed on longer time-

frames. But that’s not always recognized.For example, management strategies in the United States that seek to restore landscapesto the conditions that prevailed at the time offirst European contact often fail to considerthe events that created those conditions.Thisshort-sightedness is particularly evident inthe area of wildfire management.

On page 87 of this issue, however, Pierce et al.1 provide a long-term perspective on theeffects of fire in ‘low-elevation’ pine forests in the western United States. These dry, openforests lie above the steppe and grasslands thatoccupy most intermontane basins in theRocky Mountains; in more moist settings athigher elevations, they are replaced by closedmontane and subalpine forests. The low-elevation forests have been extensively modi-fied by human activities, and there is intensedebate about the appropriate action needed torestore them to their prehistoric state2.

In the past 15 years, the western UnitedStates has experienced some extreme fires,notable for their size and severity.The annualcosts of fire suppression now exceed $1.6 bil-lion, and the ceiling seems nowhere in sight3.In the absence of large fires during most ofthe twentieth century, many forests havebecome filled with a dense understorey ofshrubs and small trees that provide ‘ladderfuels’ that set the crowns of trees alight: thesecrown fires are the most destructive types ofwildfire.The Healthy Forest Restoration Act4,signed into law by President George W. Bushin 2003,purportedly seeks to redress the eco-logical effects of fire suppression by estab-lishing programmes of aggressive thinning,deliberate burning, and replanting to createopen conditions. For local communitieswith economies based on timber extraction,this law is good news; for environmentalists,it is a travesty that limits scientific analysisand public participation in decision-makingand policy.

But are the fires of the past 15 years

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Figure 1 Slide show. This slope failure occurred following rainfall on melting snow in 1997, in an areaof the South Fork Payette River, Idaho, that was severely burned in 1989. Herbs and low shrubs hadregrown after the fire. But the decay of tree roots probably caused the fatal weakening of the slope.

Land management

Forests, fires and climateCathy Whitlock

A new analysis of the effect of climatic variation on forest fires goesback several thousand years. One take-home message is that a one-size-fits-all forest management strategy is, literally, short-sighted.

Manchester M13 9PT, UK.e-mail: martin.humphries@man.ac.uk1. Carman, C. V. & Springer, T. A. Curr. Opin. Cell Biol. 15,

547–556 (2003).

2. Mould, A. P. & Humphries, M. J. Curr. Opin. Cell Biol. 16,

544–551 (2004).

3. Xiao, T., Takagi, J., Coller, B. S., Wang, J.-H. & Springer, T. A.

Nature 432, 59–67 (2004).

4. Xiong, J.-P. et al. Science 294, 339–345 (2001).

5. Liddington, R. C. Structure 10, 605–607 (2002).

6. Beglova, N. et al. Nature Struct. Biol. 9, 282–287 (2002).

7. Takagi, J., Petre, B. M., Walz, T. & Springer, T. A. Cell 110,

599–611 (2002).

8. Chigaev, A. et al. Biophys. J. 85, 3951–3962 (2003).

9. Mould, A. P. et al. J. Biol. Chem. 278, 17028–17035 (2003).

10.Xiong, J.-P. et al. Science 296, 151–155 (2002).

G.A

.ME

YE

R

hybrid domain and knee regions that occurswhen integrins are in a high-affinity state6,9.Movement of the hybrid domain is also linkedto changes in the shape of the neighbouring�I-domain. These changes allow the headregion to undergo a metaphorical facelift so that ligands can bind with higher affinity.The major recognition site for ligands,includ-ing the classical arginine–glycine–aspartateamino-acid sequence found in many extra-cellular proteins, is in a groove between the �- and �-subunits (as shown10 for integrin�v�3); however, the new structure reveals alarger subregion of the �-subunit that pro-vides a secondary ligand-binding site (Fig.2).

Although many of the long-standingmysteries of integrin structure have nowbeen solved, several gaps remain. Forinstance, there is still a need to obtain a co-crystal between an integrin and a larger(macromolecular) ligand fragment, so thatthe ligand-binding pocket can be completelydefined. Furthermore, nine integrins con-tain an additional ligand-binding region,called the �A- or I-domain, inserted into thehead. Solving the structure of one of theseintegrins would explain the atomic basis ofcommunication between this domain andthe �I-domain.

In addition, the paper by Xiao et al.3 raisesseveral specific questions. First, given thatdifferent �IIb�3-binding therapeutic peptidesstabilized similar integrin conformations,how is the binding of different ligands to integrins converted into a graded signalinside the cell? One possibility is that variable‘outside-in’ signalling is determined by dif-ferences in the kinetics of leg separation indifferent ligand–integrin complexes. Alter-natively, there might be situations in whichdifferent ligands stabilize conformationswith subtle differences in the angles of thejoints (Fig.1c).Determining the atomic basisof knee flexing will help in this regard.Second, to what extent are the same confor-mational changes involved in inside-out andoutside-in signal transduction? In particular,to what extent does inside-out signallingcause unbending or the hybrid domain toswing out?

Finally, inappropriate integrin–ligandinteractions contribute to aberrant celladhesion in many diseases, including infla-mmation, the blockage of blood vessels byblood clots, and tumour progression. Canthe availability of structures of integrin �IIb�3

in complex with therapeutic peptides aid therational design of drugs to target other integ-rins? Perhaps: it is certainly likely that thestrategy of crystallizing a truncated form of�IIb�3 could also be used for other integrins(including �4�1 and �v�3) that are majortherapeutic targets in rheumatoid arthritis,multiple sclerosis and cancer. ■

A. Paul Mould and Martin J. Humphries are at theWellcome Trust Centre for Cell-Matrix Research,Faculty of Life Sciences, University of Manchester,

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