electronic effects can influence both AFMand STM images.

Scanning microscopes will be vital ele-ments in the atom engineer’s toolbox, andour understanding of their operation con-tinues to advance rapidly. We can look for-ward to finding a sound basis not only forimaging and spectroscopy of single atoms,but also their manipulation and the creationof wholly novel nanostructures. ■

John B. Pethica is in the Department of Materials,University of Oxford, Parks Road, Oxford OX1 3PH,UK.Russ Egdell is in the Inorganic Chemistry

Laboratory, University of Oxford, South Parks Road,Oxford OX1 3QR, UK.e-mails: john.pethica@materials.ox.ac.ukruss.egdell@chem.ox.ac.uk1. Barth, C. & Reichling, M. Nature 414, 54–57 (2001).2. Giessibl, F. J. Science 267, 68–71 (1995).3. Bobrov, K., Mayne, A. J. & Dujardin, G. Nature 413, 616–619

(2001).4. Libuda, J. et al. Surf. Sci. 318, 61–73 (1994).5. Chang, C. C. J. Appl. Phys. 39, 5570–5573 (1968).6. Renaud, G., Villette, B., Vilfan, I. & Bourret, A. Phys. Rev. Lett.

73, 1825–1828 (1994).7. Gillet, E. & Ealet, B. Surf. Sci. 273, 427–436 (1992).8. Yokoyama, K., Ochi, T., Sugawara, Y. & Morita, S. Phys. Rev.

Lett. 83, 5023–5026 (1999).9. Foster, A. S., Barth, C., Shluger, A. L. & Reichling, M. Phys. Rev.

Lett. 86, 2373–2376 (2001).

(residues 35–139) binds to SicP in an extend-ed, non-globular conformation in which itssecondary structures (a-helices and b-strands) remain intact (Fig. 1). The groovesand crevices in SicP that make intricate con-tact with the SptP fragment are probably thebasis for type III chaperone specificity. Theamphipathic helix in the chaperone wasthought to be important in protein–proteininteractions7, but it has no direct interactionwith the effector and is not involved in chaper-one dimerization. So it is likely to be a generalstructural feature of these chaperones.

The protein’s structure was crystallized asa crossed-over SicP–SptP 4:2 complex (Fig.1). Luo et al.8 have used light scattering toshow that other type III chaperone–effectorcomplexes exist in a 2:1 stoichiometry. In thecrystal structure reported here, there is a potential domain swap involving helix 5.This domain swap may occur during thecrystallization process and subsequently bestabilized by a disulphide bond that isobserved in the crystal structure but not inthe purified complex before crystallography.So, as the authors point out, it is possible thatthe biologically relevant complex has a 2:1stoichiometry.

Type III effector proteins have one ormore functional domains. For a protein totravel through the secretion needle, eachdomain must physically be able to fit insidethe cylindrical cavity of the channel. If thedomain is wider than the secretion tube, itcan’t pass through it. On the evidence of itspreviously solved crystal structure, SptP hastwo domains. The diameter of the secretionchannel has been estimated to be about 30 Å

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NATURE | VOL 414 | 1 NOVEMBER 2001 | www.nature.com 29

Many bacterial pathogens use a com-plex secretion system to inject pro-teins, known as ‘effectors’, into target

host cells. This process is part of a molecularsubversion tactic that allows bacteria to per-sist and cause disease, and requires specificmolecular chaperones. Our understandingof how these chaperones work is boosted by a report on page 77 of this issue1, whereStebbins and Galán describe a chaperone–effector complex from the type III proteinsecretion system used by many bacterialpathogens, including Salmonella.

Cellular life requires that linear poly-peptide chains fold into functional three-dimensional domains, which are used tobuild up larger supramolecular structures.However, the exposure of hydrophobic surfaces during protein folding can lead tothe non-productive aggregation of macro-molecules. To combat this problem, cells usemolecular chaperones, which, like humanchaperones, have the job of preventing theircharges (in this case proteins) from makingunacceptable non-productive interactions,while encouraging them to encounter andinteract with acceptable partners2. To bringabout the folding, assembly and secretion of effector proteins, pathogenic bacteria usespecific chaperones, some of which func-tion by donating missing steric informationto couple folding3 with the simultaneous capping of interactive surfaces4.

Various bacterial pathogens produce asurface appendage known as the type IIIsecretion apparatus. The type III structures(injectosomes) provide a means of squirtingthe effector proteins into cells; in turn, theseproteins manipulate various cellular pro-cesses to the advantage of the bacterium5.Type III secretion appendages6 have a cylin-

drical structure like the needle of a syringe,and translocation of effector proteinsthrough them requires specific chaperones7.

Stebbins and Galán1 now present thecrystal structure of a type III chaperone(SicP) bound to the amino-terminal domainof its effector protein (SptP). The SicP pro-tein is a kidney-bean-shaped homodimerwith much of its solvent-accessible surfacecovered with clusters of hydrophobic resi-dues. These hydrophobic highways providethe interface where SptP binds. SptP

Cell biology

Bacteria thread the needleCraig L. Smith and Scott J. Hultgren

When bacteria attack another organism, one of the first steps is theinjection of ‘virulence effector proteins’ into its cells. Two of the mainplayers in such a system have been caught in action.

Figure 1 Formation of the complex between SicP (the chaperone) and SptP (the Salmonella effectorprotein). The non-globular, chaperone-binding domain of SptP (yellow and red) wraps around a SicP homodimer (blue). The crystal structure reported by Stebbins and Galán1 is a 4:2 complex,created by the combination of two 2:1 SicP–SptP complexes.

SptP (residues 35–139)

SicP homodimer

SicP–SptP complex

© 2001 Macmillan Magazines Ltd

(ref. 6). The dimensions of the SptP domainsare approximately 74242239 Å, whichparadoxically seem too big to fit inside thesecretion channel.

The structure presented by Stebbins andGalán explains at least part of this paradox.The SicP chaperone binds to the amino-terminal domain of SptP to keep it in a semi-unfolded conformation that would be able tofit into the secretion tube. But the other twodomains not bound by the chaperone pre-sumably exist in a folded state, and so wouldbe too large to fit into the secretion tube.Indeed, Luo and colleagues’ biochemicalwork8 on the chaperone–effector complexesthey studied (SigE–SigD and CesT–Tir) suggest that the domains not bound to thechaperone remain folded. So either the channel has to get bigger or the domains haveto unravel into a linear conformation.

Figure 2 provides an outline of how Sal-monella injects effector protein into a cellthat it is attacking. But we are still left withplenty of questions, especially as to how aneffector protein is targeted to and travelsthrough the injectosome and into the cell.The amino-terminal 35 amino acids wereproteolytically cleaved before crystalliza-tion, suggesting that this region is also notprotected by the chaperone. The regioncould be part of a motif that facilitates target-ing of the complex to the type III secretionsystem, consistent with reports for othertype III effectors in Yersinia5,9. After targetingof the complex to the secretion tube, what isthe mechanism of chaperone dissociation,and how are the folded domains of SptPunfolded so that it can move through theneedle complex? Is ATP needed for dissocia-tion of the SicP chaperone and/or to unfoldthe effector? How does SptP achieve its activeconformation once it has been injected intothe cell being attacked (in the absence of itschaperone)? Indeed, might effector proteinsnot even travel through the needle, butinstead somehow pass into the host cell in analready folded state?

Stebbins and Galán’s structure1 is thefirst of its kind to be solved, and providesinsight into type III secretion systems in general. It also reveals fundamental cluesabout chaperone function and mechanismof action, and will influence our understand-ing of the basic principles of protein foldingand pathogenesis. ■

Craig L. Smith and Scott J. Hultgren are in theDepartment of Molecular Microbiology, WashingtonUniversity School of Medicine, Box 8230, 660 SouthEuclid Avenue, St Louis, Missouri 63110, USA.

e-mails: smith@borcim.wustl.edu hultgren@borcim.wustl.edu1. Stebbins, C. E. & Galán, J. E. Nature 414, 77–81 (2001).2. Ellis, R. J. Semin. Cell Dev. Biol. 11, 1–5 (2000).3. Sauer, F. G. et al. Science 285, 1058–1061 (1999).4. Barnhart, M. M. et al. Proc. Natl Acad. Sci. USA 97, 7709–7714

(2000).5. Hueck, C. J. Microbiol. Mol. Biol. Rev. 62, 379–433 (1998).6. Kubori, T. et al. Science 280, 602–605 (1998).7. Wattiau, P., Woestyn, S. & Cornelis, G. R. Mol. Microbiol. 20,

255–262 (1996).8. Luo, Y. et al. Nature Struct. Biol. (2001);

http://dx.doi.org/10.1038/nsb717.9. Smith, C. L., Khandelwal, P., Kellikuli, K., Zuiderweg, E. R. P.

& Saper, M. A. Mol. Microbiol. (in the press).

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NATURE | VOL 414 | 1 NOVEMBER 2001 | www.nature.com 31

Figure 2 Model of chaperone-assisted type III secretion in Salmonella. a, Creation of the complex between the chaperone (SicP, blue) and thevirulence effector protein (SptP, black) to be injected into the target cell. b, The complex docks onto the type III secretion apparatus (red),depicted here as lying between the bacterium’s inner and outermembranes, with a ‘needle’ passing into the plasma membrane of

the cell under attack. c, Powered by ATP, the effector protein passesthrough the needle into the cell. d, The protein folds into its active form inside the cell, and subverts cellular function to the bacterium’sadvantage. The SicP–SptP structure produced by Stebbins and Galán1

helps clarify events at the beginning of this sequence, but later eventsremain unclear.

Creation of chaperone–effectorcomplex inside the bacterium

a b d

Effectorprotein(SptP)

Plasma membraneof cell under attack

Bacterialmembrane

Docking of complex ontotype III secretion system

c ATP-driven translocation of effectorprotein through the ‘needle’

Folding of the protein intoits active form

Chaperone(SicP)

‘Needle’

ATPase

During the past 40 years, understandingquantum systems involving many particles has been one of the main

goals of theoretical physics. This kind ofresearch is designed not to work out the laws of interactions between particles, but,assuming that these interactions are alreadyknown, to calculate their effects on a systemof n particles. A system where n is large constitutes the ‘many-body problem’, andcan exhibit rich behaviour, including phasetransitions, superconductivity and Bose–Einstein condensation. The impact of exactlysolvable theoretical models on research into these systems is undeniable. With fewexceptions, previous exact solutions haveapplied only to one-dimensional systems.But writing in Physical Review LettersDukelsky et al.1 introduce a new family ofexactly solvable theoretical models dealingwith quantum many-body systems in anynumber of dimensions: one, two, three oreven more.

A wide range of many-body systems hasbeen studied, with varying numbers of particles. For example, systems of nuclei(nö102 nucleons) are important in nuclearphysics, and atomic and molecular physicsdeal with systems involving nö102 elec-trons, whereas mesoscopic (nö102–106)and macroscopic (nö1023) systems arise incondensed-matter physics. Real systems areusually extraordinarily complex and involvea large set of parameters, most of which areirrelevant for discussing the phenomenaunder investigation. So theoretical physi-cists begin by defining a model — that is, anidealized system much simpler than the realone, but retaining all the necessary ingredi-ents to discuss the physical properties ofinterest. However, there are only a few examples of ‘exactly solvable’ models of this type in which one can calculate exactlyall the possible quantum states and their energies and/or the various thermodynamicquantities of the system. Such exact solu-

Theoretical physics

In search of exact solutionsMichel Héritier

Many-body systems, such as electrons flowing in a superconductor, areamong the most difficult theoretical problems to study. A new family ofexactly solvable models may offer some answers.

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