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The history of human culture can be viewed as theprogressive development of new energy sourcesand their associated conversion technologies.These developments have increased the comfort,longevity and affluence of humans, as well as

their numbers. Most of these energy technologies rely onchemical bonds of hydrocarbons. Nature has favoured thestorage of solar energy in the hydrocarbon bonds of plantsand animals, and human cultural evolution has exploitedthis hydrocarbon energy profitably.

A key event in the evolution of human society was thedevelopment of spear heads and knife blades, devices thatallowed humans to exploit a much broader and largeranimal-resource base for food and skins. Another was the

harnessing of the energy in the hydrocarbon bonds of wood,using fire, which allowed humans to exploit even more foodresources, to smelt metals and to bake ceramics. All thesedevelopments assisted humans in their exploitation of colder,more northerly ecosystems. The most important of thesenew energy-based technologies was agriculture, which redi-rected photosynthetic energy from natural to humanfood chains.

The principal energy sources of antiquity were allderived directly from the sun: human and animal musclepower, wood, flowing water and wind. About 300 years ago,the industrial revolution began with stationary wind-pow-ered and water-powered technologies, which were essen-tially replaced by fossil hydrocarbons: coal in the nineteenth

century, oil since the twentieth century, and now, increas-ingly, natural gas. The global use of hydrocarbons for fuel byhumans has increased nearly 800-fold since 1750 and about12-fold in the twentieth century.

Hydrocarbon-based energy is important for the threemain areas of human development: economic, social andenvironmental1 (Fig. 1). Both the popular and some scien-tific presses have suggested that we have entered a post-industrial society, where computers and, more generally,human knowledge have replaced raw energy and materialsin the generation of wealth. Bottom-up analysis, applied byengineers, physicists and some environmentalists, suggeststhat a substantial decoupling of energy and economic pro-duction is now underway2. Nevertheless, there continues tobe a strong connection between energy and economic activ-ity for most industrialized3 and developing economies4.

Top-down macroeconomic analysis indicates that wherethere is a decline in the ratio of energy to gross domesticproduct in industrial nations, it is due principally to a shiftto higher quality fuels, improvements in fuel efficiency dri-ven by higher fossil fuel prices and structural changes innational economies5. Energy prices have an important effecton almost every major aspect of macroeconomic perfor-mance, because energy is used directly and indirectly in theproduction of all goods and services. Both theoretical mod-els and empirical analyses of economic growth suggest that adecrease in the rate of increase in energy availability willhave serious impacts6. For example, most US recessionsafter the second World War were preceded by rising oilprices, and there tends to be a negative correlation between

oil price changes and and both stock prices and returns7

incountries that are net importers of oil and gas. Energy priceshave also been key determinants of inflation and unemploy-ment.

There is a strong correlation between per capita energyuse and social indicators such as the UNs Human Develop-ment Index. By contrast, the use of hydrocarbons to meeteconomic and social needs is a major driver of our mostimportant environmental changes, including global climatechange, acid deposition, urban smog and the release ofmany toxic materials. Increased access to energy also pro-vided the means to deplete or destroy once-rich resourcebases, from the megafaunal extinctions associated with eachnew invasion of spear-equipped humans, to the destruction

of natural ecosystems and soils through, for example, over-fishing and intensive agriculture and other types of devel-opment. Such problems are exacerbated by the increase inhuman populations that each new technology has allowed,as well as the overdependence of societies on those once-abundant resources. Energy is a double-edged sword.

How long can we depend on oil?At present, oil supplies about 40% (natural gas 25%) of theworlds non-solar energy, and most future assessments indi-cate that the demand for oil will increase substantially. Whatdo we know about the future of oil? Predictions of impend-ing oil shortages are as old as the industry itself, and the liter-ature is full of arguments between optimists and pes-simists about how much oil there is and what otherresources might be available. There are four principal issues

Hydrocarbons and the evolution ofhuman cultureCharles Hall1,2, Pradeep Tharakan1,3, John Hallock1, Cutler Cleveland4,5 and Michael Jefferson6

1Departments of Environmental and Forest Biology and Graduate Program in Environmental Sciences, State University of New York College of

Environmental Science and Forestry, Syracuse, New York 13210, USA (SUNY ESF); 2Flathead Lake Biological Station, University of Montana,Polson, Montana, USA; 3Maxwell School of Citizenship and Public Affairs, Syracuse University, Syracuse, New York, USA; 4Center for Energy and

Environmental Studies, Boston University, 675 Commonwealth Avenue, Boston, Massachusetts 02215, USA; 5Department of Geography at

Boston University, 675 Commonwealth Avenue, Boston, Massachusetts 02215, USA; 6Global Energy & Environmental Consultants, The Old

Stables, Felmersham, Bedfordshire MK43 7HJ, UK (e-mails: chall@esf.edu; cutler@bu.edu;jeffers@dircon.co.uk)

Most of the progress in human culture has required the exploitation of energy resources. About 100 years ago,the major source of energy shifted from recent solar to fossil hydrocarbons, including liquid and gaseouspetroleum. Technology has generally led to a greater use of hydrocarbon fuels for most human activities,making civilization vulnerable to decreases in supply. At this time our knowledge is not sufficient for us tochoose between the different estimates of, for example, resources of conventional oil.

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that we need to understand to assess the availability of oil, and, byextension, other hydrocarbons, for the future. We need to know: first,the quality of the reserves; second, the quantity of the reserve; third,the likely patterns of exploitation of the resource over time; andfourth, who gets, and who benefits from, the oil. All of these factorsultimately affect the economics of oil production and use.

Quality of petroleumWhat we call oil is actually a large family of diverse hydrocarbonswhose physical and chemical qualities reflect the different originsand, especially, different degrees of natural processing of these hydro-carbons8. In general, humans have exploited the large reservoirs ofshorter-chain light oil resources first because larger reservoirs areeasier to find and exploit, and lighter oils are more valuable andrequire less energy to extract and refine. Therefore, over time inmature regions, lower quality has often required the exploitation ofincreasingly small, deep, offshore and heavy resources (Figs 2 and 3).Progressive depletion also means that oil in older fields that oncecame to the surface through natural drive mechanisms, such as gaspressure, must now be extracted using energy-intensive secondary

and enhanced technologies. Thus, technological progress is in a racewith the depletion of higher-quality resources. Another aspect of thequality of an oil resource is that oil reserves are normally defined bytheir degree of certainty and their ease of extraction, classed asproven, probable, possible or speculative. In addition, there areunconventional resources such as heavy oil, deep-water oil, oil sandsand shale oils that are very energy intensive to exploit.

Quantity of petroleumMost estimates of the quantity of conventional oil resources remainingare based on expert opinion, which is the carefully considered opinionof geologists and others familiar with a particular region (Table 1). Theultimate recoverable resource (URR) is the total quantity of oil that willever be produced, including the nearly 1 trillion barrels extracted todate. Recent estimates of URR for the world have tended to fall intotwo camps. Lower estimates come from several high-profile analysts

with long histories in the oil industry. They suggest that the URR is nogreater than about 2.3 trillion barrels, and may even be less (for exam-ple, ref. 9). A higher estimate of 3 trillion barrels is the middle esti-mate, and 4 trillion is the highest estimate, from the most recent studyby the US Geological Survey (USGS)10,11. About half of the roughly1.4 trillion barrels that the USGS predicts remain to be discovered are

from new discoveries and about half are from reserve growth. The lat-ter describes the process by which technical improvements and cor-rection of earlier conservative estimates increase the projected recov-ery from existing fields. This relatively new addition to the USGSmethodology is based on experience in the US and a few other well-documented regions. The new totals assume, essentially, that petro-leum reserves everywhere in the world will be developed with thesame level of technology, economic incentives and efficacy as in theUS. Time will tell the extent to which these assumptions are realized.

Pattern of use over timeThe best-known model of oil production was proposed by MarionKing Hubbert, who proposed that the discovery, and production, ofpetroleum over time would follow a single-peaked, symmetric bell-

shaped curve with a peak in production when 50% of the URR hadbeen extracted. This hypothesis seems to have been based principallyon Hubberts intuition, and it was not a bad guess as he famously pre-dicted in 1956 that US oil production would peak in 1970, which infact it did12. Hubbert also predicted that the US production of naturalgas would peak in about 1980, which it did, although it has sinceshown signs of recovery. He also predicted that world oil productionwould peak in about 2000. There was a slight downturn in world pro-duction in 2000, but production in the first half of 2003 is runningslightly above the rate in 2000.

In the past decade, a number of neohubbertarians have madepredictions about the timing of peak global production using severalvariations of Hubberts approach. Various forecasts of the year of theglobal peak have ranged from one predicted for 1989 (made in 1989)to many predicted for the first decade of the twenty-first century toone as late as 2030 (ref. 9). Their predictions begin with an a priori

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NATURE | VOL 426 | 20 NOVEMBER 2003 | www.nature.com/nature 319

Figure 1 Former oil fields in Southern

Louisiana. This area was once a

productive salt marsh that contributed

greatly to Louisiana's extremely rich

fisheries. The numerous straight lines in

the picture are the result of past dredging

operations to float oil rigs into areas

where they extracted oil. The dredging

has resulted in enormous land erosion,exacerbated by sea-level increase, which

in turn was partly a consequence of

greenhouse gas emissions from burning

that oil. The oil production is gone, but

the environmental degradation remains.

Now oil operations have moved offshore,

where there are 4,000 energy-intensive

oil platforms off Louisiana. There are still

oil operations in the coastal region that

receive offshore and foreign oil.

Louisiana, once the fourth largest oil-

producing state (and number one for gas)

in the USA, now uses as much oil as it

produces and serves mainly as anenergy-intensive conduit and processor

for foreign oil moving into the US interior

(courtesy of Louisiana Department of

Wildlife and Fisheries).

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assumption about the volume of ultimately recoverable oil. Most ofthese studies assumed world URR volumes of roughly 2 trillion barrelsand that oil production would peak when 50% of the ultimateresource had been extracted. In comparison, the USGS low estimate(which they state has a 95% probability of being exceeded) is2.3 trillion barrels. One analysis fitted the left-hand side of Hubbert-type curves to data on actual production while constraining the totalquantity under the curve to 2, 3 and 4 trillion barrels for world URR.The resultant peaks were predicted to occur from 2004 to 2030.

Other forecasts for world oil production do not rely on suchcurve-fitting techniques to make future projections and/or a prioriassumptions about URR. According to the most recent forecast bythe US Energy Information Agency (EIA) (2003), world oil supply in2025 will exceed the 2001 level by 53% (ref. 13). The EIA reviewed fiveother world oil models and found that all of them predict that pro-duction will increase in the next two decades to around 100 millionbarrels per day, substantially more than the 77 million barrels per day

produced in 2001. Several of these models rely on the new USGS esti-mates of URR for oil. It should be noted that almost all oil-supplyforecasts for which we are able to examine the predictions againstreality had a dismal track record, regardless of method. Most recentresults of curve-fitting methods showed a consistent tendency to pre-dict a peak within a few years, and then a decline, no matter when thepredictions were made14. It is now a well-established fact that eco-nomic and institutional factors, as well as geology, were responsiblefor the US peak in production in 1970 (ref. 15), forces that are explic-

itly excluded from the curve-fitting models. Thus, the ability (or theluck) of Hubberts model (and its variants) to forecast production inthe 48 lower states (that is, contiguous)accurately cannot necessarilybe extrapolated to other regions. It is too early to tell.

Economic forecasts fare no better in explaining US oil production inthe lower 48 states. In the period after the Second World War, oil produc-tion often increased as oil prices decreased, and viva versa16, a behaviourthat is exactly the opposite of predictions of economic theory.Economic theory also assumes that oil prices will follow an optimalpath towards the choke price the price at which demand for oil fallsto zero and the market signals a seamless transition to substitutes. Infact, even if such a path exists, prices may not increase smoothlybecause empirical evidence indicates that producers respond differ-ently to price increases than they do to price decreases15. Significant

deviation from basic economic theory undermines the de facto poli-cy for managing the depletion of conventional oil supplies a beliefthat the competitive market will generate a smooth transition fromoil. It also suggests the need for a greater degree of government inter-vention in the transition from oil than is currently envisaged by mostpolicy makers.

GeographyOil is used by all of the ~220 nations of the world, but significantamounts are produced by only about 42 countries, 38 of which exportimportant amounts. This number is likely to change because of thedepletion of the once-vast resources of North and South America,and owing to the increasing domestic use of oil by many of theexporters. The number of exporters outside the Middle East and the

former Soviet Union will drop in the coming decades, perhapssharply, which in turn will greatly reduce the supply diversity to the180 or so importing nations17. Such an increase in reliance on WestAfrican, former Soviet Union and especially Persian Gulf oil hasmany strategic, economic and political implications.

Energy and political costs of getting oilThe future of oil supplies is normally analysed in economic terms.But the economic terms are likely to be dependent on other costs. Inearlier work we summarized the energy costs of obtaining US oil andother energy resources and found, in general, that the energyreturned on energy invested (EROI) tended to decline over time forall energy resources examined. This includes the energy cost ofobtaining oil by trading (energy-requiring) goods and services for

energy itself

18

. For example, the EROI of oil in the US has decreasedfrom a value of at least 100 to 1 for oil discoveries in the 1930s, toabout 17 to 1 today for oil and gas extraction (Fig. 4). We are notaware of such estimates for other parts of the world, although we doknow that both heavy oil in Venezuela and tar sands in Albertarequire a very large part of the energy produced as well as substantialsupplies of hydrogen from natural gas to make the oil fluid. The verylow economic cost of finding or producing new oil supplies in theArabian Peninsula implies that it has a very high EROI value, which inturn supports the probability that productivity will be concentratedthere in future decades. Alternative liquid fuels such as ethanol fromcorn have a very low EROI. An EROI of much greater than 1 to 1 isneeded to run a society, because energy is also required to make themachines that use the energy, feed, house, train and provide healthcare for necessary workers and so on.

No one who watches the news can fail to be aware of the impor-

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320 NATURE | VOL 426 | 20 NOVEMBER 2003 | www.nature.com/nature

Figure 3 Deck of a

North Sea oil well.

Copyright Shell

International

Photographics

Services.

Figure 2 Oil tanker

from an oil rig in the

North Sea. Copyright

Shell International

Photographics

Services.

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tance of cultural and political differences between those nations thathave the most oil and those that import it. How these factors will playout over the next few decades is extremely important but also impos-sible to predict. Most of the remaining oil reserves are in SouthernRussia, the Middle East and North and West Africa, countries orregions with either Muslim governments or significant Muslimgroups. For a long period, frustration and resentment has beenbuilding up among Muslim populations, not least because of theirperception that the main Western powers have failed to generate

even-handed policies to address the conflict in the Middle East overthe past half-century. It also is the case that the huge revenues earnedby the oil-exporting nations have been very unevenly distributedamong their respective populations, adding to internal and externalpressure to adopt a more equitable approach to human development.Suffice it to say that there will continue to be high risks of internation-al and national terrorism, overthrow of existing governments anddeliberate supply disruption in the years ahead. In addition, export-ing nations may wish to keep their oil in the ground to maintain theirtarget price range. Thus, there are considerable political and socialuncertainties that could result in less oil being available than existingmodels predict.

Our need to reduce supply uncertainties

Many once-proud ancient cultures have collapsed, in part, because oftheir inability to maintain energy resources and societal complexi-ty19. Our own civilization has become heavily dependent on enor-mous flows of cheap hydrocarbons, partly to compensate for otherdepleted resources (for example, fertilizers and long-range fishingboats), so it seems important to assess our main energy alternatives.Some of our most promising new oil fields have turned out to be verydisappointing20. If indeed we are approaching the oil scarcity thatsome predict, it is not reflected in price and few investments are beingmade at the scale required. An even greater problem may be that anincreasing number of decision-makers sense that the market hasresolved this issue before and will and should do so again, and alsothat government programmes are too inefficient to resolve possible

impending energy problems. We view this as a recipe for disaster, and

it is enhanced by the failure of science to be used as fully as it shouldbe. Thus, in 2003, the state of oil-supply modelling is in some ways nodifferent than it was in Hubberts time; in other words, a wide range ofopinion exists.

What can science do to help resolve this uncertainty? Our princi-pal conclusion is that these critical issues could be and should be theprovince of open scientific analysis in visible meetings where allsides attend and argue. This analysis should be informed by the peer-review process, statistical analysis, hypothesis-generating and test-ing, and so on, rather than by the experts one chooses. These issuesshould be the basis of open competitive government grant pro-grammes, graduate seminars and even undergraduate courses inuniversities, and our courses in economics should become at least as

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Figure 4 Servicevessels and

infrastructure for

off-shore oil

facilities in Southern

Louisiana.(C. Hall)

Table 1Published estimates of world oil ultimate recovery

Source Volume (trillions of barrels)

USGS, 2000 (high) (ref. 11) 3.9

USGS, 2000 (mean) (ref. 11) 3.0USGS, 2000 (low) (ref. 11) 2.25

Campbell, 1995 1.85

Masters, 1994 2.3

Campbell, 1992 1.7Bookout, 1989 2.0

Masters, 1987 1.8

Martin, 1984 1.7

Nehring, 1982 2.9Halbouty, 1981 2.25

Meyerhoff, 1979 2.2

Nehring, 1978 2.0

Nelson, 1977 2.0Folinsbee, 1976 1.85

Adam and Kirby, 1975 2.0

Linden, 1973 2.9

Moody, 1972 1.9Moody, 1970 1.85

Shell, 1968 1.85

Weeks, 1959 2.0

MacNaughton, 1953 1.0Weeks, 1948 0.6

Pratt, 1942 0.6

Source: ref. 21.

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much about real biophysical resources, such as hydrocarbon reserves,as about market mechanisms. And we need to think much harderabout the alternatives.

The future: other technologiesThe world is not about to run out of hydrocarbons, and perhaps it isnot going to run out of oil from unconventional sources any timesoon. What will be difficult to obtain is cheap petroleum, becausewhat is left is an enormous amount of low-grade hydrocarbons,

which are likely to be much more expensive financially, energetically,politically and especially environmentally. As conventional oilbecomes less important, society has a great opportunity to makeinvestments in a different source of energy, one freeing us for the firsttime from our dependence on hydrocarbons.

There are a wide range of options and an equally wide range ofopinions on the feasibility and desirability of each. Nuclear powerfaces formidable obstacles. Experience of the past several decades hasshown that electricity from nuclear power plants is an expensive formof power when all public and private costs are considered. Nuclearpower generates high-level radioactive wastes that remain hazardousfor thousands of years and increases the likelihood of nuclear-weapon proliferation. These are high costs to impose on future gen-erations. Even with improved reactor design, the safety of nuclear

plants remains an important concern. Can these technological, eco-nomic, environmental and public safety problems be overcome? Thisremains an unanswered question.

Renewable energies present a mixed bag of opportunities. Somehave clear advantages over hydrocarbons in terms of economic via-bility, reliability, equitable access and environmental benefits. Infavourable locations, wind power has a high EROI. The cost of photo-voltaic (solar electric) power has come down sharply, making it aviable alternative in areas without access to electricity grids. Withproper attention to environmental concerns, biomass-based energygeneration is competitive in some cases relative to conventionalhydrocarbon-based energy generation. By contrast, liquid-fuel pro-duction from grain and solar thermal power has a relatively lowEROI. Hydrogen is an energy carrier, not an energy source, but ener-

gy and environmental communities have shown enormous interestin its potential. Hydrogen generated from renewable energy sourcesor electricity-driven hydrolysis is currently expensive for most appli-cations, but it merits further research and development.

Subsidies and externalities, social as well as environmental, affectenergy markets. With few exceptions, these subsidies and externali-ties tilt the playing field towards conventional sources of energy. Thispresents a clear case for public-policy intervention that wouldencourage the research, development and adoption of renewable

forms of energy. Policy intervention, in concert with ongoing privateinvestment, will speed up the process of sorting the wheat from thechaff in the portfolio of feasible renewable energy technologies. It istime to think about possibilities other than the next cheapest hydro-carbons, if for no other reason than to protect our atmosphere, andfor this task we must use all of our science, both natural science andsocial science, more intelligently than we have done so far .

doi:10.1038/nature02130

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Supplementary Informationaccompanies the paper at www.nature.com/nature .

Acknowledgements We thank S. Ulgiati, R. Kaufmann and C. Levitan for discussions, J.Laherrre for insights into the functioning of the oil industry and for directing us to therecent ASPO data.

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N-terminal bundle of Vh establish that the structure of this domainis regulated by contacts with cytoskeletal proteins. For example, thebinding of talin between helices a1 and a2 displaces Vt, anda-actinin binding to Vh also displaces Vt, yet talin and a-actininbind to Vh in a mutually restricted manner. The exclusive inter-actions of these a-helices with Vh would thus serve to properlydirect cytoskeletal and signalling decisions induced by focal adhe-sions versus adherens junctions (Fig. 5).

The remarkable structural changes in the a-helices of the N-terminal bundle of Vh establish helical bundle conversion as amechanism of control in signal transduction pathways. Helicalbundle conversion is fundamentally different from helical exchange,where the binding of one a-helix simply displaces the binding ofanother without altering the structure of the displaced helix(Supplementary Fig. S4). Rather, helical bundle conversion pro-vokes dramatic changes in the conformation ofa-helices, allowingproteins to expand their repertoire of structures, substrates andfunctions. A

MethodsDetailed information on methodological aspects of X-ray data collection, structuredetermination and refinement is provided as Supplementary Information.

Protein preparation

Vinculin complementary DNA (GenBank accession number NM 003373) was generatedby polymerase chain reaction with reverse transcription (RTPCR) of human fibroblastmessenger RNA, and was cloned into the pET3 expression vector (Novagen). The finalconstructs were N-terminal hexahistidine fusion tags proceeded by Met-Glu and includedamino acids 1258 for human Vh and 8791066 for human Vt. Proteins were expressed inEscherichiacoli BL21(DE3) or in B834(DE3)for selenomethionine (SeMet)incorporation.Cells were lysed in Tris-HCl (pH 8), 0.5 M NaCl and PMSF, and expressed proteins werepurified usinga chelatingnickelaffinity column (Amersham). Theproteinwas eluted overa gradient to 0.5 M imidazole. Vh was purified using an anion-exchange column (QSepharose, Amersham), whereas Vt was purified using a cation-exchange column (SPSepharose, Amersham) and a Superdex 75 gel-filtration column in 200 mM NaCl and10 mM Tris-acetate (pH 7.6). Proteins were dialysed into Tris-acetate (pH 7.6), 10 mMdithiothreitol (DTT) and 1 mM EDTA. For Vt dialysis buffer also included 150mM NaCl.Proteins were concentrated to 10 mg ml21, aliquoted and stored at 220 8C.

VhVt crystallization

Native VhVt crystals and native Vh in complex with SeMet-substituted Vt crystals were

obtained by vapour diffusion by equilibrating 1.5 mol Vt per mol of Vh against a reservoircontaining15% polyethyleneglycolof molecular mass3350 Da (PEG-3350), 50 mMNaCl,100 mM Tris (pH 8), and 10 mM DTT. Crystals of approximate dimensions0.2 0.15 0.05mm3 appeared overnight at room temperature. These crystals belong tospace group P21212 with one heterodimer in the asymmetric unit, a solvent content of46%, and a volumeto mass ratio of 2.3A3 Da21. Crystals werecryoprotected in 30% PEG-3350.

VhVBS3 crystallization

Talin VBS3 (residues 19441969) was synthesized and purified by high-performanceliquid chromatography in our in-house facility. Initial crystallization conditions wereidentified at the HauptmanWoodward Institute. Native and SeMet VhVBS3 crystalswere obtained by equilibrating 2.4mol VBS3 per mol Vh against a reservoir of 2% MPD,100 mM citric acid (pH 4) and 100 mM CdCl. Crystals of approximate dimensions of(0.15mm)3 appearedwithinone weekat roomtemperature. Thesecrystalsbelongto spacegroup I4132 with one heterodimer in the asymmetric unit, a solvent content of 44% and avolume to mass ratio of 2.2 A3 Da21. The VhVBS3 crystals were cryoprotected inparatone oil.

Received 28 August; accepted 9 December 2003; doi:10.1038/nature02281.Published online 31 December 2003.

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by the FERM domain of talin. Nature 420, 8589 (2002).

14. Pokutta, S. & Weiss, W. I. Structure of the dimerization and b-catenin-binding region ofa-catenin.

Mol. Cell 5, 533543 (2000).

15. Yang, J., Dokurno, P., Tonks, N. K. & Barford, D. Crystal structure of the M-fragment ofa-catenin:

implications for modulation of cell adhesion. EMBO J. 20, 36453656 (2001).

16. Pokutta,S., Drees,F.,Takai, Y., Nelson,W.J. & Weis,W. I. Biochemicaland structuraldefinitionof the

l-afadin- and actin-binding sites ofa-catenin. J. Biol. Chem. 277, 1886818874 (2002).

17. Weiss, E. E., Kroemker, M., Rudiger, A.-H., Jockusch, B. M. & Rudiger, M. Vinculin is part of the

cadherin-catenin junctionalcomplex: complexformation betweena-cateninand vinculin.J. Cell Biol.

131, 755764 (1997).

18. Watabe-Uchida, M. et al. a-catenin-vinculin interaction functions to organize the apical junctional

complex in epithelial cells. J. Cell Biol. 142, 847857 (1998).

19. Johnson, R. P. & Craig, S. W. An intramolecular association between the head and tail domains of

vinculin modulates talin binding. J. Biol. Chem. 269, 1261112619 (1994).

20. Bass,M. D.etal. Furthercharacterizationof theinteractionbetween thecytoskeletal proteinstalinand

vinculin. Biochem. J. 362, 761768 (2002).

21. Lawrence, M. C. & Colman, P. M. Shape complementarity at protein/protein interfaces. J. Mol. Biol.

234, 946950 (1993).

22. Johnson, R. P. & Craig, S. W. An intramolecular association between the head and tail domains of

vinculin modulates talin binding. J. Biol. Chem. 269, 1261112619 (1994).23. Hayashi, I., Vuori, K. & Liddington, R. C. The focal adhesiontargeting (FAT) regionof focal adhesion

kinase is a four-helical bundle that binds paxillin. Nature Struct. Biol. 9, 101106 (2002).

24. Hoellerer, M. K. etal. Molecular recognitionof paxillinLD motifs byfocal adhesiontargetingdomain.

Structure 11, 12071217 (2003).

Supplementary Information accompanies the paper on www.nature.com/nature.

Acknowledgements WethankJ. Clevelandfor manyhelpfuldiscussions.Wealso thank V. Morris,

K. Brown and C. Kirby for technical assistance; C. Vonrhein for expert advice and help with

autoSHARP; C. Ross for maintaining the X-ray and computing facilities; L. Messerle for the

tantalum compound; and M. Kastan for critical review of the manuscript. We are grateful to the

staff at the Advanced Photon Source, COM-CAT, SBC-CAT and SER-CAT, and at the Advanced

Light Source, Lawrence Berkeley Laboratory, 5.0.2, for synchrotron support. This work was

supported in part by the Cancer Center Support (CORE) Grant and by the American Lebanese

Syrian Associated Charities (ALSAC). P.B. is a Van Vleet Fellow.

Competing interests statement The authors declare that they have no competing financial

interests.

Correspondence and requests for materials should be addressed to T.I. (tina.izard@stjude.org).

Theatomic coordinatesand structurefactors have beendepositedin theProteinData Bankunder

accession codes 1RKE and 1RKC for the VhVt and VhVBS3 structures, respectively.

..............................................................

erratum

Hydrocarbons and the evolution of

human cultureCharles Hall, Pradeep Tharakan, John Hallock, Cutler Cleveland

& Michael Jefferson

Nature 426, 318322 (2003)..............................................................................................................................................................................

In Table 1 of this Insight, the USGS estimate of world oil ultimaterecovery should have cited ref. 10, not ref. 11. References 10 and 11should read as below10,11. In addition, in ref. 17, P. Tharakanssurname was misspelt as Tharkan. A

10. United States Geological Survey (USGS) U.S. Geological Survey World Petroleum Assessment 2000 -

Description and Results. Version 1.1 (USGS Digital Data Series DDS-60, United States Geological

Survey, Washington DC, 2000).

11. Energy Information Administration, United States Department of Energy (EIA/DOE) Long-term

World Oil Supply: A Resource Base/Production Path Analysis (US DOE, Washington DC, 2000); at

khttp://tonto.eia.doe.gov/FTPROOT/presentations/long_term_supply/index.htm l.

letters to nature

NATURE| VOL 427| 8 JANUARY 2004| www.nature.com/nature 1752004 Nature PublishingGroup

7/27/2019 Nature 02130

7/7

N-terminal bundle of Vh establish that the structure of this domainis regulated by contacts with cytoskeletal proteins. For example, thebinding of talin between helices a1 and a2 displaces Vt, anda-actinin binding to Vh also displaces Vt, yet talin and a-actininbind to Vh in a mutually restricted manner. The exclusive inter-actions of these a-helices with Vh would thus serve to properlydirect cytoskeletal and signalling decisions induced by focal adhe-sions versus adherens junctions (Fig. 5).

The remarkable structural changes in the a-helices of the N-terminal bundle of Vh establish helical bundle conversion as amechanism of control in signal transduction pathways. Helicalbundle conversion is fundamentally different from helical exchange,where the binding of one a-helix simply displaces the binding ofanother without altering the structure of the displaced helix(Supplementary Fig. S4). Rather, helical bundle conversion pro-vokes dramatic changes in the conformation ofa-helices, allowingproteins to expand their repertoire of structures, substrates andfunctions. A

MethodsDetailed information on methodological aspects of X-ray data collection, structuredetermination and refinement is provided as Supplementary Information.

Protein preparation

Vinculin complementary DNA (GenBank accession number NM 003373) was generatedby polymerase chain reaction with reverse transcription (RTPCR) of human fibroblastmessenger RNA, and was cloned into the pET3 expression vector (Novagen). The finalconstructs were N-terminal hexahistidine fusion tags proceeded by Met-Glu and includedamino acids 1258 for human Vh and 8791066 for human Vt. Proteins were expressed inEscherichiacoli BL21(DE3) or in B834(DE3)for selenomethionine (SeMet)incorporation.Cells were lysed in Tris-HCl (pH 8), 0.5 M NaCl and PMSF, and expressed proteins werepurified usinga chelatingnickelaffinity column (Amersham). Theproteinwas eluted overa gradient to 0.5 M imidazole. Vh was purified using an anion-exchange column (QSepharose, Amersham), whereas Vt was purified using a cation-exchange column (SPSepharose, Amersham) and a Superdex 75 gel-filtration column in 200 mM NaCl and10 mM Tris-acetate (pH 7.6). Proteins were dialysed into Tris-acetate (pH 7.6), 10 mMdithiothreitol (DTT) and 1 mM EDTA. For Vt dialysis buffer also included 150mM NaCl.Proteins were concentrated to 10 mg ml21, aliquoted and stored at 220 8C.

VhVt crystallization

Native VhVt crystals and native Vh in complex with SeMet-substituted Vt crystals were

obtained by vapour diffusion by equilibrating 1.5 mol Vt per mol of Vh against a reservoircontaining15% polyethyleneglycolof molecular mass3350 Da (PEG-3350), 50 mMNaCl,100 mM Tris (pH 8), and 10 mM DTT. Crystals of approximate dimensions0.2 0.15 0.05mm3 appeared overnight at room temperature. These crystals belong tospace group P21212 with one heterodimer in the asymmetric unit, a solvent content of46%, and a volumeto mass ratio of 2.3A3 Da21. Crystals werecryoprotected in 30% PEG-3350.

VhVBS3 crystallization

Talin VBS3 (residues 19441969) was synthesized and purified by high-performanceliquid chromatography in our in-house facility. Initial crystallization conditions wereidentified at the HauptmanWoodward Institute. Native and SeMet VhVBS3 crystalswere obtained by equilibrating 2.4mol VBS3 per mol Vh against a reservoir of 2% MPD,100 mM citric acid (pH 4) and 100 mM CdCl. Crystals of approximate dimensions of(0.15mm)3 appearedwithinone weekat roomtemperature. Thesecrystalsbelongto spacegroup I4132 with one heterodimer in the asymmetric unit, a solvent content of 44% and avolume to mass ratio of 2.2 A3 Da21. The VhVBS3 crystals were cryoprotected inparatone oil.

Received 28 August; accepted 9 December 2003; doi:10.1038/nature02281.Published online 31 December 2003.

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Mol. Cell 5, 533543 (2000).

15. Yang, J., Dokurno, P., Tonks, N. K. & Barford, D. Crystal structure of the M-fragment ofa-catenin:

implications for modulation of cell adhesion. EMBO J. 20, 36453656 (2001).

16. Pokutta,S., Drees,F.,Takai, Y., Nelson,W.J. & Weis,W. I. Biochemicaland structuraldefinitionof the

l-afadin- and actin-binding sites ofa-catenin. J. Biol. Chem. 277, 1886818874 (2002).

17. Weiss, E. E., Kroemker, M., Rudiger, A.-H., Jockusch, B. M. & Rudiger, M. Vinculin is part of the

cadherin-catenin junctionalcomplex: complexformation betweena-cateninand vinculin.J. Cell Biol.

131, 755764 (1997).

18. Watabe-Uchida, M. et al. a-catenin-vinculin interaction functions to organize the apical junctional

complex in epithelial cells. J. Cell Biol. 142, 847857 (1998).

19. Johnson, R. P. & Craig, S. W. An intramolecular association between the head and tail domains of

vinculin modulates talin binding. J. Biol. Chem. 269, 1261112619 (1994).

20. Bass,M. D.etal. Furthercharacterizationof theinteractionbetween thecytoskeletal proteinstalinand

vinculin. Biochem. J. 362, 761768 (2002).

21. Lawrence, M. C. & Colman, P. M. Shape complementarity at protein/protein interfaces. J. Mol. Biol.

234, 946950 (1993).

22. Johnson, R. P. & Craig, S. W. An intramolecular association between the head and tail domains of

vinculin modulates talin binding. J. Biol. Chem. 269, 1261112619 (1994).23. Hayashi, I., Vuori, K. & Liddington, R. C. The focal adhesiontargeting (FAT) regionof focal adhesion

kinase is a four-helical bundle that binds paxillin. Nature Struct. Biol. 9, 101106 (2002).

24. Hoellerer, M. K. etal. Molecular recognitionof paxillinLD motifs byfocal adhesiontargetingdomain.

Structure 11, 12071217 (2003).

Supplementary Information accompanies the paper on www.nature.com/nature.

Acknowledgements WethankJ. Clevelandfor manyhelpfuldiscussions.Wealso thank V. Morris,

K. Brown and C. Kirby for technical assistance; C. Vonrhein for expert advice and help with

autoSHARP; C. Ross for maintaining the X-ray and computing facilities; L. Messerle for the

tantalum compound; and M. Kastan for critical review of the manuscript. We are grateful to the

staff at the Advanced Photon Source, COM-CAT, SBC-CAT and SER-CAT, and at the Advanced

Light Source, Lawrence Berkeley Laboratory, 5.0.2, for synchrotron support. This work was

supported in part by the Cancer Center Support (CORE) Grant and by the American Lebanese

Syrian Associated Charities (ALSAC). P.B. is a Van Vleet Fellow.

Competing interests statement The authors declare that they have no competing financial

interests.

Correspondence and requests for materials should be addressed to T.I. (tina.izard@stjude.org).

Theatomic coordinatesand structurefactors have beendepositedin theProteinData Bankunder

accession codes 1RKE and 1RKC for the VhVt and VhVBS3 structures, respectively.

..............................................................

erratum

Hydrocarbons and the evolution of

human cultureCharles Hall, Pradeep Tharakan, John Hallock, Cutler Cleveland

& Michael Jefferson

Nature 426, 318322 (2003)..............................................................................................................................................................................

In Table 1 of this Insight, the USGS estimate of world oil ultimaterecovery should have cited ref. 10, not ref. 11. References 10 and 11should read as below10,11. In addition, in ref. 17, P. Tharakanssurname was misspelt as Tharkan. A

10. United States Geological Survey (USGS) U.S. Geological Survey World Petroleum Assessment 2000 -

Description and Results. Version 1.1 (USGS Digital Data Series DDS-60, United States Geological

Survey, Washington DC, 2000).

11. Energy Information Administration, United States Department of Energy (EIA/DOE) Long-term

World Oil Supply: A Resource Base/Production Path Analysis (US DOE, Washington DC, 2000); at

khttp://tonto.eia.doe.gov/FTPROOT/presentations/long_term_supply/index.htm l.

letters to nature

NATURE| VOL 427| 8 JANUARY 2004| www.nature.com/nature 1752004 NaturePublishingGroup