Editors' Choice

Science  30 May 2008:
Vol. 320, Issue 5880, pp. 1134

    Upside of a Double Negative

    1. Jake Yeston

    Chemical bonds tend to form most easily by the attack of an ion on an oppositely polarized center, or by the neutral interactions of radical centers bearing unpaired electrons. Bisai et al. took the somewhat counterintuitive approach of preparing two negatively charged sites and then adding an oxidant to draw them together. The deprotonation of both a carbon and a nitrogen center came at a late stage in the synthesis of the polycyclic organic natural product lyconadin A. When more traditional approaches toward linking C and N to close the ring had failed, the authors relied on the likelihood that a lithium cation would stabilize a dianion through simultaneous coordination to both centers. Treatment with iodine then induced C-N bond formation in 80% yield, affording an impressive overall product yield of 10% over the 18 steps of the synthesis. — JSY

    J. Am. Chem. Soc. 130, 10.1021/ja8028069 (2008).


    Out With the Old, In With the New

    1. Gilbert Chin

    Might this adage, which some pundits have claimed as the basis for the vernal electoral calamities that have befallen the Labour Party in the United Kingdom, apply equally forcefully to the turnover of neurons in the brain? Adar et al. have performed a painstaking histological and immunofluorescence accounting of the survival likelihoods of newly born neurons in the brain of the zebra finch, a songbird that serves as an animal model for studying innate and learned influences on vocal communication. They focused on the nidopallium caudale (NC) region because it participates in auditory processing and is activated by social stimuli (other songbirds in this notably social species). By varying the complexity of the social environment, they found that the youngest cells—which had recently migrated from the site of their birth and were still becoming integrated, quite literally, as they established syn-aptic connections with existing NC neurons—were more likely to have survived if the bird had been exposed to a large group of male and female birds; conversely, in birds housed with only one other individual, the survival of older (though still relatively young) cells was enhanced. One interpretation of these data is that an increase in demand—in the form of an upturn in auditory/social inputs needing to be processed—acts as a selective pressure favoring the survival of new recruits. — GJC

    J. Neurosci. 28, 5394 (2008).


    The School of Hard Knocks

    1. Paula A. Kiberstis

    The identification of a disease-causing gene mutation in humans is typically followed by a flurry of research aimed at elucidating the normal function of the gene and how disruption of that function produces the specific pathological features of the disease. These projects often rely on the phenotypic characterization of mice in which the murine ortholog of the gene has been inactivated (knock-out mice) or in which the specific disease-causing mutation has been introduced into the murine germline (knock-in mice).

    Although such models are informative, a recent analysis serves as a reminder that mice are not men, especially when it comes to protein quality-control systems. By examining the Mouse Genome Informatics database and the literature, Liao and Zhang identified 120 genes known to be essential for human survival and found that 22% of these are nonessential in mice. Interestingly, nearly half of these 27 genes encode proteins localized to vacuoles, which are membrane-bound compartments that help remove cellular waste such as misfolded proteins. In independent studies, Kobuke et al. and Bartoli et al. found that a missense mutation responsible for a specific type of muscular dystrophy in humans (an R77C substitution in alpha-sarcoglycan) caused no disease phenotype when introduced into mice. In this case also, the cross-species difference was tentatively traced to the quality-control systems that recognize and process defective proteins. — PAK

    Proc. Natl. Acad. Sci. U.S.A. 105, 6987 (2008); Hum. Mol. Genet. 17, 1201; 1214 (2008).


    At a Loss

    1. H. Jesse Smith

    Sea-ice coverage in the Arctic plummeted in the summer of 2007 to levels never before observed, surprising even experts who had witnessed the decades-long decline and predicted that the ice pack would continue to shrink at an increasingly rapid rate. Why did so much ice disappear? Zhang et al. conducted a retrospective modeling study of the evolution of Arctic sea-ice coverage and found that preconditioning, anomalous winds, and ice-albedo feedback were responsible for most of the retreat. Years of warming climate there preconditioned the ice for disappearance by thinning it significantly, pushing it ever closer to the point of complete melting, while stronger than normal winds pushed unusually large amounts out of the Arctic basin. The ice thinning and exposure of open water that these processes caused left the remaining ice even more susceptible than normal to loss due to heating of the upper ocean, increasing the intensity of the positive ice-albedo feedback and accelerating the rate of ice loss. Once summer had passed and temperatures had dropped low enough for ice to begin to regrow, 10% more ice than usual had vanished, 70% of it due to melting and 30% due to ice advection. The large ice loss, coupled with prevailing climate trends, suggests that Arctic sea ice has become particularly vulnerable to anomalous atmospheric forcing. — HJS

    Geophys. Res. Lett. 10.1029/2008GL034005 (2008).


    Close Enough

    1. Valda Vinson

    The classical view that protein function is associated with a well-defined three dimensional fold has been eroded, slightly, by the discoveries that intrinsically disordered proteins do exist and that disorder might play an important role in protein interactions. Catalysis would seem more structurally demanding. Although it is increasingly recognized that dynamics contributes to enzyme activity, most would have assumed that this occurs in the context of a folded protein; nevertheless, catalytic activity has been observed in an engineered enzyme with molten globule properties, where activity is apparently coupled to substrate-induced folding. Bemporad et al. show that the partially folded Sulfolobus solfataricus acylphosphatase is active and that this does not derive from a global substrate-induced folding. Molecular dynamics simulations revealed that an ensemble of partly folded molecules is characterized by substantial structural flexibility of the catalytic region; the remainder of the protein forms a scaffold that restricts the conformational space of the flexible region so that in a large fraction of the ensemble, residues important for catalysis remain close together. The authors suggest that scaffold regions in proteins might allow functional regions to mutate without compromising overall stability, thus facilitating the evolution of new activities. It remains to be seen if this is a rare case or whether catalysis in the absence of well-defined folded structure is a more common but underappreciated enzyme property. — VV

    EMBO J. 27, 10.1038/emboj.2008.82 (2008).


    Free to Switch

    1. Phil Szuromi

    In many of the reported examples of switching molecular conductivity from low to high states, conformational changes have been induced with voltage pulses from a scanning tunneling microscope (STM) tip. Such changes are highly localized and involve serial processing, whereas optically induced changes could allow for faster parallel processing. However, the quenching of excited states near metal surfaces, as well as steric constraints, often limit this approach. Kumar et al. show that azobenzene-functionalized thiol derivatives, chemisorbed within domains of decanethiol monolayers on gold, undergo reversible trans-cis photoswitching upon irradiation with ultraviolet and visible light, respectively. The exposed azobenzene group exhibits a large change in apparent height (1.4 Å) upon switching from the much more conductive trans conformation to the cis state. — PDS

    Nano Lett. 8, 10.1021/nl080323+ (2008).


    I Need My Space

    1. Stella M. Hurtley

    Protein chaperones not only promote protein folding but also help to prevent protein misfolding. The GroEL-GroES chaperonin system operates as a nanomachine in the folding of proteins in Escherichia coli and contains an internal compartment thought to protect substrate proteins as they fold. Tang et al. wanted to ascertain whether this folding compartment was important in intact cells when they folded newly synthesized proteins. To do this, they generated mutant forms of the chaperone with a smaller folding compartment or whose compartment characteristics had been altered to be less amenable to the folding reaction. The viability of cells expressing the altered chaperonins was reduced when the size of the folding compartment was reduced or when the folding cavity was rendered less friendly. Despite this, for the protein substrate green fluorescent protein, the rate of folding actually increased with a slightly smaller folding cage, probably because of steric effects. Thus, even though mutant chaperonins are able to promote the folding of proteins that do not enter the folding chamber in vitro, the chamber itself is indeed critical for cell viability. — SMH

    EMBO J. 27, 10.1038/emboj.2008.77 (2008).