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Nature: Small, Smaller, Smallest A Pocket-size Device, Nano-size Electrical Conduits, and Amyloid Protein Fibril Structure by Sabine Heinhorst and Gordon C. Cannon photo: Gemma Reguera
A “Palm Fuser”? In recent years, detection of explosives and hazardous chemicals has become a priority, and numerous research efforts are focused on developing portable measuring devices and assays with ever higher sensitivity. To date, bombardment of the matter in question with neutrons is commonly used to identify the elemental composition of potentially hazardous material through the element-specific energies of ␥-rays that are emitted as a consequence of the interaction between neutrons and the nuclei of their target matter. Complex design and considerable size of currently used neutron generators, however, preclude their widespread use. The work by Naranjo and colleagues from The University of California Los Angeles (2005, 434, April 28, 1115– 1117) represents a proof of concept that a palm-size neutron generator is no longer a matter of fiction but is on its way to becoming reality in the very near future. The authors used a small crystal (1 cm high, 1.5 cm radius) of lithium tantalate (LiTaO3), whose two faces become oppositely charged and establish an electric field of >80 kV in response to moderate heating in a vacuum. A fine tungsten tip connected to the crystal’s positively charged side yields the 25 gigavolts/m necessary to ionize the surrounding low pressure deuterium gas, a process known as field ionization. Accelerated under the influence of the electric field, the positively charged deuterium nuclei fuse with deuterium nuclei in their erbium deuteride target and produce 3He and neutrons of 2.45 MeV. M. J. Saltmarsh, who coined the term “warm fusion” for the pyroelectric pocket-size neutron generator in his News and Views commentary (2005, 434, April 28, 1079–1080), is quick to point out the lack of a connection between this work and the “cold fusion” boondoggle of the recent past. Although not yet developed to the marketing stage, the pocket-size portable neutron generator promises to facilitate elemental analyses in a variety of settings.
paradigm and establish a direct role of pili, the filamentous appendages of these bacteria, in the reduction of extracellular electron acceptors (Figure 1). Because the complete Geobacter sulfurreducens genome sequence is known, the authors were able to identify candidate genes necessary for pili formation in this organism through comparative genomics studies. By altering the sequence of these genes, Geobacter mutants were created that are unable to form pili. These were tested for their ability to reduce insoluble and soluble extracellular electron acceptors, to adhere to immobilized Fe(III) oxides, and to move on a solid surface. Surprisingly, the results from these studies point to a direct role of pili in electron transfer from the bacterium to the extracellular electron acceptor. Conducting-probe atomic force microscopy measurements revealed that Geobacter sulfurreducens pili are highly conductive and likely serve as the electrical conduit between intracellular bacterial electron carriers and electron acceptors in their extracellular environment, raising the intriguing possibility that such “biological nanowires” may be useful for future nanoelectronics applications.
Bacterial Nanowires
Structural Core of Amyloid Protein Fibrils
We had previously reported ( J. Chem. Educ. 2004, 81, 1404–1405) on findings that implicate bacteria of the genus Geobacter (http://www.geobacter.org/; accessed Jul 2005) in leaching arsenic from groundwater in India and Bangladesh through their reduction of Fe(III) and Ar(V) soil minerals. This process was thought to be mediated by cytochromes, small electron-shuttling proteins that are associated with the outer membrane of the bacterium. In a recent issue of Nature (2005, 435, June 23, 1098–1101), however, Reguera and colleagues from the University of Massachusetts shift this
The amyloid fibrils formed by structural (folding) variants of normal proteins are the hallmark of many human diseases such as Alzheimer’s, type II diabetes, Kuru, Creutzfeldt–Jakob and other prion-transmitted diseases.1 The misfolded amyloid proteins are able to induce similar structural changes in their normal cellular counterparts and are the infective entities responsible for disease transmission. Until the recent report by David Eisenberg’s group at the University of California Los Angeles (2005, 435, June 9, 2005, 773– 778 by Nelson and colleagues), the atomic structure of the
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Figure 1. Electron micrograph of two Geobacter sulfurreducens cells (large ovals in right half of field). Fe(III) oxide precipitates (black) preferentially associate with the bacterial pili (red arrows).
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Figure 2: Panel A: The pair of -sheets (purple and gray) that forms the core of amyloid fibrils. The long axis of the fibril is indicated by the long black upward arrow. Panel B: View down the fibril axis of the tight contacts between the interdigitating shape-complementary amino acid side chains that form the dehydrated interface between a pair of model peptides in -conformation. Water molecules are indicated by red “plus” signs. Figure courtesy Michael Sawaya.
protein fibrils, which were refractory to crystallization, was unknown. A combination of biophysical and molecular biological approaches that include cryo-electron microscopy and mutagenesis studies had established that the fibrils share a common “cross-” core, which consists of stacked -sheets aligned parallel to the long axis of the fibril; their interaction is believed to hold the key to the exceptional stability of amyloid fibrils and to their ability to induce conformational changes in their normal protein counterparts. Eisenberg’s group was able to crystallize the model peptides GNNQQNY and NNQQNY from the prion-like yeast protein Sup35, which are able to form fibrils like the full length protein. The peptides are in the extended -conformation and align in sheets of parallel, in-register -strands. Pairs of -sheets are in close contact (8.5 Å distance) and form “steric zippers” through interdigitation of glutamine and asparagine side chains that extend towards their common interface (Figure 2a). Remarkably, water is excluded from this interface, and the polar amino acid chains forming the “zipper” do not form hydrogen bonds but, because of the complementarity of their shapes (Figure 2b), are in close van der Waals contact. Fiber formation is stimulated by high concentrations of the amyloidogenic protein and by nucleation events that help to overcome the high entropic cost of dehydration and “zipper” formation. Published in the same issue of Nature are two additional studies that address structure–function relationships in amyloid fibrils. Through NMR structural determinations coupled
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with mutagenesis studies, Ritter et al. established that a similar core structure of paired -sheets is necessary for fibril formation and responsible for infectivity of a larger peptide derived from the prion protein Het-s of the filamentous fungus Podospora anserina (pp 844–848). An extensive fluorescence study by Krishnan and Lindquist (pp 765–772) with larger wild type and variant fragments of Sup35 assessed the nature of the nucleation event and elucidated intermediates in the folding pathway that leads to fibril formation. These three seminal studies provide crucial structural information that forms the basis for future approaches towards preventing fibril formation and developing effective therapies for patients afflicted with or at risk for protein misfolding diseases. Note 1. For an overview on prions, see Stanley Prusiner’s Nobel Lecture; Proc. Natl. Acad. Sci. USA 1998, 95, 13363–13383. The lecture is also accessible online at http://www.pnas.org; click Archives, then select the year 1998; select the November 10 issue of 1998, which will bring up the Table of Contents; select Nobel Lecture. You have the choice of viewing the article’s abstract only, seeing the full text, or downloading it as a pdf file (accessed Jul 2005).
Sabine Heinhorst and Gordon C. Cannon are in the Department of Chemistry and Biochemistry, University of Southern Mississippi, Hattiesburg, MS 39406-5043; email:
[email protected] and
[email protected].
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