Table Of Contents Page, PNAS Volume 104, Number 7
This Week in PNAS
Commentaries
Biological Science
Biochemistry
We have studied a naturally occurring small-molecule antimitotic called diazonamide
A. Diazonamide A is highly effective at blocking spindle assembly in mammalian cell
culture and does so through a unique mechanism. A biotinylated form of diazonamide
A ...
Physical Sciences
Chemistry
Due to their small size, nanoparticles have distinct properties compared with the
bulk form of the same materials. These properties are rapidly revolutionizing many
areas of medicine and technology. Despite the remarkable speed of development of ...
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2007 Cozzarelli Prize recipients
Interview with Cozzarelli Prize Winner Kenneth A. Dawson
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Here, we report a catalytic beacon sensor for uranyl (UO22+) based on an in vitro-selected UO22+-specific DNAzyme. The sensor consists of a DNA enzyme strand with a 3′ quencher and
a DNA substrate with a ribonucleotide adenosine (rA) in the middle and a ...
The highly efficient glycolytic enzyme, triosephosphate isomerase, is expected to
differentially stabilize the proposed stable reaction species: ketone, aldehyde, and
enediol(ate). The identity and steady-state populations of the chemical entities bound
...
Individual posttranslational modifications (PTMs) on histones have well established
roles in certain biological processes, notably transcriptional programming. Recent
genomewide studies describe patterns of covalent modifications, such as H3 methylation
...
In Escherichia coli, the switch between aerobic and anaerobic metabolism is controlled primarily by FNR
(regulator of fumarate and nitrate reduction), the protein that regulates the transcription
of >100 genes in response to oxygen. Under oxygen-limiting ...
Intrachain loop formation allows unfolded polypeptide chains to search for favorable
interactions during protein folding. We applied triplet–triplet energy transfer between
a xanthone moiety and naphthylalanine to directly measure loop formation in ...
Cytochrome c oxidase, the terminal enzyme of the respiratory chain, pumps protons across the inner
mitochondrial membrane against an opposing electrochemical gradient by reducing oxygen
to water. To explore the fundamental mechanisms of such redox-coupled ...
We present a strategy for the analysis of the yeast phosphoproteome that uses endo-Lys
C as the proteolytic enzyme, immobilized metal affinity chromatography for phosphopeptide
enrichment, a 90-min nanoflow-HPLC/electrospray-ionization MS/MS experiment ...
Physics
In the presence of ATP, kinesin proceeds along the protofilament of microtubule by
alternated binding of two motor domains on the tubulin binding sites. Because the
processivity of kinesin is much higher than other motor proteins, it has been speculated
...
Biological Sciences
Biochemistry
Trypanosomes are unique eukaryotic cells, in that they virtually lack mechanisms to
control gene expression at the transcriptional level. These microorganisms mostly
control protein synthesis by posttranscriptional regulation processes, like mRNA ...
The universally conserved ribonucleoprotein RNase P is involved in the processing
of tRNA precursor transcripts. RNase P consists of one RNA and, depending on its origin,
a variable number of protein subunits. Catalytic activity of the RNA moiety so far
...
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Uniformity amid diversity in RNase P
This article has a correction:Correction for Kikovska et al., Eukaryotic RNase P RNA mediates cleavage in the absence of protein
Blocking cell division through the inhibition of mitosis is one of the most successful
clinical strategies for the treatment of cancer. Taxanes and vinca alkaloids are in
widespread use and have demonstrated substantive therapeutic efficacy. Both classes
...
The highly efficient glycolytic enzyme, triosephosphate isomerase, is expected to
differentially stabilize the proposed stable reaction species: ketone, aldehyde, and
enediol(ate). The identity and steady-state populations of the chemical entities bound
...
Individual posttranslational modifications (PTMs) on histones have well established
roles in certain biological processes, notably transcriptional programming. Recent
genomewide studies describe patterns of covalent modifications, such as H3 methylation
...
In Escherichia coli, the switch between aerobic and anaerobic metabolism is controlled primarily by FNR
(regulator of fumarate and nitrate reduction), the protein that regulates the transcription
of >100 genes in response to oxygen. Under oxygen-limiting ...
The active sites of intramembrane proteases are positioned in the lipid bilayer to
facilitate peptide bond hydrolysis in the membrane. Previous crystallographic analysis
of Escherichia coli GlpG, an intramembrane protease of the rhomboid family, has ...
Notch receptors control differentiation and contribute to pathologic states such as
cancer by interacting directly with a transcription factor called CSL (for CBF-1/Suppressor
of Hairless/Lag-1) to induce expression of target genes. A number of Notch-...
The DNA architectural protein Xis regulates the construction of higher-order nucleoprotein
intasomes that integrate and excise the genome of phage lambda from the Escherichia coli chromosome. Xis modulates the directionality of site-specific recombination ...
Most restriction endonucleases use Mg2+ to hydrolyze phosphodiester bonds at specific DNA sites. We show here that BfiI,
a metal-independent restriction enzyme from the phospholipase D superfamily, catalyzes
both DNA hydrolysis and transesterification ...
The mosquito Anopheles gambiae is a primary vector of Plasmodium parasites in Africa. The effect of aging on reproductive output in A. gambiae females from three strains that differ in their ability to melanize Plasmodium and in their systemic levels of ...
Aminoacyl-tRNA synthetases are multidomain proteins responsible for the attachment
of specific amino acids to their tRNA substrates. Prolyl-tRNA synthetases (ProRSs)
are notable due to their particularly diverse architectures through evolution. For
...
In mammals, growth hormone-releasing hormone (GHRH) is the most important neuroendocrine
factor that stimulates the release of growth hormone (GH) from the anterior pituitary.
In nonmammalian vertebrates, however, the previously named GHRH-like peptides ...
Previous studies indicated that the vaccinia virus D10 protein, which is conserved
in all sequenced poxviruses, participates in the rapid turnover of host and viral
mRNAs. D10 contains a motif present in the family of Nudix/MutT enzymes, a subset
of which ...
The chaperonin GroEL assists protein folding by binding nonnative forms through exposed
hydrophobic surfaces in an open ring and mediating productive folding in an encapsulated
hydrophilic chamber formed when it binds GroES. Little is known about the ...
The crystal structure of the RCK-containing MthK provides a molecular framework for
understanding the ligand gating mechanisms of K+ channels. Here we examined the macroscopic currents of MthK in enlarged Escherichia coli membrane by patch clamp and rapid ...
Nitric oxide (NO) bioactivity is mainly conveyed through reactions with iron and thiols,
furnishing iron nitrosyls and S-nitrosothiols with wide-ranging stabilities and reactivities. Triiodide chemiluminescence
methodology has been popularized as uniquely ...
Biophysics
Intrachain loop formation allows unfolded polypeptide chains to search for favorable
interactions during protein folding. We applied triplet–triplet energy transfer between
a xanthone moiety and naphthylalanine to directly measure loop formation in ...
Cytochrome c oxidase, the terminal enzyme of the respiratory chain, pumps protons across the inner
mitochondrial membrane against an opposing electrochemical gradient by reducing oxygen
to water. To explore the fundamental mechanisms of such redox-coupled ...
In the presence of ATP, kinesin proceeds along the protofilament of microtubule by
alternated binding of two motor domains on the tubulin binding sites. Because the
processivity of kinesin is much higher than other motor proteins, it has been speculated
...
Actin filament polymerization generates force for protrusion of the leading edge in
motile cells. In protrusive structures, multiple actin filaments are arranged in cross-linked
webs (as in lamellipodia or pseudopodia) or parallel bundles (as in filopodia)...
Human progesterone receptors (PR) exist as two functionally distinct isoforms, PR-A
and PR-B. The proteins are identical except for an additional 164 residues located
at the N terminus of PR-B. To determine the mechanisms responsible for isoform-specific
...
Cell Biology
We present a strategy for the analysis of the yeast phosphoproteome that uses endo-Lys
C as the proteolytic enzyme, immobilized metal affinity chromatography for phosphopeptide
enrichment, a 90-min nanoflow-HPLC/electrospray-ionization MS/MS experiment ...
Electron transfer dissociation (ETD) is a recently introduced mass spectrometric technique
that provides a more comprehensive coverage of peptide sequences and posttranslational
modifications. Here, we evaluated the use of ETD for a global phosphoproteome ...
Werner syndrome (WS) is a rare human premature aging disease caused by mutations in
the gene encoding the RecQ helicase WRN. In addition to the aging features, this disorder
is marked by genomic instability, associated with an elevated incidence of ...
The malaria parasite can use host plasma glycerol for lipid biosynthesis and membrane
biogenesis during the asexual intraerythrocytic development. The molecular basis for
glycerol uptake into the parasite is undefined. We hypothesize that the Plasmodium ...
Ribonucleotide reductase maintains cellular deoxyribonucleotide pools and is thus
tightly regulated during the cell cycle to ensure high fidelity in DNA replication.
The Sml1 protein inhibits ribonucleotide reductase activity by binding to the R1 subunit.
...
Retrograde axonal transport plays an important role in the maintenance of neuronal
functions, but the mechanism is poorly defined partly because the constituents of
the retrograde transport system and their interactions have yet to be elucidated.
Of ...
In this article, the effect of a d(CG) DNA dinucleotide repeat sequence on RNA polymerase
II transcription is examined in yeast Saccharomyces cerevisiae. Our previous report shows that a d(CG)n dinucleotide repeat sequence located proximally upstream of ...
RNA-binding motif protein 4 (RBM4) plays a regulatory role in alternative splicing
of precursor mRNA. We show here that cell stress such as arsenite exposure induces
phosphorylation of RBM4 at serine 309 and also drives its cytoplasmic accumulation
and ...
When yeast cells are grown continuously at high cell density, a respiratory oscillation
percolates throughout the population. Many essential cellular functions have been
shown to be separated temporally during each cycle; however, the regulatory ...
Although copper has been reported to influence numerous proteins known to be important
for angiogenesis, the enhanced sensitivity of this developmental process to copper
bioavailability has remained an enigma, because copper metalloproteins are prevalent
...
Developmental Biology
Wnt and Shh signaling pathways are critical for the development and maturation of
many epithelial tissues. Both pathways have roles in stem cell maintenance, tissue
development, and tumorigenesis. However, linkage between these pathways in mammalian
...
Bone formation is carried out by the osteoblast, a mesenchymal cell whose lifespan
and activity are regulated by growth factor signaling networks. Growth factors activate
phosphatidylinositol 3-kinase (PI3K), which enhances cell survival and antagonizes
...
Ecology
The Asian snake Rhabdophis tigrinus possesses specialized defensive glands on its neck that contain steroidal toxins
known as bufadienolides. We hypothesized that R. tigrinus does not synthesize these defensive steroids but instead sequesters the toxins ...
Evolution
Darwin claimed that a unique inclusively hierarchical pattern of relationships between
all organisms based on their similarities and differences [the Tree of Life (TOL)]
was a fact of nature, for which evolution, and in particular a branching process of
...
Determining the extent of adaptive evolution at the genomic level is central to our
understanding of molecular evolution. A suitable observation for this purpose would
consist of polymorphic data on a large and unbiased collection of genes from two ...
Time-dependent selection causes the adaptive evolution of new phenotypes, and this
dynamics can be traced in genomic data. We have analyzed polymorphisms and substitutions
in Drosophila, using a more sensitive inference method for adaptations than the ...
Genetics
We have developed a two-component system involving reconstituted caspase (recCaspase)
for selective and/or conditional ablation of targeted cells. Caspases, the executioners
of programmed cell death, are normally synthesized as inactive zymogens and are ...
This article has a correction:
Correction for Chelur and Chalfie, Targeted cell killing by reconstituted caspases
Accumulating evidence has shown that many molecules, including some cyclin-dependent
kinases (Cdks) and cyclins, as well as the death-effector domain (DED)-containing
FADD, function for both apoptosis and cell cycle. Here we identified that DEDD, which
...
The nematode Caenorhabditis elegans is present in soils and composts, where it can encounter a variety of microorganisms.
Some bacteria in these rich environments are innocuous food sources for C. elegans, whereas others are pathogens. Under laboratory ...
Adaptive transcriptional responses to oxygen deprivation (hypoxia) are mediated by
the hypoxia-inducible factors (HIFs), heterodimeric transcription factors composed
of two basic helix–loop–helix–PAS family proteins. The transcriptional activity of
HIF is ...
Why are most genes dispensable? The impact of gene deletions may depend on the environment
(plasticity), the presence of compensatory mechanisms (mutational robustness), or
both. Here, we analyze the interaction between these two forces by exploring the ...
Compared with understanding of biological shape and form, knowledge is sparse regarding
what regulates growth and body size of a species. For example, the genetic and physiological
causes of heterosis (hybrid vigor) have remained elusive for nearly a ...
Immunology
Fetal loss in animals and humans is frequently associated with inflammatory conditions.
D6 is a promiscuous chemokine receptor with decoy function, expressed in lymphatic
endothelium, that recognizes and targets to degradation most inflammatory CC ...
Mast cells are immune sentinels that participate in the defense against bacteria and
parasites. Resident within the joint, mast cells become activated in human rheumatoid
arthritis and are implicated in the pathogenesis of experimental murine synovitis.
...
Medical Sciences
Klotho, an antiaging gene with restricted organ distribution, is mainly expressed in the
kidney tubules; the mutant mice have shortened life span, arteriosclerosis, anemia,
and osteoporesis, features common to patients with chronic renal failure. ...
Type 1 diabetes in both humans and nonobese diabetic (NOD) mice results from autoreactive
T cell destruction of insulin-producing β cells. Cure of type 1 diabetes may require
both reversal of autoimmunity and regeneration of β cells. Induction of ...
The advent of serum prostate-specific antigen (PSA) as a biomarker has enabled early
detection of prostate cancer and, hence, improved clinical outcome. However, a low
PSA is not a guarantee of disease-free status, and an elevated PSA is frequently ...
One of the central tasks of stem cell biology is to understand the molecular mechanisms
that control self-renewal in stem cells. Several cytokines are implicated as crucial
regulators of hematopoietic stem cells (HSCs), but little is known about ...
Apoptosis has been suggested as one of the major mechanisms of CD4+ T cell depletion during the course of HIV type 1 (HIV-1) infection. Here, we show
that interleukin 7 (IL-7), a nonredundant cytokine that plays essential roles in the
generation and ...
The concept of fractal geometry is useful for the analysis of irregular and complex
structures often seen in nature. Here we apply this concept to investigate the structural
mechanism of the development of pulmonary emphysema in the klotho mouse, which, ...
C57BL/6 (B6) mice subjected to a high-fat diet develop metabolic syndrome with obesity,
hyperglycemia, and insulin resistance, whereas 129S6/SvEvTac (129) mice are relatively
protected from this disorder because of differences in higher basal energy ...
Microbiology
The development of antimicrobials is critical in this time of increasing antibiotic
resistance of most clinically relevant bacteria. To date, all current antibiotics
focus on inhibiting crucial enzymatic activities of their protein targets (i.e., ...
A factor (2-isocapryloyl-3R-hydroxymethyl-γ-butyrolactone) is a representative of the γ-butyrolactone autoregulators
that trigger secondary metabolism and morphogenesis in the Gram-positive, filamentous
bacterial genus Streptomyces. Here, we report the A ...
The mechanisms of target cell recognition and producer cell self-protection (immunity)
are both important yet poorly understood issues in the biology of peptide bacteriocins.
In this report, we provide genetic and biochemical evidence that lactococcin A, ...
Capsular polysaccharides (CPSs) are essential virulence determinants of many pathogenic
bacteria. Escherichia coli group 1 CPSs provide paradigms for widespread surface polysaccharide assembly systems
in Gram-negative bacteria. In these systems, complex ...
The O-specific polysaccharide (O-SP) domain of Shigella LPS is both an essential virulence factor and a protective antigen for this genus.
A critical level of serum IgG anti-O-SP was shown to confer immunity to shigellosis,
likely by complement-mediated ...
Respiratory metabolism plays an important role in energy production in the form of
ATP in all aerobically growing cells. However, a limitation in respiratory capacity
results in overflow metabolism, leading to the formation of byproducts, a phenomenon
...
Proteorhodopsin (PR) is a light-powered proton pump identified by community sequencing
of ocean samples. Previous studies have established the ecological distribution and
enzymatic activity of PR, but its role in powering cells and participation in ocean
...
The recent report of the synthesis of glycoproteins by the abundant intestinal symbionts
Bacteroides showed that these organisms use a novel bacterial enzyme to decorate their surfaces
with a sugar residue derived from their environment. As a first step ...
Photorhabdus is a virulent pathogen that kills its insect host by overcoming immune responses.
The bacterium also secretes a range of antibiotics to suppress the growth of other
invading microorganisms. Here we show that Photorhabdus produces a small-...
Neuroscience
Photoreceptor apoptosis is a major cause of visual loss in retinal detachment (RD)
and several other visual disorders, but the underlying mechanisms remain elusive.
Recently, increased expression of monocyte chemoattractant protein 1 (MCP-1) was reported
...
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The neuronal soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex is essential
for synaptic vesicle exocytosis, but its study has been limited by the neonatal lethality
of murine SNARE knockouts. Here, we describe a viable ...
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration has been used, in various
mammalian species, as an experimental model of Parkinson's disease. The pathogenesis
for such pharmacologically induced Parkinson's disease involves 1-methyl-4-...
Parkinson's disease (PD), a late-onset condition characterized by dysfunction and
loss of dopaminergic neurons in the substantia nigra, has both sporadic and neurotoxic
forms. Neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and its ...
To effect movement, motoneurons must respond appropriately to motor commands. Their
responsiveness to these inputs, or excitability, is regulated by neuromodulators.
Possible sources of modulation include the abundant cholinergic “C boutons” that surround
...
Fragile X syndrome is a common heritable form of mental retardation in humans. Recent
neuroanatomical studies indicate an apparent immature appearance of neurons in fragile
X syndrome patients and fragile X mental retardation protein (FMRP)-knockout mice,
...
Honey bee queens produce a sophisticated array of chemical signals (pheromones) that
influence both the behavior and physiology of their nest mates. Most striking are
the effects of queen mandibular pheromone (QMP), a chemical blend that induces young
...
There is considerable evidence from animal studies that the mesolimbic and mesocortical
dopamine systems are sensitive to circulating gonadal steroid hormones. Less is known
about the influence of estrogen and progesterone on the human reward system. To ...
Olfactory sensory neurons (OSNs) in the main olfactory epithelium respond to environmental
odorants. Recent studies reveal that these OSNs also respond to semiochemicals such
as pheromones and that main olfactory input modulates animal reproduction, but ...
Essential roles for gonadotropins in gonadal development and reproduction are well
established. Over the past decade, however, the expression of luteinizing hormone
receptor (LHR) has also been reported in the brain of various mammals and birds. Although
...
Vertebrates display diverse patterns of neuromuscular innervation, but little is known
about how such diversity is generated. In mammals, neuromuscular junctions form predominantly
at equatorial locations, giving rise to a focal innervation pattern along ...
Dynamic manganese-enhanced magnetic resonance imaging (MEMRI) detects neuronal activity
based on the passage of Mn2+ into active neurons. Because this mechanism is independent of any hemodynamic response,
it is potentially ideal for pharmacological ...
There is emerging evidence for the existence of secretory pathways for superoxide
dismutase (SOD1) mutants linked to amyotrophic lateral sclerosis (ALS) and for neurotoxicity
of extracellular mutant SOD1. This evidence led us to test immunization ...
Estrogen receptor α (ERα) plays a pivotal role in the regulation of food intake and
energy expenditure by estrogens. Although it is well documented that a disruption
of ERα signaling in ERα knockout (ERKO) mice leads to an obese phenotype, the sites
of ...
Alzheimer's disease (AD) immunotherapy accomplished by vaccination with β-amyloid
(Aβ) peptide has proved efficacious in AD mouse models. However, “active” Aβ vaccination
strategies for the treatment of cerebral amyloidosis without concurrent induction
of ...
Because the cranial capacity of LB1 (Homo floresiensis) is only 417 cm3, some workers propose that it represents a microcephalic Homo sapiens rather than a new species. This hypothesis is difficult to assess, however, without
a clear understanding of how ...
The exchange factor directly activated by cAMP (Epac) is a newly discovered direct
target for cAMP and a guanine-nucleotide exchange factor for the small GTPase Rap.
Little is known about the neuronal functions of Epac. Here we show that activation
of ...
CASK is an evolutionarily conserved multidomain protein composed of an N-terminal
Ca2+/calmodulin-kinase domain, central PDZ and SH3 domains, and a C-terminal guanylate
kinase domain. Many potential activities for CASK have been suggested, including ...
Plant Biology
Nucleotide binding site–leucine-rich repeat (NBS–LRR) proteins mediate pathogen recognition
in both mammals and plants. The molecular mechanisms by which pathogen molecules activate
NBS–LRR proteins are poorly understood. Here we show that RPS5, a NBS–LRR ...
Sugar compartmentation into vacuoles of higher plants is a very important physiological
process, providing extra space for transient and long-term sugar storage and contributing
to the osmoregulation of cell turgor and shape. Despite the long-standing ...
During development of plant seeds, embryos import nutrients and store massive amounts
of reserves. Seed reserves are rapidly degraded and mobilized to support seedling
development after germination. HIGH-LEVEL EXPRESSION OF SUGAR-INDUCIBLE GENE 2 (HSI2)
...
The PsbQ protein defines cyanobacterial Photosystem II complexes with highest activity and stability
Light-induced conversion of water to molecular oxygen by Photosystem II (PSII) is
one of the most important enzymatic reactions in the biosphere. PSII is a multisubunit
membrane protein complex with numerous associated cofactors, but it continually ...
Corrections
Evolution
Medical Sciences
Cover image: Vasculature of the paired defensive glands located in the neck of the Asian snake Rhabdophis tigrinus, showing dense capillary beds. These nuchal glands contain cardiotonic steroid toxins (bufadienolides) sequestered from dietary toads, and the toxins may be delivered to the glands by this dense vasculature. The snakes use these glands and toxins in defensive behaviors against predators. See the article by Hutchinson et al. on pages 2265–2270. Image courtesy of Alan H. Savitzky.
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