Three-dimensional structure of the myosin V inhibited state by cryoelectron tomography

Unconventional myosin V (myoV) is an actin-based molecular motor that has a key function in organelle and mRNA transport, as well as in membrane trafficking. MyoV was the first member of the myosin superfamily shown to be processive, meaning that a single motor protein can 'walk' hand-over-hand along an actin filament for many steps before detaching. Full-length myoV has a low actin-activated MgATPase activity at low [Ca2+], whereas expressed constructs lacking the cargo-binding domain have a high activity regardless of [Ca2+] (refs 5-7). Hydrodynamic data and electron micrographs indicate that the active state is extended, whereas the inactive state is compact. Here we show the first three-dimensional structure of the myoV inactive state. Each myoV molecule consists of two heads that contain an amino-terminal motor domain followed by a lever arm that binds six calmodulins. The heads are followed by a coiled-coil dimerization domain (S2) and a carboxy-terminal globular cargo-binding domain. In the inactive structure, bending of myoV at the head-S2 junction places the cargo-binding domain near the motor domain's ATP-binding pocket, indicating that ATPase inhibition might occur through decreased rates of nucleotide exchange. The actin-binding interfaces are unobstructed, and the lever arm is oriented in a position typical of strong actin-binding states. This structure indicates that motor recycling after cargo delivery might occur through transport on actively treadmilling actin filaments rather than by diffusion.     

Ferns diversified in the shadow of angiosperms

The rise of angiosperms during the Cretaceous period is often portrayed as coincident with a dramatic drop in the diversity and abundance of many seed-free vascular plant lineages, including ferns. This has led to the widespread belief that ferns, once a principal component of terrestrial ecosystems, succumbed to the ecological predominance of angiosperms and are mostly evolutionary holdovers from the late Palaeozoic/early Mesozoic era. The first appearance of many modern fern genera in the early Tertiary fossil record implies another evolutionary scenario; that is, that the majority of living ferns resulted from a more recent diversification. But a full understanding of trends in fern diversification and evolution using only palaeobotanical evidence is hindered by the poor taxonomic resolution of the fern fossil record in the Cretaceous. Here we report divergence time estimates for ferns and angiosperms based on molecular data, with constraints from a reassessment of the fossil record. We show that polypod ferns (> 80% of living fern species) diversified in the Cretaceous, after angiosperms, suggesting perhaps an ecological opportunistic response to the diversification of angiosperms, as angiosperms came to dominate terrestrial ecosystems.     

Oligocene mammals from Ethiopia and faunal exchange between Afro-Arabia and Eurasia

Afro-Arabian mammalian communities underwent a marked transition near the Oligocene/Miocene boundary at approximately 24 million years (Myr) ago. Although it is well documented that the endemic paenungulate taxa were replaced by migrants from the Northern Hemisphere, the timing and evolutionary dynamics of this transition have long been a mystery because faunas from about 32 to 24 Myr ago are largely unknown. Here we report a late Oligocene fossil assemblage from Ethiopia, which constrains the migration to postdate 27 Myr ago, and yields new insight into the indigenous faunal dynamics that preceded this event. The fauna is composed of large paenungulate herbivores and reveals not only which earlier taxa persisted into the late Oligocene epoch but also demonstrates that one group, the Proboscidea, underwent a marked diversification. When Eurasian immigrants entered Afro-Arabia, a pattern of winners and losers among the endemics emerged: less diverse taxa such as arsinoitheres became extinct, moderately species-rich groups such as hyracoids continued into the Miocene with reduced diversity, whereas the proboscideans successfully carried their adaptive radiation out of Afro-Arabia and across the world.     

A proteomic view of the Plasmodium falciparum life cycle

The completion of the Plasmodium falciparum clone 3D7 genome provides a basis on which to conduct comparative proteomics studies of this human pathogen. Here, we applied a high-throughput proteomics approach to identify new potential drug and vaccine targets and to better understand the biology of this complex protozoan parasite. We characterized four stages of the parasite life cycle (sporozoites, merozoites, trophozoites and gametocytes) by multidimensional protein identification technology. Functional profiling of over 2,400 proteins agreed with the physiology of each stage. Unexpectedly, the antigenically variant proteins of var and rif genes, defined as molecules on the surface of infected erythrocytes, were also largely expressed in sporozoites. The detection of chromosomal clusters encoding co-expressed proteins suggested a potential mechanism for controlling gene expression.     

Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors

Aberrant methylation of CpG islands and genomic deletion are two predominant mechanisms of gene inactivation in tumorigenesis, but the extent to which they interact is largely unknown. The lack of an integrated approach to study these mechanisms has limited the understanding of tumor genomes and cancer genes. Restriction landmark genomic scanning (RLGS; ref. 1) is useful for global analysis of aberrant methylation of CpG islands, but has not been amenable to alignment with deletion maps because the identity of most RLGS fragments is unknown. Here, we determined the nucleotide sequence and exact chromosomal position of RLGS fragments throughout the genome using the whole chromosome of origin of the fragments and in silico restriction digestion of the human genome sequence. To study the interaction of these gene-inactivation mechanisms in primary brain tumors, we integrated RLGS-based methylation analysis with high-resolution deletion maps from microarray-based comparative genomic hybridization (array CGH; ref. 3). Certain subsets of gene-associated CpG islands were preferentially affected by convergent methylation and deletion, including genes that exhibit tumor-suppressor activity, such as CISH1 (encoding SOCS1; ref. 4), as well as genes such as COE3 that have been missed by traditional non-integrated approaches. Our results show that most aberrant methylation events are focal and independent of deletions, and the rare convergence of these mechanisms can pinpoint biallelic gene inactivation without the use of positional cloning.     

Germline mutations and sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk

Deletions on human chromosome 8p22-23 in prostate cancer cells and linkage studies in families affected with hereditary prostate cancer (HPC) have implicated this region in the development of prostate cancer. The macrophage scavenger receptor 1 gene (MSR1, also known as SR-A) is located at 8p22 and functions in several processes proposed to be relevant to prostate carcinogenesis. Here we report the results of genetic analyses that indicate that mutations in MSR1 may be associated with risk of prostate cancer. Among families affected with HPC, we identified six rare missense mutations and one nonsense mutation in MSR1. A family-based linkage and association test indicated that these mutations co-segregate with prostate cancer (P = 0.0007). In addition, among men of European descent, MSR1 mutations were detected in 4.4% of individuals affected with non-HPC as compared with 0.8% of unaffected men (P = 0.009). Among African American men, these values were 12.5% and 1.8%, respectively (P = 0.01). These results show that MSR1 may be important in susceptibility to prostate cancer in men of both African American and European descent.     

Modern stalagmite oxygen isotopic composition and its implications of climatic change from a high-elevation cave in the eastern Qinghai-Tibet Plateau over the past 50 years

An oxygen isotope record of a stalagmite from Huanglong Cave in the eastern Qinghai-Tibet Plateau dated with 230Th and 210Pb methods provides variations of the Asian monsoon with an average resolu-tion of 1 year over the past 50 years. This study shows that the δ18O of dripwater in the cave represents the annual mean δ18O of local meteoric precipitation and the stalagmites were deposited in isotopic equilibrium. A comparison of the stalagmite δ18O record with instrumentally meteorological data indi-cates that shifts of the δ18O are largely controlled by the amount effect of meteoric precipitation con-veyed through the southwest monsoon(the Indian monsoon) and less affected by temperature. Therefore,the variations of δ18O record reflect the changes in monsoon precipitation on inter-annual time scales under the influence of the southwest monsoon. Like many other stalagmite δ18O records in the Asian monsoon regions,the δ18O record of the stalagmite from Huanglong Cave also reveals a gradually enriched trend during the past 50 years,i.e. relatively enriched in 18O. This trend may indicate the decline of the Asian monsoon intensity which is consistent with the decrease of monsoon indices. The weakening of the modern Asian monsoon well matched with the temperature changes in strato-sphere,which may illustrate that the weakening of the monsoon mainly results from the lowering of solar radiation.