The Role of Cargo Proteins in GGA Recruitment

Coat proteins are recruited onto membranes to form vesicles that transport cargo from one compartment to another, but the extent to which the cargo helps to recruit the coat proteins is still unclear. Here we have examined the role of cargo in the recruitment of Golgi-localized, γ-ear-containing, ADP ribosylation factor (ARF)-binding proteins (GGAs) onto membranes in HeLa cells. Moderate overexpression of CD8 chimeras with cytoplasmic tails containing DXXLL-sorting signals, which bind to GGAs, increased the localization of all three GGAs to perinuclear membranes, as observed by immunofluorescence. GGA2 was also expressed at approximately twofold higher levels in these cells because it was degraded more slowly. However, this difference only partially accounted for the increase in membrane localization because there was a approximately fivefold increase in GGA2 associated with crude membranes and a ∼12-fold increase in GGA2 associated with clathrin-coated vesicles (CCVs) in cells expressing CD8-DXXLL chimeras. The effect of cargo proteins on GGA recruitment was reconstituted in vitro using permeabilized control and CD8-DXXLL-expressing cells incubated with cytosol containing recombinant GGA2 constructs. Together, these results demonstrate that cargo proteins contribute to the recruitment of GGAs onto membranes and to the formation of GGA-positive CCVs

The Jurassic–Cretaceous depositional and tectonic evolution of the southernwestern margin of the Neotethys Ocean, Northern Oman and United Arab Emirates

The concept that the autochthonous, parautochthonous and allochthonous Permian–Cretaceous sequences in the United Arab Emirates (UAE) and Oman record the transition from platform, slope to basin sedimentation within the southern part of Neotethys has been fundamental to the interpretation of the geological history of the region. The results of a major geological mapping programme of the UAE, carried out by the British Geological Survey for the Federal Government of the UAE, coupled with the detailed examination of key sections within northern Oman has led to a re-evaluation of the geological evolution of this region. This detailed study has led to a greater appreciation of the sedimentology and depositional setting of the sediments laid down along the northeastern Arabian continental margin during the Jurassic to Cretaceous, allowing a more refined model of Neotethys Ocean basin evolution to be established. The model charts the progressive breakup of the Arabian continental margin and closure of Neotethys during the mid to late Cretaceous and is divided into three main stages: Stage 1—Initial rifting and formation of the Neotethys Ocean, followed by a prolonged period of stable, passive margin sedimentation which extended from the Permian to Late Jurassic times; Stage 2—Uplift and erosion of the shelf margin during the Late Jurassic to Early Cretaceous, coincident with increased carbonate-clastic sedimentation in the outer ramp, distal slope and basinal areas; Stage 3—Increased instability during the Late Cretaceous leading to the breakup of the platform margin and foreland basin sedimentation accompanying the obduction of the Oman-UAE ophiolite. Data obtained for the upper part of the platform and platform margin to slope successions has revealed that the topography of the “shelf”-slope-basinal margin was more subdued than previously thought, with this more gentle ramp margin morphology persisting until early to mid-Cretaceous times when the platform margin started to become unstable during ophiolite obduction. The thrust-repeated allochthonous sedimentary rocks of the Hamrat Duru Group were deposited on the outer platform margin/lower slope rise to basinal plain of this basin margin and includes the dismembered remains of two turbidite fan systems which fed carbonate-rich detritus into deeper parts of the ocean. A re-evaluation of the chert-rich sequences, previously equated with deposition on the abyssal plain of Neotethys, has led to the conclusion that they may record sedimentation at a much shallower level within a starved ocean basin, possibly in a mid-ramp (above storm wave base) to outer ramp setting. A marked change in basin dynamics occurred during the mid-Cretaceous leading to the development of a shallow ramp basin margin in Oman with terrestrial to shallow marine sedimentary rocks interdigitating with red siliceous mudstones. By contrast, the contemporaneous succession in the Dibba Zone of the UAE indicates considerable instability on a steep shelf break. This instability is recorded by the presence of several major olistostrome deposits within the Aruma Group of the UAE which are thought to have been generated in advance of the rapidly obducting Oman-UAE ophiolite

Diversity in Protein Glycosylation among Insect Species

status: publishe

Genomewide association study for onset age in Parkinson disease

<p>Abstract</p> <p>Background</p> <p>Age at onset in Parkinson disease (PD) is a highly heritable quantitative trait for which a significant genetic influence is supported by multiple segregation analyses. Because genes associated with onset age may represent invaluable therapeutic targets to delay the disease, we sought to identify such genetic modifiers using a genomewide association study in familial PD. There have been previous genomewide association studies (GWAS) to identify genes influencing PD susceptibility, but this is the first to identify genes contributing to the variation in onset age.</p> <p>Methods</p> <p>Initial analyses were performed using genotypes generated with the Illumina HumanCNV370Duo array in a sample of 857 unrelated, familial PD cases. Subsequently, a meta-analysis of imputed SNPs was performed combining the familial PD data with that from a previous GWAS of 440 idiopathic PD cases. The SNPs from the meta-analysis with the lowest p-values and consistency in the direction of effect for onset age were then genotyped in a replication sample of 747 idiopathic PD cases from the Parkinson Institute Biobank of Milan, Italy.</p> <p>Results</p> <p>Meta-analysis across the three studies detected consistent association (p < 1 × 10^-5) with five SNPs, none of which reached genomewide significance. On chromosome 11, the SNP with the lowest p-value (rs10767971; p = 5.4 × 10^-7) lies between the genes <it>QSER1 </it>and <it>PRRG4</it>. Near the PARK3 linkage region on chromosome 2p13, association was observed with a SNP (rs7577851; p = 8.7 × 10^-6) which lies in an intron of the <it>AAK1 </it>gene. This gene is closely related to <it>GAK</it>, identified as a possible PD susceptibility gene in the GWAS of the familial PD cases.</p> <p>Conclusion</p> <p>Taken together, these results suggest an influence of genes involved in endocytosis and lysosomal sorting in PD pathogenesis.</p

Crystal structure and biochemical analyses reveal Beclin 1 as a novel membrane binding protein

The Beclin 1 gene is a haplo-insufficient tumor suppressor and plays an essential role in autophagy. However, the molecular mechanism by which Beclin 1 functions remains largely unknown. Here we report the crystal structure of the evolutionarily conserved domain (ECD) of Beclin 1 at 1.6 Å resolution. Beclin 1 ECD exhibits a previously unreported fold, with three structural repeats arranged symmetrically around a central axis. Beclin 1 ECD defines a novel class of membrane-binding domain, with a strong preference for lipid membrane enriched with cardiolipin. The tip of a surface loop in Beclin 1 ECD, comprising three aromatic amino acids, acts as a hydrophobic finger to associate with lipid membrane, consequently resulting in the deformation of membrane and liposomes. Mutation of these aromatic residues rendered Beclin 1 unable to stably associate with lipid membrane in vitro and unable to fully rescue autophagy in Beclin 1-knockdown cells in vivo. These observations form an important framework for deciphering the biological functions of Beclin 1