Yeast Ysl2p, Homologous to Sec7 Domain Guanine Nucleotide Exchange Factors, Functions in Endocytosis and Maintenance of Vacuole Integrity and Interacts with the Arf-Like Small GTPase Arl1p

Q3 · BIOLOGY

Article

Author: Jackson, David ; Singer-Krüger, Birgit ; Jochum, Alexandra ; Pipkorn, Rüdiger ; Schwarz, Heinz

ABSTRACT We previously described the isolation of ysl2 - 1 due to its genetic interaction with Δ ypt51/vps21 , a mutant with a deletion of the coding sequence for the yeast Rab5 homolog, which regulates endocytic traffic between early and late endosomes. Here we report that Ysl2p is a novel 186.8-kDa peripheral membrane protein homologous to members of the Sec7 family. We provide multiple genetic and biochemical evidence for an interaction between Ysl12p and the Arf-like protein Arl1p, consistent with a potential function as an Arf guanine nucleotide exchange factor (GEF). The temperature-sensitive alleles ysl2 - 307 and ysl2 - 316 are specifically defective in ligand-induced degradation of Ste2p and α-factor and exhibit vacuole fragmentation directly upon a shift to 37°C. In living cells, green fluorescent protein (GFP)-Ysl2p colocalizes with endocytic elements that accumulate FM4-64. The GFP-Ysl2p staining is sensitive to a mutation in VPS27 resulting in the formation of an aberrant class E compartment, but it is not affected by a sec7 mutation. Consistent with the idea that Ysl2p and Arl1p have closely related functions, Δ arl1 cells are defective in endocytic transport and in vacuolar protein sorting.

01 Jan 2000·Genome informatics. Workshop on Genome Informatics

An infrastructure for comparative genomics to functionally characterize genes and proteins.

Article

Author: Clemens Suter-Crazzolara ; Gunther Kurapkat

Current genome projects are resulting in a flood of sequence data. The interpretation of these sequences is lagging, and optimized data analysis strategies need to be developed. Much can be learned from comparing different genomes, as genomes of distant organisms may still encode proteins with high sequence similarity. The order of genes (co linearity) in genomes may also be conserved to some extend. We have employed both these observations to create a multi-functional, computational analysis system (genomeSCOUT) which allows for rapid identification and functional characterization of genes and proteins through genome comparison. With a number of independent algorithms, information about different levels of protein homology (concerning e.g. paralogs, orthologs and clusters of orthologous groups, COGs) and gene order is collected and stored in several value added databases. These databases are then used for interactive comparison of genomes and subsequent analysis. The application is based on the well established data integration system SRS. This ensures (1) fast handling of large genomic data sets, (2) straightforward access to a multitude of biological databases, (3) unique linking functions between these databases, (4) highly efficient collection of information on genes and proteins, and 5. fully integrated and user friendly graphical representations of search results. This application can be used for projects as diverse as the correct annotation of genomes, the optimization of (micro) organisms for industrial production, or the identification of drug targets.

Prospective Evaluation of Structure-based ADME Predictions: Knowing When the Experiment is the Prudent Course of Action

Author: Bremer, Troy ; Holme, Kevin ; Athwal, Jehangir ; Sage, Carleton R.

Statistically based computational models that predict a biol. output from structural inputs are interpolative systems likely to perform poorly when used for extrapolation.The ADME (Absorption, Distribution, Metabolism, Excretion) properties of a compound are largely unrelated to its pharmacol. target; the "space" described by ADME models is largely unconstrained, and data representation within this space is sparse.Therefore, methods to describe when a prediction is an interpolation or an extrapolation should be useful in prospectively determining prediction validity.We have used robust statistical methods to develop predictive models for CYP2D6, CYP3A4, FDP, and Caco-2 effective permeability.To encourage the appropriate use of these predictive tools, we have developed methods that provide a measure of uncertainty associated for each prediction.When used in the evaluation of completely external test sets, the measures of uncertainty results have been useful in the identification of poor predictions, allowing their prospective use in prediction evaluation.

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