The Parkinson-associated protein PINK1 interacts with Beclin1 and promotes autophagy.

in Cell death and differentiation (2010), 17(6), 962-74

Mutations in the PINK1 gene cause autosomal recessive Parkinson's disease. The PINK1 gene encodes a protein kinase that is mitochondrially cleaved to generate two mature isoforms. In addition to its ... [more ▼]

Mutations in the PINK1 gene cause autosomal recessive Parkinson's disease. The PINK1 gene encodes a protein kinase that is mitochondrially cleaved to generate two mature isoforms. In addition to its protective role against mitochondrial dysfunction and apoptosis, PINK1 is also known to regulate mitochondrial dynamics acting upstream of the PD-related protein Parkin. Recent data showed that mitochondrial Parkin promotes the autophagic degradation of dysfunctional mitochondria, and that stable PINK1 silencing may have an indirect role in mitophagy activation. Here we report a new interaction between PINK1 and Beclin1, a key pro-autophagic protein already implicated in the pathogenesis of Alzheimer's and Huntington's diseases. Both PINK1 N- and C-terminal are required for the interaction, suggesting that full-length PINK1, and not its cleaved isoforms, interacts with Beclin1. We also demonstrate that PINK1 significantly enhances basal and starvation-induced autophagy, which is reduced by knocking down Beclin1 expression or by inhibiting the Beclin1 partner Vps34. A mutant, PINK1(W437X), interaction of which with Beclin1 is largely impaired, lacks the ability to enhance autophagy, whereas this is not observed for PINK1(G309D), a mutant with defective kinase activity but unaltered ability to bind Beclin1. These findings identify a new function of PINK1 and further strengthen the link between autophagy and proteins implicated in the neurodegenerative process. [less ▲]

Sequence analysis of the Methanococcus jannaschii genome and the prediction of protein function

in Computer Applications in the Biosciences [=CABIOS] (1997), 13(4), 481-483

GeneCrunch: Experiences on the SGI POWER CHALLENGEarray with Bioinformatics applications

in Supercomputer 96: Anwendungen, Architekturen, Trends (1996)

Analyzing genomic data is a computationally intensive and complicated process in which scientists must typically choose among multiple databases and analysis methods and make expert judgements inspecting ... [more ▼]

Analyzing genomic data is a computationally intensive and complicated process in which scientists must typically choose among multiple databases and analysis methods and make expert judgements inspecting multiple results. GeneQuiz, an automated software system for large scale genome analysis developed at the EMBL/EBI, tackles this problem by using an automated, rigorous, rule-based system to select among the results of sequence analysis and database searches, builds informative annotation and aims at predicting the function of new genes. In a demonstration project more than 6000 proteins from the Baker’s yeast, for which the complete genomic sequence was completed in 1996, were analyzed on a Silicon Graphics POWERCHALLENGEarray with 64 processors (R8000 @90 MHz) so that the analysis could be completed in 3 days. The results of the analysis were published on two web servers as they were computed. [less ▲]

Fast and sensitive search of information databases for biological relationships

in Statustagung des BMBF, HPSC 95, Stand und Perspektiven des Parallelen Höchstleistungsrechnens und seiner Anwendungen (1995)

Sequence comparison has become an essential and standard tool in the analysis of genomic data. Genome projects will decipher much of the genetic information in many organisms, including humans. As a ... [more ▼]

Sequence comparison has become an essential and standard tool in the analysis of genomic data. Genome projects will decipher much of the genetic information in many organisms, including humans. As a result, the computational cost of databank searches will increase dramatically. In addition, the search for biologically meaningful homology between a newly determined sequence and sequences already stored in the various databanks becomes increasingly important as most of the new data will be in raw, not understood form. The detection of sufficient similarity between a newly determined sequence to a protein of know function or even known 3D-structure in a databank allows one to transfer most of the knowledge from one sequence to the other. The result can be enormous savings in genetic and biochemical laboratory efforts. [less ▲]

GeneQuiz: a workbench for sequence analysis

in Proceedings of the Second International Conference on Intelligent Systems for Molecular Biology, ISMB-94 (1994)

We present the prototype of a software system, called GeneQuiz, for large-scale biological sequence analysis. The system was designed to meet the needs that arise in computational sequence analysis and ... [more ▼]

We present the prototype of a software system, called GeneQuiz, for large-scale biological sequence analysis. The system was designed to meet the needs that arise in computational sequence analysis and our past experience with the analysis of 171 protein sequences of yeast chromosome III. We explain the cognitive challenges associated with this particular research activity and present our model of the sequence analysis process. The prototype system consists of two parts: (i) the database update and search system (driven by perl programs and rdb, a simple relational database engine also written in perl) and (ii) the visualization and browsing system (developed under C++/ET++). The principal design requirement for the first part was the complete automation of all repetitive actions: database updates, efficient sequence similarity searches and sampling of results in a uniform fashion. The user is then presented with "hit-lists" that summarize the results from heterogeneous database searches. The expert's primary task now simply becomes the further analysis of the candidate entries, where the problem is to extract adequate information about functional characteristics of the query protein rapidly. This second task is tremendously accelerated by a simple combination of the heterogeneous output into uniform relational tables and the provision of browsing mechanisms that give access to database records, sequence entries and alignment views. Indexing of molecular sequence databases provides fast retrieval of individual entries with the use of unique identifiers as well as browsing through databases using pre-existing cross-references. The presentation here covers an overview of the architecture of the system prototype and our experiences on its applicability in sequence analysis. [less ▲]