Biomedical subjects

Robert Preissner

Publications and source records attributed to Robert Preissner.

24 records · Page 2Linked to original sources

PubMed2003

Accelerating screening of 3D protein data with a graph theoretical approach.

MOTIVATION: The Dictionary of Interfaces in Proteins (DIP) is a database collecting the 3D structure of interacting parts of proteins that are called patches. It serves as a repository, in which patches similar to given query patches can be found. The computation of the similarity of two patches is time consuming and traversing the entire DIP requires some hours. In this work we address the question of how the patches similar to a given query can be identified by scanning only a small part of DIP. The answer to this question requires the investigation of the distribution of the similarity of patches. RESULTS: The score values describing the similarity of two patches can roughly be divided into three ranges that correspond to different levels of spatial similarity. Interestingly, the two iso-score lines separating the three classes can be determined by two different approaches. Applying a concept of the theory of random graphs reveals significant structural properties of the data in DIP. These can be used to accelerate scanning the DIP for patches similar to a given query. Searches for very similar patches could be accelerated by a factor of more than 25. Patches with a medium similarity could be found 10 times faster than by brute-force search.

Algorithms↗

PubMed2003

Inhomogeneous molecular density: reference packing densities and distribution of cavities within proteins.

MOTIVATION: There is no consensus in the literature about how the deepest portions of protein structures are packed. Using an improved Voronoi procedure, we calculate reference packing densities for different regions in the protein interior. Furthermore, we want to clarify where cavities are located. RESULTS: Sets of reference packing densities are provided for regions in proteins that differ in their distance to the surface and to internal cavities, supplementing previous data. Packing in the protein interior is tight but generally inhomogeneous. There are about 4.4 cavities per 100 amino acids in protein structures, they occur in all regions, most frequently in a depth of 2.5-3.6 A underneath the Connolly surface. However, the deepest protein regions have a lower mean packing density than circumjacent regions, because more contacts to cavities occur in the core. AVAILABILITY/SUPPLEMENTARY INFORMATION: Calculation software and detailed packing data are available on request.

Amino Acid Sequence↗

PubMed2003

Inverse sequence similarity of proteins does not imply structural similarity.

There is a debate on the folding of proteins with inverted sequences. Theoretical approaches and experiments give contradictory results. Many proteins in the Protein Data Bank (PDB) show conspicuous inverse sequence similarity (ISS) to each other. Here we analyze whether this ISS is related to structural similarity. For the first time, we performed a large scale three-dimensional (3-D) superposition of corresponding Calpha atoms of forwardly and inversely aligned proteins and tested the degree of secondary structure identity between them. Comparing proteins of less than 50% pairwise sequence identity, only 0.5% of the inversely aligned pairs had similar folds (99 out of 19073), whereas about 9% of forwardly aligned proteins in the same score and length range show similar 3-D structures (1731 out of 19248). This observation strongly supports the view that the inversion of sequences in almost all cases leads to a different folding property of the protein. Inverted sequences are thus suitable as protein-like sequences for control purposes without relations to existing proteins.

Algorithms↗

PubMed2003

A comprehensive view on proteasomal sequences: implications for the evolution of the proteasome.

Proteasomes are large multimeric self-compartmentizing proteases, which play a crucial role in the clearance of misfolded proteins, breakdown of regulatory proteins, processing of proteins by specific partial proteolysis, cell cycle control as well as preparation of peptides for immune presentation. Two main types can be distinguished by their different tertiary structure: the 20S proteasome and the proteasome-like heat shock protein encoded by heat shock locus V, hslV. Usually, each biological kingdom is characterized by its specific type of proteasome. The 20S proteasomes occur in eukarya and archaea whereas hslV protease is prevalent in bacteria. To verify this rule we applied a genome-wide sequence search to identify proteasomal sequences in data of finished and yet unfinished genome projects. We found several exceptions to this paradigm: (1) Protista: in addition to the 20S proteasome, Leishmania, Trypanosoma and Plasmodium contained hslV, which may have been acquired from an alpha-proteobacterial progenitor of mitochondria. (2) Bacteria: for Magnetospirillum magnetotacticum and Enterococcus faecium we found that each contained two distinct hslVs due to gene duplication or horizontal transfer. Including unassembled data into the analyses we confirmed that a number of bacterial genomes do not contain any proteasomal sequence due to gene loss. (3) High G+C Gram-positives: we confirmed that high G+C Gram-positives possess 20S proteasomes rather than hslV proteases. The core of the 20S proteasome consists of two distinct main types of homologous monomers, alpha and beta, which differentiated into seven subtypes by further gene duplications. By looking at the genome of the intracellular pathogen Encephalitozoon cuniculi we were able to show that differentiation of beta-type subunits into different subtypes occurred earlier than that of alpha-subunits. Additionally, our search strategy had an important methodological consequence: a comprehensive sequence search for a particular protein should also include the raw sequence data when possible because proteins might be missed in the completed assembled genome. The structure-based multiple proteasomal alignment of 433 sequences from 143 organisms can be downloaded from the URL dagger and will be updated regularly.

Amino Acid Sequence↗

PubMed2002

The RTP site shared by the HIV-1 Tat protein and the 11S regulator subunit alpha is crucial for their effects on proteasome function including antigen processing.

The human immunodeficiency virus-1 Tat protein inhibits the peptidase activity of the 20S proteasome and competes with the 11S regulator/PA28 for binding to the 20S proteasome. Structural comparison revealed a common site in the Tat protein and the 11S regulator alpha-subunit (REGalpha) called the REG/Tat-proteasome-binding (RTP) site. Kinetic assays found amino acid residues Lys51, Arg52 and Asp67 forming the RTP site of Tat to be responsible for the effects on proteasomes in vitro. The RTP site identified in REGalpha consists of the residues Glu235, Lys236 and Lys239. Mutation of the REGalpha amino acid residues Glu235 and Lys236 to Ala resulted in an REGalpha mutant that lost the ability to activate the 20S proteasome even though it still forms complexes with REGbeta and binds to the 20S proteasome. The REGalpha RTP site is needed to enhance the presentation of a cytomegalovirus pp89 protein-derived epitope by MHC class I molecules in mouse fibroblasts. Cell experiments demonstrate that the Tat amino acid residues 37-72 are necessary for the interaction of the viral protein with proteasomes in vivo. Full-length Tat and the Tat peptide 37-72 suppressed 11S regulator-mediated presentation of the pp89 epitope. In contrast, the Tat peptide 37-72 with mutations of amino acid residues Lys51, Arg52 and Asp67 to Ala was not able to reduce antigen presentation.

Amino Acid Sequence↗

PubMedDate not supplied

Comparison of 2D similarity and 3D superposition. Application to searching a conformational drug database.

In a database of about 2000 approved drugs, represented by 10(5) structural conformers, we have performed 2D comparisons (Tanimoto coefficients) and 3D superpositions. For one class of drugs the correlation between structural resemblance and similar action was analyzed in detail. In general Tanimoto coefficients and 3D scores give similar results, but we find that 2D similarity measures neglect important structural/funtional features. Examples for both over- and underestimation of similarity by 2D metrics are discussed. The required additional effort for 3D superpositions is assessed by implementation of a fast algorithm with a processing time below 0.01 s and a more sophisticated approach (0.5 s per superposition). According to the improvement of similarity detection compared to 2D screening and the pleasant rapidity on a desktop PC, full-atom 3D superposition will be an upcoming method of choice for library prioritization or similarity screening approaches.

Database Management Systems↗