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Biomedical subjects

S Sri Krishna

Publications and source records attributed to S Sri Krishna.

9 recordsLinked to original sources
PubMed2005

PALSSE: a program to delineate linear secondary structural elements from protein structures.

BACKGROUND: The majority of residues in protein structures are involved in the formation of alpha-helices and beta-strands. These distinctive secondary structure patterns can be used to represent a protein for visual inspection and in vector-based protein structure comparison. Success of such structural comparison methods depends crucially on the accurate identification and delineation of secondary structure elements. RESULTS: We have developed a method PALSSE (Predictive Assignment of Linear Secondary Structure Elements) that delineates secondary structure elements (SSEs) from protein Calpha coordinates and specifically addresses the requirements of vector-based protein similarity searches. Our program identifies two types of secondary structures: helix and beta-strand, typically those that can be well approximated by vectors. In contrast to traditional secondary structure algorithms, which identify a secondary structure state for every residue in a protein chain, our program attributes residues to linear SSEs. Consecutive elements may overlap, thus allowing residues located at the overlapping region to have more than one secondary structure type. CONCLUSION: PALSSE is predictive in nature and can assign about 80% of the protein chain to SSEs as compared to 53% by DSSP and 57% by P-SEA. Such a generous assignment ensures almost every residue is part of an element and is used in structural comparisons. Our results are in agreement with human judgment and DSSP. The method is robust to coordinate errors and can be used to define SSEs even in poorly refined and low-resolution structures. The program and results are available at http://prodata.swmed.edu/palsse/.

Algorithms↗
PubMed2004

Structural drift: a possible path to protein fold change.

SUMMARY: Along with their mutating sequences, protein structures change in time. Analyzing a formate dehydrogenase domain that is evolutionarily related to ferredoxin, but simultaneously contains all the structural elements of a beta-Grasp fold, we illustrate here a mechanism termed as structural drift, by which changes to a protein fold can occur. CONTACT: grishin@chop.swmed.edu.

Carrier Proteins↗
PubMed2004

4SCOPmap: automated assignment of protein structures to evolutionary superfamilies.

BACKGROUND: Inference of remote homology between proteins is very challenging and remains a prerogative of an expert. Thus a significant drawback to the use of evolutionary-based protein structure classifications is the difficulty in assigning new proteins to unique positions in the classification scheme with automatic methods. To address this issue, we have developed an algorithm to map protein domains to an existing structural classification scheme and have applied it to the SCOP database. RESULTS: The general strategy employed by this algorithm is to combine the results of several existing sequence and structure comparison tools applied to a query protein of known structure in order to find the homologs already classified in SCOP database and thus determine classification assignments. The algorithm is able to map domains within newly solved structures to the appropriate SCOP superfamily level with approximately 95% accuracy. Examples of correctly mapped remote homologs are discussed. The algorithm is also capable of identifying potential evolutionary relationships not specified in the SCOP database, thus helping to make it better. The strategy of the mapping algorithm is not limited to SCOP and can be applied to any other evolutionary-based classification scheme as well. SCOPmap is available for download. CONCLUSION: The SCOPmap program is useful for assigning domains in newly solved structures to appropriate superfamilies and for identifying evolutionary links between different superfamilies.

Algorithms↗
PubMed2004

The finger domain of the human deubiquitinating enzyme HAUSP is a zinc ribbon.

Human deubiquitinating enzyme HAUSP is a cysteine protease that regulates the levels of the tumor suppressor protein p53. By comparative sequence and structural analysis, we show that the previously uncharacterized finger domain insert to the catalytic core of HAUSP is a zinc ribbon that has lost its zinc-binding ability.

Amino Acid Sequence↗
PubMed2004

Influence of a mutation in the ATP-binding region of Ca2+/calmodulin-dependent protein kinase II on its interaction with peptide substrates.

CaMKII (Ca2+/calmodulin-dependent protein kinase II) is expressed in high concentrations in the brain and is found enriched in the postsynaptic densities. The enzyme is activated by the binding of calmodulin to the autoregulatory domain in the presence of high levels of intracellular Ca2+, which causes removal of auto-inhibition from the N-terminal catalytic domain. Knowledge of the 3D (three-dimensional) structure of this enzyme at atomic resolution is restricted to the association domain, a region at the extreme C-terminus. The catalytic domain of CaMKII shares high sequence similarity with CaMKI. The 3D structure of the catalytic core of CaMKI comprises ATP- and substrate-binding regions in a cleft between two distinct lobes, similar to the structures of all protein kinases solved to date. Mutation of Glu-60, a residue in the ATP-binding region of CaMKII, to glycine exerts different effects on phosphorylation of two peptide substrates, syntide and NR2B ( N -methyl-D-aspartate receptor subunit 2B) 17-mer. Although the mutation caused increases in the Km values for phosphorylation for both the peptide substrates, the effect on the kcat values for each was different. The kcat value decreased in the case of syntide, whereas it increased in the case of the NR2B peptide as a result of the mutation. This resulted in a significant decrease in the apparent kcat/Km value for syntide, but the change was minimal for the NR2B peptide. These results indicate that different catalytic mechanisms are employed by the kinase for the two peptides. Molecular modelling suggests structural changes are likely to occur at the peptide-binding pocket in the active state of the enzyme as a consequence of the Glu-60-->Gly mutation.

Adenosine Triphosphate↗
PubMed2004

A zinc-binding dual-specificity YVH1 phosphatase in the malaria parasite, Plasmodium falciparum, and its interaction with the nuclear protein, pescadillo.

Biochemical evidence revealed protein tyrosine kinase and phosphatase activities in the human malarial parasite Plasmodium falciparum, a member of the Apicomplexa. A novel cDNA sequence of a dual-specificity phosphatase was identified in both sexual and asexual stages of P. falciparum, and named PfYVH1, since the predicted primary structure of the 278-amino acid polypeptide showed significant similarity to the human and yeast YVH1 phosphatases. The N-terminal half of PfYVH1 contained a conserved tyrosine phosphatase catalytic domain within a dual-specificity phosphatase domain. The C-terminal region, consisting of one histidine and eight cysteines, represented a zinc-binding domain with a potentially unconventional architecture. Recombinant PfYVH1 contained 2mol of zinc per mol protein and dephosphorylated both phosphoserine and phosphotyrosine residues. Mutation of specific Cys residues in the putative zinc finger region abolished zinc binding and drastically reduced phosphatase activity, suggesting an allosteric role of zinc in catalysis. PfYVH1 was expressed in essentially all erythrocytic stages of the parasite, and shuttled between the nucleus and the cytoplasm in a stage-specific manner. A Plasmodium ortholog of the nuclear pescadillo protein (PfPES) was also characterized and shown to interact with PfYVH1, thus implicating PfYVH1 in the regulation of parasitic development. PfYVH1 represents the first dual-specificity zinc-finger phosphatase characterized in the protozoan kingdom.

Amino Acid Sequence↗
PubMed2003

Structural classification of zinc fingers: survey and summary.

Zinc fingers are small protein domains in which zinc plays a structural role contributing to the stability of the domain. Zinc fingers are structurally diverse and are present among proteins that perform a broad range of functions in various cellular processes, such as replication and repair, transcription and translation, metabolism and signaling, cell proliferation and apoptosis. Zinc fingers typically function as interaction modules and bind to a wide variety of compounds, such as nucleic acids, proteins and small molecules. Here we present a comprehensive classification of zinc finger spatial structures. We find that each available zinc finger structure can be placed into one of eight fold groups that we define based on the structural properties in the vicinity of the zinc-binding site. Three of these fold groups comprise the majority of zinc fingers, namely, C2H2-like finger, treble clef finger and the zinc ribbon. Evolutionary relatedness of proteins within fold groups is not implied, but each group is divided into families of potential homologs. We compare our classification to existing groupings of zinc fingers and find that we define more encompassing fold groups, which bring together proteins whose similarities have previously remained unappreciated. We analyze functional properties of different zinc fingers and overlay them onto our classification. The classification helps in understanding the relationship between the structure, function and evolutionary history of these domains. The results are available as an online database of zinc finger structures.

Algorithms↗
PubMed2003

CASP5 assessment of fold recognition target predictions.

We present an overview of the fifth round of Critical Assessment of Protein Structure Prediction (CASP5) fold recognition category. Prediction models were evaluated by using six different structural measures and four different alignment measures, and these scores were compared to those assigned manually over a diverse subset of target domains. Scores were combined to compare overall performance of participating groups and to estimate rank significance. The methods used by a few groups outperformed all other methods in terms of the evaluated criteria and could be considered state-of-the-art in structure prediction. We discuss a few examples of difficult fold recognition targets to highlight the progress of ab initio-type methods on difficult structure analogs and the difficulties of predicting multidomain targets and selecting prediction models. We also compared the results of manual groups to those of automatic servers evaluated in parallel by CAFASP, showing that the top performing automated server structure predictions approached those of the best manual predictors.

Algorithms↗