The rapid accumulation of genome sequences and protein structures during the last decade has been paralleled by major advances in sequence database search methods. The powerful Position-Specific Iterating BLAST (PSI-BLAST) method developed at the NCBI formed the basis of our work on protein motif analysis. In addition, Hidden Markov Models (HMM) and protein structure comparison methods were applied. During the last year, we made further progress in detailed analysis of the classification, evolution, and functions of several classes of proteins. Specifically, we studied in detail the protein domains that are involved in eukaryotic RNA interference mechanisms and showed that the protein machinery of eukaryotic RNAi was pieced together from ancestral archaeal, bacterial and phage proteins that are involved in DNA repair and RNA processing. We also used computational methods to identify a novel prokaryotic toxin-antitoxin systems that are predicted to function via RNA binding or cleavage and other, diverse mechanisms. We explored the evolution of the eukaryotic phagocytosis system and demonstrated the presence of actin-related domains in a distinct set of crenarchaeota and korarchaeota, suggesting that the archaeal ancestor of eukaryotes might have already possessed a primitive form of branched cytoskeleton that facilitated engulfment of other prokaryotes. We further investigated the evolution and genomic context of prokaryotic homologs of the eukaryotic argonaute protein (the key component of the RNAi system) and showed that the genes encoding these proteins tend to be located within """"""""genomic islands"""""""" that also contain many other genes for various defense systems. These findings suggest that the prokaryotic homologs of argonaute are components of a novel defense system that also includes a variety of other putative nucleases that we identifies using sensitive methods of domain analysis. We additionally contributed to experimental and structural analysis of a variety of domains previously identified in our computational studies, in particular, the key components of the prokaryotic CRSIPR-associated acqauired immunity system.
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