webPRC: the Profile Comparer for alignment-based searching of public domain databases

Profile–profile methods are well suited to detect remote evolutionary relationships between protein families. Profile Comparer (PRC) is an existing stand-alone program for scoring and aligning hidden Markov models (HMMs), which are based on multiple sequence alignments. Since PRC compares profile HMMs instead of sequences, it can be used to find distant homologues. For this purpose, PRC is used by, for example, the CATH and Pfam-domain databases. As PRC is a profile comparer, it only reports profile HMM alignments and does not produce multiple sequence alignments. We have developed webPRC server, which makes it straightforward to search for distant homologues or similar alignments in a number of domain databases. In addition, it provides the results both as multiple sequence alignments and aligned HMMs. Furthermore, the user can view the domain annotation, evaluate the PRC hits with the Jalview multiple alignment editor and generate logos from the aligned HMMs or the aligned multiple alignments. Thus, this server assists in detecting distant homologues with PRC as well as in evaluating and using the results. The webPRC interface is available at http://www.ibi.vu.nl/programs/prcwww/

Evolution of genes and repeats in the Nimrod superfamily

The recently identified Nimrod superfamily is characterized by the presence of a special type of EGF repeat, the NIM repeat, located right after a typical CCXGY/W amino acid motif. On the basis of structural features, nimrod genes can be divided into three types. The proteins encoded by Draper-type genes have an EMI domain at the N-terminal part and only one copy of the NIM motif, followed by a variable number of EGF-like repeats. The products of Nimrod B-type and Nimrod C-type genes (including the eater gene) have different kinds of N-terminal domains, and lack EGF-like repeats but contain a variable number of NIM repeats. Draper and Nimrod C-type (but not Nimrod B-type) proteins carry a transmembrane domain. Several members of the superfamily were claimed to function as receptors in phagocytosis and/or binding of bacteria, which indicates an important role in the cellular immunity and the elimination of apoptotic cells. In this paper, the evolution of the Nimrod superfamily is studied with various methods on the level of genes and repeats. A hypothesis is presented in which the NIM repeat, along with the EMI domain, emerged by structural reorganizations at the end of an EGF-like repeat chain, suggesting a mechanism for the formation of novel types of repeats. The analyses revealed diverse evolutionary patterns in the sequences containing multiple NIM repeats. Although in the Nimrod B and Nimrod C proteins show characteristics of independent evolution, many internal NIM repeats in Eater sequences seem to have undergone concerted evolution. An analysis of the nimrod genes has been performed using phylogenetic and other methods and an evolutionary scenario of the origin and diversification of the Nimrod superfamily is proposed. Our study presents an intriguing example how the evolution of multigene families may contribute to the complexity of the innate immune response