S A Teichmann

..Remarkably, the effects observed are consistently larger in E. coli and S. cerevisiae than in H. sapiens, suggesting that promiscuous protein-protein interactions may be freer to accumulate in the human lineage...

..We found only three out of 131 (2%) DBD families shared by the three superkingdoms...

..A study of the contributions of different mechanisms of domain gain in animal proteins suggests that gene fusion is likely to be most frequent...

..Their binding to cis-regulatory modules of target genes mediates the precise cell- and context-specific activation and repression of genes. The expression of TFs should therefore reflect the core expression program of each cell...

..However, it is not well understood how this has given rise to the enormous diversity of metazoa present today...

..The mechanisms driving the emergence and evolution of these modules are still unclear. Here we investigate the evolutionary origins of protein complexes, modules in physical protein-protein interaction networks...

..A strong or even moderate change in constraints in functional regions, for example in coding regions, can have significant evolutionary consequences...

..Recognising these patterns and unravelling how they have arisen may allow us to understand the functional relationships between domains and understand how the protein repertoire has evolved...

..elegans, a framework for refinement and extension of the repertoire as gene and protein definitions improve, and the basis for investigations of their function and for comparisons with the repertoires of other organisms...

..The PDB domain matches also describe the domain structure of the matched sequences: just over a quarter contain one domain and the rest have combinations of two or more domains...

..This trend is independent of whether the proteins are involved in informational functions (transcription, translation and replication) or not and of protein dispensability...

..In addition, we conclude that evolution has been incremental, rather than making entire regulatory circuits or motifs by duplication with inheritance of interactions...

..Our analysis reveals that the number of conserved co-regulated genes is small in eukaryotes, as has been shown previously in prokaryotes, indicating that there are extensive variations in the gene regulatory network across organisms...

..These assignments give a new perspective on domain structures, gene duplications, protein families and protein folds in genome sequences...

....

..This is analogous to a mosaic in which a stone of a certain colour is selected to fill a position in the picture...

..Most of the domains that form SMM pathways have homologues in non-SMM pathways. Taken together, these results imply a pervasive "mosaic" model for the formation of protein repertoires and pathways...

..A new approach using intermediate sequences was tested as a shortcut to iterative multiple sequence search methods such as PSI-BLAST...

..Finally, we compare the set of the domain combinations in the genomes to those in the RCSB Protein Data Bank, and discuss the implications for structural genomics...

..Of particular interest are those combinations that occur in the largest number of multi-domain proteins, and several of these frequent novel combinations contain DNA-binding domains...

..Proteins of known structure can be matched to about 50% of genome sequences, and these data provide a quantitative description and can suggest hypotheses about the origins of these processes...

..Given that all proteins consist of their evolutionary units, the domains, all interactions occur between these domains. The interactions between domains belonging to different protein families will be the second topic of my talk...

....

....

..This type of pattern can be described by a scale-free network. Finally, we study domain repeats and we compare the set of the domain combinations in the genomes to those in PDB, and discuss the implications for structural genomics...

..We have developed a software package called EpiChIP that carries out this type of analysis, including integration with and visualization of gene expression data...

....

..Eukaryotes follow a slower rate of increase in TFs than prokaryotes, which could be due to the presence of splice variants or an increase in combinatorial control...

..These results suggest that the expansion of this protein superfamily is one of the factors that have contributed to the formation of the more complex physiological features that are found in Drosophila...

..Our model of self-assembly allows reliable prediction of evolution and assembly of a complex solely from its crystal structure...

....

..A report on the Cold Spring Harbor Laboratory/Wellcome Trust conference on Network Biology, Hinxton, UK, 27-31 August 2008...

..Fidelity in signaling may require that most IUPs be available in appropriate amounts and not present longer than needed...

..We propose that, in addition to other molecular mechanisms, change in genomic neighborhood is an important factor that drives transcriptome evolution...

....

..This article deals with the computational identification of TFs (how to find them in genomes) and with online resources such as the FlyTF database of Drosophila site-specific TFs (how to find them online)...

..As pointed out before, prokaryotic TFs increase faster than linearly. We further observe a similar relationship in eukaryotic genomes with a slower increase in TFs...

..This allows homologous extracellular receptors to attain specialized functions and become specific to tissues and/or developmental stages...

..Our classification, available as a database and Web server at http://www.3Dcomplex.org, will be a starting point for future work aimed at understanding the structure and evolution of protein complexes...

..Variable interdomain geometries can be found in homologous structures with high sequence identities (70%)...

..Since this is the case for only a quarter of the supra-domains, we provide a list of the most important unknown supra-domains as potential targets for structural genomics projects...

..Interactions are conserved to varying degrees among genomes. Insights from the structure and evolution of these networks can be translated into predictions and used for engineering of the regulatory networks of different organisms...

..This predictive scheme is tested against protein complexes in the Protein Quaternary Structure (PQS) database, and is used to predict domain-domain contacts within 705 interacting protein pairs taken from our pooled data set...

..Some of the pair-wise domain combinations that are highly duplicated also recur frequently with other partner domains, and thus represent evolutionary units larger than single protein domains, which we term "supra-domains"...

..We found that fusion events are approximately four times more common than fission events, and we established that, in most cases, any particular fusion or fission event only occurred once during the course of evolution...

..We show that duplicated complexes retain the same overall function, but have different binding specificities and regulation, revealing that duplication of these modules is associated with functional specialization...

..Future work will require a domain-centric functional classification scheme and efforts to determine structures of domain combinations...

..Users can browse, search or download the predictions by genome, domain family or sequence identifier, view families of transcription factors based on domain architecture and receive predictions for a protein sequence...

..We also provide a perspective on the evolutionary mechanisms driving the growth of other modular cellular networks such as transcriptional regulatory and metabolic networks...

..We propose a set of 753 TFs in the fruit fly, of which 23 are confident novel predictions of this function for previously uncharacterized proteins...

..The methods for biological network analysis introduced here can be applied generally to study other networks, and these predictions can be used to guide specific experiments...

..Furthermore, recent studies indicate that multidomain proteins have evolved mechanisms to minimize the problems of interdomain misfolding...

..Also, we briefly discuss the pathway of their assembly in solution...

..A structural model of the pentapeptide repeats is presented...

..Much remains to be explored, but this study provides a solid foundation for future investigations to elucidate regulatory mechanisms underlying diverse mammalian biological processes...

..SMM exploits regulatory strategies involving chromosomal location, isozymes and the reuse of enzymes...

..BloodExpress thus constitutes a platform for the discovery of novel gene functions across the haematopoietic tree. BloodExpress is freely accessible at http://hscl.cimr.cam.ac.uk/bloodexpress/...

..Only one fifth of the common enzymes have nonhomologous domains between the two organisms. Around the common core very different extensions have been made to small molecule metabolism in the two organisms...

..We conclude that these properties are complementary rather than contradictory, while describing the protein universe from different perspectives...

..We anticipate that many of the concepts presented here--particularly the large-scale topological changes and hub transience--will apply to other biological networks, including complex sub-systems in higher eukaryotes...

..We propose that such low sequence identities could have a crucial and general role in safeguarding proteins against misfolding and aggregation...

..We discuss possible explanations that relate to the order of appearance of AS and GD in a gene family, and to the selection pressure imposed by the environment...

....

..parvum, whereas the other is shared with (but has previously gone unnoticed in) all known genomes of the Coccidia and Haemosporida. These motifs appear to be unique in their structure, distribution and sequences...