Abstract
BackgroundWhile many authors have discussed models and tools for studying protein evolution at the sequence level, molecular function is usually mediated by complex, higher order features such as independently folding domains and linear motifs that are based on or embedded in a particular arrangment of features such as secondary structure elements, transmembrane domains and regions with intrinsic disorder. This ‘protein architecture’ can, in its most simplistic representation, be visualized as domain organization cartoons that can be used to compare proteins in terms of the order of their mostly globular domains.MethodologyHere, we describe a visual approach and a webserver for protein comparison that extend the domain organization cartoon concept. By developing an information-rich, compact visualization of different protein features above the sequence level, potentially related proteins can be compared at the level of propensities for secondary structure, transmembrane domains and intrinsic disorder, in addition to PFAM domains. A public Web server is available at www.proteinarchitect.net, while the code is provided at protarchitect.sourceforge.net.Conclusions/SignificanceDue to recent advances in sequencing technologies we are now flooded with millions of predicted proteins that await comparative analysis. In many cases, mature tools focused on revealing hits with considerable global or local similarity to well-characterized proteins will not be able to lead us to testable hypotheses about a protein's function, or the function of a particular region. The visual comparison of different types of protein features with ProteinArchitect will be useful when assessing the relevance of similarity search hits, to discover subgroups in protein families and superfamilies, and to understand protein regions with conserved features outside globular regions. Therefore, this approach is likely to help researchers to develop testable hypotheses about a protein's function even if is somewhat distant from the more characterized proteins, by facilitating the discovery of features that are conserved above the sequence level for comparison and further experimental investigation.
Highlights
Mature tools focused on revealing hits with considerable global or local similarity to well-characterized proteins will not be able to lead us to testable hypotheses about a protein’s function, or the function of a particular region
There is no lack of useful computational tools for the analysis of proteins and their sequences, it can be time-consuming to put the results obtained with those tools together into a coherent picture that facilitates visual comparison of different types of protein features
Stimulated by those challenges in protein sequence analysis, in particular for proteins with large non-globular regions, we have developed a Java-based framework and Web server that produce a visualization of different protein modules, including PFAM domains that are reliably detected with HMMs (Hidden Markov Models), transmembrane domains predicted by TMHMM, secondary structure propensities predicted by PSI-PRED, and propensities for intrinsic disorder as predicted by DISOPRED2
Summary
There is no lack of useful computational tools for the analysis of proteins and their sequences, it can be time-consuming to put the results obtained with those tools together into a coherent picture that facilitates visual comparison of different types of protein features Such an integrated picture is often needed when a comparison at the sequence level itself is not informative enough, for example when assessing similarity search hits that are not clearly homologous to the protein of reference, or when analyzing functionally relevant subgroups in protein families or superfamilies. This ‘protein architecture’ can, in its most simplistic representation, be visualized as domain organization cartoons that can be used to compare proteins in terms of the order of their mostly globular domains
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