Tandem repeats in proteins: From sequence to structure

Abstract

The bioinformatics analysis of proteins containing tandem repeats requires special computer programs and databases, since the conventional approaches predominantly developed for globular domains have limited success. Here, I survey bioinformatics tools which have been developed recently for identification and proteome-wide analysis of protein repeats. The last few years have also been marked by an emergence of new 3D structures of these proteins. Appraisal of the known structures and their classification uncovers a straightforward relationship between their architecture and the length of the repetitive units. This relationship and the repetitive character of structural folds suggest rules for better prediction of the 3D structures of such proteins. Furthermore, bioinformatics approaches combined with low resolution structural data, from biophysical techniques, especially, the recently emerged cryo-electron microscopy, lead to reliable prediction of the protein repeat structures and their mode of binding with partners within molecular complexes. This hybrid approach can actively be used for structural and functional annotations of proteomes.

Introduction

Dramatic growth of genomic data presents new challenges for scientists: making sense of millions of protein sequences requires systematic approaches and information about their 3D structure as well as about their evolutionary and functional relationships. The majority of protein sequences are aperiodic and usually have globular 3D structures carrying a number of various functions. The foremost efforts of researchers were devoted to these types of proteins and, as a result, significant progress has been made in the development of bioinformatics tools for their analysis. However, proteins also contain a large portion of periodic sequences representing arrays of repeats that are directly adjacent to each other (Heringa, 1998). These tandem repeats are considerably diverse, ranging from the repetition of a single amino acid to domains of 100 or more residues. They are ubiquitous in genomes and occur in at least 14% of all proteins (Marcotte et al., 1999). Furthermore, they are present in almost every third human protein and even in every second protein from Plasmodium falciparum or Dictyostelium discoideum (Pellegrini et al., 1999, Jorda and Kajava, 2010). The tandem repeat regions are highly polymorphic compared to the background rate of point mutations (Buard and Vergnaud, 1994, Ellegren, 2000). The two main mechanisms underlying this hypermutability are: (i) replication slippage within DNA microsatellite regions (repeat is less than 10 nucleotides) and (ii) recombination events for longer minisatellite and satellite regions.

Over the last decade, numerous studies demonstrated the fundamental functional importance of such tandem repeats and their involvement in human diseases. A number of evidences has also been gathered about the high incidence of tandem repeats in the sequences of virulence factors of pathogenic agents, toxins and allergens (Kajava et al., 2006). Genetic instability of these regions can allow a rapid response to environmental changes and thus can lead to emerging infection threats. Furthermore, tandem repeats frequently occur in amyloidogenic and other disease-related sequences (Baxa et al., 2006, Nelson and Eisenberg, 2006). This implies that this class of sequences may have a broader role in human diseases than was previously recognized.

Thus, tandem repeat regions are abundant in proteomes and are related to major health threats of the modern society. Along this line, the discovery of these domains, understanding of their sequence–structure–function relationship and mechanisms of their evolution promise to be a fertile direction for research leading to the identification of targets for new medicines and vaccines. However, the conventional bioinformatics approaches for annotation of proteomes that are developed for globular domains have limited success when applied to the tandem repeat regions. They require special computer programs and databases. Here, I survey available bioinformatics tools for analysis of protein repeats with emphasis on the sequences, 3D structures, sequence–structure relationship as well as highlighting successful strategies for the prediction of the protein structure.