Abstract
BackgroundKnowledge of the protein structure is a pre-requisite for improved understanding of molecular function. The gap in the sequence-structure space has increased in the post-genomic era. Grouping related protein sequences into families can aid in narrowing the gap. In the Pfam database, structure description is provided for part or full-length proteins of 7726 families. For the remaining 52% of the families, information on 3-D structure is not yet available. We use the computationally designed sequences that are intermediately related to two protein domain families, which are already known to share the same fold. These strategically designed sequences enable detection of distant relationships and here, we have employed them for the purpose of structure recognition of protein families of yet unknown structure.ResultsWe first measured the success rate of our approach using a dataset of protein families of known fold and achieved a success rate of 88%. Next, for 1392 families of yet unknown structure, we made structural assignments for part/full length of the proteins. Fold association for 423 domains of unknown function (DUFs) are provided as a step towards functional annotation.ConclusionThe results indicate that knowledge-based filling of gaps in protein sequence space is a lucrative approach for structure recognition. Such sequences assist in traversal through protein sequence space and effectively function as ‘linkers’, where natural linkers between distant proteins are unavailable.ReviewersThis article was reviewed by Oliviero Carugo, Christine Orengo and Srikrishna Subramanian.
Highlights
Knowledge of the protein structure is a pre-requisite for improved understanding of molecular function
We considered structural domain associations given in Protein families (Pfam) and PDBfam [34] with an additional condition of better than 60% length coverage of the Structural Classification of proteins (SCOP) domain in order to exclude indiscriminate or false structural associations (Additional file 1: Table S1)
Though high sequence identity between sequences is a strong correlate for homology implying similar structure and function, members of a structural fold can often share very low sequence similarity [40,41,42]
Summary
Knowledge of the protein structure is a pre-requisite for improved understanding of molecular function. Despite substantial growth in the protein structure database (Protein Data Bank - PDB), contributed by improvements in structural genomics approaches [1] and recently by Cryo-EM techniques [2], we still observe that the number of available structures for proteins is limited. Though it has been over five decades since the advent of X-ray crystallography, unavailability of structures for many protein sequences remains a daunting problem, creating a bottle-neck in function annotation [3, 4]. Iterative sequence-profile driven searches [16, 17] or profile- based search routines [18,19,20] have been shown to be sensitive in homology detection
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