Exploration of Uncharted Regions of the Protein Universe

Abstract

Author SummaryMore than 40% of known proteins lack any annotation within public databases and are usually referred to as hypothetical proteins despite most of them being real and many being evolutionarily conserved and thus expected to play important biological roles. Determination of the three-dimensional structures of representatives of more than 240 families of protein domains of unknown function by the Protein Structure Initiative has provided a unique sample of regions of the protein universe that, until this systematic effort, were completely uncharacterized. Analysis of these structures reveals that most of the 240 families can be considered as remote homologs of already known protein families. Such distant evolutionary links can sometimes be predicted by current state-of-the-art sequence comparison tools, but structural analysis has led to the first hypotheses about biological functions for many of these uncharacterized proteins, and serves as a starting point for experimental studies. The rapid pace of discovery of such relationships appears to suggest that the protein universe is made up of a relatively small and stable number of ‘extended neighborhoods’ that bring together distantly related protein families. Thus, the vast uncharacterized part of protein universe, called by some “the dark matter of protein space”, may consist mainly of highly divergent homologs. Continued structural characterization of these previously under-investigated regions of the protein universe should further help unravel the patterns and rules that led to such divergence in the evolution of protein structure and function.