Unexpected, pervasive, conserved secondary structure in highly charged protein regions.

Abstract

Understanding the relationship between protein sequence and function remains a defining challenge in molecular biology. Two approaches have yielded enormous insight: structure-based, in which the precise positions of amino acids are crucial for function, and disorder-based, in which dynamical and statistical features confer function. In general, one or the other tends to be strongly favored for specific classes of sequences. Here, we globally examine highly charged protein regions (>40% charged residues), which previously have been overwhelmingly analyzed through a disorder lens. Using experimentally-measured structures and advanced structure prediction, we find that alpha-helices are surprisingly common in such regions. Features thought to serve as strong proxies for disorder—high charge density, low hydrophobicity, low sequence complexity, and variation in length over evolutionary time—are also displayed by these helices. We create a simple composition-driven classifier that can more accurately predict structure in these regions than commonly used heuristics. Finally, we show that in these regions the density of charged residues, and in certain cases the structural properties, are evolutionarily conserved, implying that they are functionally important. This work suggests that relatively simple structural features may play crucial roles in the function of many highly charged regions and more broadly demonstrates the importance of balancing structure- and disorder-based approaches when evaluating regions of unusual amino acid composition.