Exploring the sequence–structure–function relationship for the intrinsically disordered βγ-crystallin Hahellin

Abstract

βγ-Crystallins are a superfamily of proteins containing crystallin-type Greek key motifs. Some βγ-crystallin domains have been shown to bind Ca2+. Hahellin is a newly identified intrinsically disordered βγ-crystallin domain from Hahella chejuensis. It folds into a typical βγ-crystallin structure upon Ca2+ binding and acts as a Ca2+-regulated conformational switch. Besides Hahellin, another two putative βγ-crystallins from Caulobacter crescentus and Yersinia pestis are shown to be partially disordered in their apo-form and undergo large conformational changes upon Ca2+ binding, although whether they acquire a βγ-crystallin fold is not known. The extent of conformational disorder/order of a protein is determined by its amino acid sequence. To date how this sequence–structure relationship is reflected in the βγ-crystallin superfamily has not been investigated. In this work, we comparatively studied the sequence and structure of Hahellin with those of Protein S, an ordered βγ-crystallin, via various computational biophysical techniques. We found that several factors, including presence of a C-terminal disorder prone region, high content of energetic frustrations, and low contact density, may promote the formation of the disordered state of apo-Hahellin. We also analyzed the disorder propensities for other putative disordered βγ-crystallin domains. This study provides new clues for further understanding the sequence–structure–function relationship of βγ-crystallins.