Structural and Energetic Characterization of the Ankyrin Repeat Protein Family

Ankyrin repeat containing proteins are one of the most abundant solenoid folds. Usually implicated in specific protein-protein interactions, these proteins are readily amenable for design, with promising biotechnological and biomedical applications. Studying repeat protein families presents technical challenges due to the high sequence divergence among the repeating units. We developed and applied a systematic method to consistently identify and annotate the structural repetitions over the members of the complete Ankyrin Repeat Protein Family, with increased sensitivity over previous studies. We statistically characterized the number of repeats, the folding of the repeat-arrays, their structural variations, insertions and deletions. An energetic analysis of the local frustration patterns reveal the basic features underlying fold stability and its relation to the functional binding regions. We found a strong linear correlation between the conservation of the energetic features in the repeat arrays and their sequence variations, and discuss new insights into the organization and function of these ubiquitous proteins.Author Summary: Some natural proteins are formed with repetitions of similar amino acid stretches. Ankyrin-repeat proteins constitute one of the most abundant families of this class of proteins that serve as model systems to analyze how variations in sequences exert effects in structures and biological functions. We present an in-depth analysis of the ankyrin repeat protein family, characterizing the variations in the repeating arrays both at the structural and energetic level. We introduce a consistent annotation for the repeat characteristics and describe how the structural differences are related to the sequences by their underlying energetic signatures.