Dissecting relationships among sequence, structures and functions in the ankyrin repeat protein family/Analyzing periodicities in repeat protein structures

PARRA, RG; ESPADA, R; FERREIRO, DU

Oro Verde

Congreso; 3rd Argentinian Conference on Bioinformatics and Computational Biology; 2012

Asociación Argentina de Bioinformática y Biología Computacional

Repeat proteins are made up of tandem arrays of similar 20~40 amino acid stretches that usually fold up in elongated structures mainly stabilized by local interactions. Due to their apparently simple architecture, these proteins constitute useful models to dissect relationships between sequences, structures and functions. The Ankyrin Repeat Protein family (ARPs) is widely distributed in nature. A canonical ankyrin repeat consist in a 33 amino-acids length motif that usually folds into a beta-hairpin-helix-loop-helix upon interaction with its nearest neighbours. Their biological function is attributed mediating specific protein-protein interactions with versatility of recognition paralleled to that of antibodies. Thus, their function (or lack of) plays crucial roles in the developing of various pathological processes and in bacterial or viral infections. We have built a relational database to statistically characterize ARPs architecture at various levels of description. We have collected, depurated and catalogued all available ARPs sequences, structures and functional data, that delineates the general properties of this protein family. Usually Hidden Markov Models (HMMs) derived from Multiple Sequence Alignments (MSAs) are used to detect repeats in protein sequences. This methodology has many disadvantages as it fails to detect those repeats (or parts of them) with a high degree of divergence.. We developed a robust scheme to perform structural alignments and detect symmetries to define the repeating units within a repeat array and between natural protein pairs. The derived metrics were compared in terms of sequence and structural similarity. We detected subgroups within the ARPs family that appear to correspond to known functional classes. We found that the most common methods used to characterize globular protein domains are insufficient to capture essential characteristics of the ARP family. We hypothesize that this is due to strong evolutionary divergence in sequences that tolerate insertions and rearrangements within a repeating array. We show that the divergent regions can usually be mapped to binding sites. We postulate that the functional constraints imposed by specific binding conflicts with robust folding of these proteins, and that these signals could be used to inform energetic terms in folding dynamics models.