κ-helix and the helical lock and key model: A pivotal way of looking at polyproline II

Motivation

Polyproline II (PPII) is a common conformation, comparable to α-helix and β-sheet and is a candidate for being the most prevalent secondary structure. PPII, recently termed with a more generic name – κ-helix, adopts a left-handed structure with 3-fold rotational symmetry. Lately, a new type of binding mechanism – the helical lock and key model was introduced in SH3-domain complexes, where the interaction is characterized by a sliding helical pattern. However, whether this binding mechanism is unique only to SH3 domains is unreported.

Results

Here, we show that the helical binding pattern is a universal feature of the κ-helix conformation, present within all the major target families - SH3, WW, profilin, MHC-II, EVH1, and GYF domains. Based on a geometric analysis of 255 experimentally solved structures, we found that they are characterized by a distinctive rotational angle along the helical axis. Furthermore, we found that the range of helical pitch varies between different protein domains or peptide orientations and that the interaction is also represented by helical dynamic motion. The discovery of rotational interactions as a mechanism, reveals a new dimension in the realm of protein-protein interactions, which introduces a new layer of information encoded by the helical conformation. Due to the extensive involvement of the conformation in functional interactions, we anticipate our model to expand the current molecular understanding of the relationship between protein structure and function.