Received for publication October 31, 2007.
Revised January 16, 2008.
Accepted for publication January 17, 2008.

Wide turn diversity in protein transmembrane helices - implications for G-protein coupled receptor and other polytopic membrane protein structure and function

Abstract

Previously we showed that perturbations of protein transmembrane helices are manifested as one of three types of non-canonical structures (wide turns, tight turns and kinks), which, as compared to -helices, are evident by distinctive C_iC_x distances. Here we report the analysis of over 3,000 transmembrane helices in 244 crystal structures from which we identified 70 wide turns (29 proline- and 41 non-proline-induced). Based on differences in the C_iC_i-4 and C_iC_i-5 profiles, we show that wide turns can be subclassified into three distinct subclasses (W₁, W₂ and W₃) that differ with regards to the number and position of backbone i i-5 H-bonds formed N-terminal to the perturbing or signature proline or non-proline residue. Although wide turns generally produce changes in helical direction of 20°-30° and a lateral shift in the helical axis, some of the W₃ subclass are associated with changes of < 5°. We also show that the distinct architectural features of wide turns allow the carbonyl bond of the i-4th residue, which is located on the widened loop of a wide turn, to be directed away from the helical axis. This provides regions of flexibility within helical regions allowing, for example, unique opportunities for interhelical H-bonding, including interactions with glycine zipper motifs, and for ion and cofactor binding. Further, differences in wide turn subtype usage by related protein family members, such as the G-protein coupled receptors, rhodopsin and the ₂-adrenergic receptor, can significantly impact the orientation and position of residues critical for ligand binding and receptor activation.

Key words: Structure determinations, Structure-activity relationships and modeling, Prediction of structure-function/proteomics