Non-canonical helical transitions and conformational switching are associated with characteristic flexibility profiles in ligand-gated TRP channels and voltage-dependent Kv channels

Abstract

The transient receptor potential (TRP) superfamily of cation channels is divided into several subfamilies. The TRPV (vanilloid) subfamily is composed of proteins that undergo a closed-to-open gating transition in response to various physical and chemical stimuli, including heat transfer phenomena. TRPV1, the prototypical member of these thermo-TRP channels, is activated under physiological conditions by noxious high temperatures (>42°C), and by pungent chemicals including capsaicin and resiniferatoxin . Like TRPV1, TRPV2 is also activated at >52°C as well as 2-aminoethoxydiphenyl borate and cannabidiol. On the other hand, the main stimulus for Kv channels is the potential difference across the membrane. Notwithstanding these differences in their activation temperatures, ligand- or voltage-dependence, the gating mechanisms of these channels exhibit conformational transition pathways in common. Understanding these conformational changes in terms of the sequence determinants underlying these structural transitions helps to reveal residues with great functional relevance. This work examines the side-chain flexibility in regions undergoing peculiar helical transitions. We found that α-to-π helical transitions are associated with patterns of local rigidity whereas α-to-3 transitions are mainly associated with high local flexibility profiles. We also study the relationship between flexibility and protein order, both in these dynamic regions and in the rest of the transmembrane domains of these proteins. Our analysis shows that flexibility and protein disorder are two complementary parameters that could reveal conformational heterogeneity and the dynamic behavior of specific segments.