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 10 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.