Graphic insights into the network basis for heat-gated TRPV1

Abstract

The capsaicin receptor TRPV1 can be activated by heat and thus serves as a thermometer in a primary afferent sensory neuron for noxious heat detection. However, the underlying molecular mechanism is unclear. Here, a hairpin topological structural model, together with graph theory, was developed to examine a role of temperature-dependent hairpin melting in controlling non-covalent interactions along the heat-evoked gating pathway of TRPV1. The results showed that heat-dependent hairpin melting rearranges non-covalent interactions, releases the resident lipid, and induces TRPV1 gating. A larger hairpin in the outer pore initiates a temperature threshold as a heat starter for channel opening while some smaller hairpins in the S4-S5 linker and the outer pore stabilize the heat efficacy and avoid heat denaturation as a heat fuse. The heat-induced global gating rearrangement may be responsible for the high heat sensitivity. This hairpin model may provide a broad structural basis for the thermo-gated ion channels.

Network Basis for the Heat-Adapted Structural Thermostability of Bacterial Class II Fructose Bisphosphate Aldolase

“…When a noncovalent interaction in the grid is broken at a temperature, that temperature is defined as a melting threshold ( T th ). If both a DNA hairpin and the biggest grid melt in a similar manner and the melting is rate-limiting for the thermal inactivation, the T th for the changes in the thermostability of proteins was calculated from the T m of the biggest grid along the single polypeptide chain using the following equation, as described previously , T normalm 0.25em ( ° C ) = 34 + ( n − 2 ) × 10 + ( 20 − S max ) × 2 where n is the total number of the H-bonds equivalent to noncovalent interactions in the biggest grid and S max is the size of the biggest grid.…”

“…In either state, the grid-based systemic thermal instability ( T i ) along the single polypeptide chain was defined using the following equation, as described previously , T normali = S / N where S is the total grid sizes along the single polypeptide chain of one subunit in a functional state and N is the total noncovalent interactions and metal bridges along the same single polypeptide chain of one subunit in the same functional state.…”

“…In either state, the grid-based systemic thermal instability (T i ) along the single polypeptide chain was defined using the following equation, as described previously 13,14 T S N…”

“…10 Standards for Noncovalent Interactions. In order to secure results to be reproduced with high sensitivity, the same standard definition as described previously, 13,14 together with structure visualization software, UCSF Chimera, was exploited to identify stereo-or regioselective interdomain diagonal and intradomain lateral noncovalent interactions in WT class II E. coli FBP aldolase at 293 K and to examine their potential roles in shaping topological grids with minimal sizes to govern the T m for the changes in the tertiary structures of the WT enzyme and the evolved variants in each generation and related T i values. Those noncovalent interactions included salt bridges, cation/CH/lone pair/π−π interactions, and H-bonds along the single polypeptide chain from D15 to F349.…”