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Review
. 2019 Dec:84:102106.
doi: 10.1016/j.ceca.2019.102106. Epub 2019 Nov 1.

Structural biology of thermoTRPV channels

Peng Yuan  1
Affiliations
Review

Structural biology of thermoTRPV channels

Peng Yuan. Cell Calcium. 2019 Dec.

Abstract

Essential for physiology, transient receptor potential (TRP) channels constitute a large and diverse family of cation channels functioning as cellular sensors responding to a vast array of physical and chemical stimuli. Detailed understanding of the inner workings of TRP channels has been hampered by a lack of atomic structures, though structural biology of TRP channels has been an enthusiastic endeavor since their molecular identification two decades ago. These multi-domain integral membrane proteins, exhibiting complex polymodal gating behavior, have been a challenge for traditional X-ray crystallography, which requires formation of well-ordered protein crystals. X-ray structures remain limited to a few TRP channel proteins to date. Fortunately, recent breakthroughs in single-particle cryo-electron microscopy (cryo-EM) have enabled rapid growth of the number of TRP channel structures, providing tremendous insights into channel gating and regulation mechanisms and serving as foundations for further mechanistic investigations. This brief review focuses on recent exciting developments in structural biology of a subset of TRP channels, the calcium-permeable, non-selective and thermosensitive vanilloid subfamily of TRP channels (TRPV1-4), and the permeation and gating mechanisms revealed by structures.

Keywords: Cryo-EM; Crystallography; Ion channel; TRP channel; TRPV; ThermoTRPV.

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Figures

Fig. 1
Fig. 1
Architecture of TRPVs. a, Representative structure of a TRPV3 channel (PDB: 6MHO) with the most complete atomic model. Each subunit of the tetrameric channel is in a distinct color. The cytoplasmic inter-subunit interface critical for channel gating is highlighted. The linker domain preceding the transmembrane domain and the C-terminal domain following the TRP helix are both involved in inter-subunit packing with the ARD of an adjacent subunit. b, View from the extracellular side. c, Domain structure of a single channel subunit.
Fig. 2
Fig. 2
Ion binding sites at the selectivity filter region of TRPVs revealed by X-ray crystallography. a, TRPV2 (PDB: 6BWM). b, TRPV4 (PDB: 6C8G). c, TRPV6 (PDB: 5IWP). Bound divalent ions are shown as yellow spheres.
Fig. 3
Fig. 3
Pore profiles of thermoTRPV channels representing distinct functional states. a, The TRPV1 ion-conduction pore in the apo, closed (PDB: 3J5P), capsaicin-bound (PDB: 3J5R), and RTX/DkTx-bound, open states (PDB: 3J5Q). b, The TRPV2 ion permeation pathway in distinct conformational states (from left to right, PDB ID: 5AN8, 6BO5, and 6BO4). c, Closed (PDB: 6MHO) and open (PDB: 6DVZ) ion-conduction pore of TRPV3. d, Ion-conduction pore of TRPV4 (PDB: 6BBJ). e, Sequence alignment of human TRPV1–4 in the pore region. Residues forming the gates are highlighted in red boxes.
Fig. 4
Fig. 4
Two-fold symmetry in tetrameric TRPV channels. a, Crystal structure of TRPV2 in complex with RTX (PDB: 6BWJ) showing pronounced symmetry reduction at the selectivity filter. The selectivity filter dimension is shown for each pair of two diagonal subunits. Also shown are the side chains of M643 at the S6 bundle-crossing gate. b, Cryo-EM structure of human TRPV3 in the presence of 2-APB (PDB: 6MHW) showing two-fold symmetry at the S6 bundle-crossing gate. The side chains of M677 are shown for each pair of two diagonal subunits.
Fig. 5
Fig. 5
Channel-lipid interactions. a, Cryo-EM structure of TRPV1 in lipid nanodiscs (PDB: 5IRZ). Lipid molecules are shown in ball-and-stick representation. b, Orthogonal view as in (a). Also shown are closed-up views of lipid binding in the pocket formed by the TRP helix and the intracellular half of the S1–S4 domain (bottom left) and in the vanilloid pocket (bottom right).
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