TRP ion channels: Proteins with conformational flexibility

Abstract

Ion channels display conformational changes in response to binding of their agonists and antagonists. The study of the relationships between the structure and the function of these proteins has witnessed considerable advances in the last two decades using a combination of techniques, which include electrophysiology, optical approaches (i.e. patch clamp fluorometry, incorporation of non-canonic amino acids, etc.), molecular biology (mutations in different regions of ion channels to determine their role in function) and those that have permitted the resolution of their structures in detail (X-ray crystallography and cryo-electron microscopy). The possibility of making correlations among structural components and functional traits in ion channels has allowed for more refined conclusions on how these proteins work at the molecular level. With the cloning and description of the family of Transient Receptor Potential (TRP) channels, our understanding of several sensory-related processes has also greatly moved forward. The response of these proteins to several agonists, their regulation by signaling pathways as well as by protein-protein and lipid-protein interactions and, in some cases, their biophysical characteristics have been studied thoroughly and, recently, with the resolution of their structures, the field has experienced a new boom. This review article focuses on the conformational changes in the pores, concentrating on some members of the TRP family of ion channels (TRPV and TRPA subfamilies) that result in changes in their single-channel conductances, a phenomenon that may lead to fine-tuning the electrical response to a given agonist in a cell.

Autoinhibition of TRPV6 Channel and Regulation by PIP2

“…TRPV6 structures determined by X-ray crystallography and cryo-electron microscopy (EM) revealed proximity of the C-terminal TRP helix with the N-terminal pre-S1 and intracellular S4-S5 linker ( McGoldrick et al., 2018 ; Saotome et al., 2016 ). Similar physical arrangements were also seen in other TRP members of resolved structures, whereas TRPP channels have a TRP-like helix ( Liao et al., 2013 ; Lopez-Romero et al., 2019 ; Su et al., 2018 ). However, whether and how these domains interact with each other and the functional implications of these interactions are poorly understood.…”

TRPM6 N-Terminal CaM- and S100A1-Binding Domains

“…The TRPV6/CaM and TRPV5/CaM structures confirmed the presence of mutual binding sites for one CaM molecule by different TRP tails or subunits [36,42]. This can drive a coordinated conformational changes ongoing across the whole channel, leading to its functional modulation [36,59]. This complex process can be used to multiply the ligand signal into a channel structure to transfer structural changes more rapidly to the target location of the channel via its allostery.…”

Oxidative stress promotes ventilator-induced lung injury through activating NLRP3 inflammasome and TRPM2 channel

“…The transient receptor potential (TRP) channels are important cation channels on the cell membrane, which are permeable to calcium ions. The TRP channels have 6 subfamilies: TRPC, TRPY, TRPM, TRPA, TRPP and TRPML [18,19]. TRPM2 channel is a class of non-selective cation channel of calcium ions, which is highly expressed in the brain tissues [20].…”