Structure of the TRPA1 Ion Channel Suggests Regulatory Mechanisms

Paulsen, Candice E.; Armache, Jean-Paul; Gao, Yuan; Cheng, Yifan; Julius, David

doi:10.1016/j.bpj.2015.11.202

Cited by 49 publications

(108 citation statements)

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“…Our structure reveals a pore region with two constrictions or gates as observed in other TRP channels 5,6,19 . In the absence of ligands, TRPV2 displays wider upper and lower gates compared with closed and agonist-activated TRPV1.…”

supporting

confidence: 55%

“…The general architecture of apo-TRPV2 has been proposed to be similar to the structures of other TRP channels, as well as distantly related voltage-and ligand-gated channels 6,19,[22][23][24][25] . The 2D class averages and the final 3D reconstructed map of TRPV2 unambiguously show a tetrameric assembly similar to TRPV1 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…2). Like TRPV1 and TRPA1, the pore of apo-TRPV2 consists of two constrictions or gates 5,6,19 : an upper gate resides at the selectivity filter in the outer pore region of the channel and a lower gate is comprised of the distal end of S6 (Fig. 2a).…”

Section: Resultsmentioning

confidence: 99%

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Structure of the Full-Length TRPV2 Channel by Cryo-EM

et al. 2016

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Transient receptor potential (TRP) proteins form a superfamily Ca 2 þ -permeable cation channels regulated by a range of chemical and physical stimuli. Structural analysis of a 'minimal' TRP vanilloid subtype 1 (TRPV1) elucidated a mechanism of channel activation by agonists through changes in its outer pore region. Though homologous to TRPV1, other TRPV channels (TRPV2-6) are insensitive to TRPV1 activators including heat and vanilloids. To further understand the structural basis of TRPV channel function, we determined the structure of full-length TRPV2 at B5 Å resolution by cryo-electron microscopy. Like TRPV1, TRPV2 contains two constrictions, one each in the pore-forming upper and lower gates. The agonist-free full-length TRPV2 has wider upper and lower gates compared with closed and agonist-activated TRPV1. We propose these newly revealed TRPV2 structural features contribute to diversity of TRPV channels.

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supporting

confidence: 55%

Section: Resultsmentioning

confidence: 99%

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Structure of the Full-Length TRPV2 Channel by Cryo-EM

et al. 2016

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“…TRP helix 2 and the loop between the two TRP helices are buried in the lower leaflet of the membrane; the loop also participates in the formation of the cavity with S1-S4 by patching the side opening. The TRP helix 2 is not present in TRPV or TRPA channel structures but was observed in NOMPC 32,42,43 .…”

Section: Resultsmentioning

confidence: 99%

Structures of the calcium-activated, non-selective cation channel TRPM4

Guo

She

Zeng

et al. 2017

Nature

178

196

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TRPM4 is a calcium-activated, phosphatidylinositol bisphosphate (PtdInsP2) modulated, non-selective cation channel, and belongs to the family of melastatin-related transient receptor potential (TRPM) channels. Here we present the cryo-EM structures of the mouse TRPM4 channel with and without ATP. TRPM4 consists of multiple transmembrane and cytosolic domains, which assemble into a three-tiered architecture. The N-terminal nucleotide binding domain (NBD) and the C-terminal coiled coil participate in the tetrameric assembly of the channel; ATP binds at NBD and inhibits channel activity. TRPM4 has an exceptionally wide filter but is only permeable to monovalent cations; filter residue Gln973 is essential in defining monovalent selectivity. S1-S4 domain and post-S6 TRP domain form the central gating apparatus that likely house the Ca2+ and PtdInsP2 binding sites. These structures provide an essential starting point for elucidating the complex gating mechanisms of TRPM4 and also reveal the molecular architecture of the TRPM family for the first time.

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“…33,34 The voltage-sensing domains discussed up to here, even though fulfilling very different physiological roles, are structurally very similar. In Figure 1, I compare these structures and as can be seen, it is possible to align all the VSDs to the structure of the paddle chimaera.…”

Section: Introductionmentioning

confidence: 96%

Functional diversity of potassium channel voltage-sensing domains

Islas¹

2016

Channels

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Voltage-gated potassium channels or Kv's are membrane proteins with fundamental physiological roles. They are composed of 2 main functional protein domains, the pore domain, which regulates ion permeation, and the voltage-sensing domain, which is in charge of sensing voltage and undergoing a conformational change that is later transduced into pore opening. The voltagesensing domain or VSD is a highly conserved structural motif found in all voltage-gated ion channels and can also exist as an independent feature, giving rise to voltage sensitive enzymes and also sustaining proton fluxes in proton-permeable channels. In spite of the structural conservation of VSDs in potassium channels, there are several differences in the details of VSD function found across variants of Kvs. These differences are mainly reflected in variations in the electrostatic energy needed to open different potassium channels. In turn, the differences in detailed VSD functioning among voltage-gated potassium channels might have physiological consequences that have not been explored and which might reflect evolutionary adaptations to the different roles played by Kv channels in cell physiology.

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Structure of the TRPA1 Ion Channel Suggests Regulatory Mechanisms

Cited by 49 publications

References 0 publications

Structure of the Full-Length TRPV2 Channel by Cryo-EM

Structure of the Full-Length TRPV2 Channel by Cryo-EM

Structures of the calcium-activated, non-selective cation channel TRPM4

Functional diversity of potassium channel voltage-sensing domains

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