Crystal structure of the N-terminal ankyrin repeat domain of TRPV3 reveals unique conformation of finger 3 loop critical for channel function

Shi, Di-Jing; Ye, Sheng; Cao, Xu; Zhang, Rongguang; Wang, Kewei

doi:10.1007/s13238-013-3091-0

Cited by 38 publications

(33 citation statements)

References 39 publications

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“…Structural studies by cryo‐electron microscopy (cryo‐EM) resulted in low‐resolution (>13 Å) structures of several TRP channels . X‐ray crystallography was also used to determine high‐resolution structures for various fragments of the TRP channels, including the ARD of the TRPV channels . But high‐resolution structures of full‐length TRP channels remained unavailable until recently.…”

Section: Introductionmentioning

confidence: 99%

Toward elucidating the heat activation mechanism of the TRPV1 channel gating by molecular dynamics simulation

2016

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As a key cellular sensor, the TRPV1 cation channel undergoes a gating transition from a closed state to an open state in response to various physical and chemical stimuli including noxious heat. Despite years of study, the heat activation mechanism of TRPV1 gating remains enigmatic at the molecular level. Toward elucidating the structural and energetic basis of TRPV1 gating, we have performed molecular dynamics (MD) simulations (with cumulative simulation time of 3 μs), starting from the high-resolution closed and open structures of TRPV1 solved by cryo-electron microscopy. In the closed-state simulations at 30°C, we observed a stably closed channel constricted at the lower gate (near residue I679), while the upper gate (near residues G643 and M644) is dynamic and undergoes flickery opening/closing. In the open-state simulations at 60°C, we found higher conformational variation consistent with a large entropy increase required for the heat activation, and both the lower and upper gates are dynamic with transient opening/closing. Through ensemble-based structural analyses of the closed state vs. the open state, we revealed pronounced closed-to-open conformational changes involving the membrane proximal domain (MPD) linker, the outer pore, and the TRP helix, which are accompanied by breaking/forming of a network of closed/open-state specific hydrogen bonds. By comparing the closed-state simulations at 30°C and 60°C, we observed heat-activated conformational changes in the MPD linker, the outer pore, and the TRP helix that resemble the closed-to-open conformational changes, along with partial formation of the open-state specific hydrogen bonds. Some of the residues involved in the above key hydrogen bonds were validated by previous mutational studies. Taken together, our MD simulations have offered rich structural and dynamic details beyond the static structures of TRPV1, and promising targets for future mutagenesis and functional studies of the TRPV1 channel.

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Section: Introductionmentioning

confidence: 99%

Toward elucidating the heat activation mechanism of the TRPV1 channel gating by molecular dynamics simulation

2016

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“…The first strategy was a “divide and concur” approach, which provided structures of smaller soluble domains at atomic resolution (Fujiwara & Minor, 2008; Inada et al, 2012; Jin, Touhey & Gaudet, 2006; Lau, Procko & Gaudet, 2012; Lishko et al, 2007; Phelps et al, 2008; Phelps et al, 2010; Shi et al, 2013; Yamaguchi et al, 2001). A second strategy utilized electron microscopy (EM), which revealed full-length TRP channel structures (Cao et al, 2013; Cvetkov et al, 2011; Huynh et al, 2014; Liao et al, 2013; Moiseenkova-Bell et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Application of Amphipols for Structure–Functional Analysis of TRP Channels

2014

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Amphipathic polymers (amphipols), such as A8-35 and SApol, are a new tool for stabilizing integral membrane proteins in detergent-free conditions for structural and functional studies. Transient receptor potential (TRP) ion channels function as tetrameric protein complexes in a diverse range of cellular processes including sensory transduction. Mammalian TRP channels share ~20% sequence similarity and are categorized into six subfamilies: TRPC (canonical), TRPV (vanilloid), TRPA (ankyrin), TRPM (melastatin), TRPP (polycystin), and TRPML (mucolipin). Due to the inherent difficulties in purifying eukaryotic membrane proteins, structural studies of TRP channels have been limited. Recently, A8-35 was essential in resolving the molecular architecture of the nociceptor TRPA1 and led to the determination of a high resolution structure of the thermosensitive TRPV1 channel by cryo-EM. Newly developed maltose-neopentyl glycol (MNG) detergents have also proven useful in stabilizing TRP channels for structural analysis. In this review, we will discuss the impact of amphipols and MNG detergents on structural studies of TRP channels by cryo-EM. We will compare how A8-35 and MNG detergents interact with the hydrophobic transmembrane (TM) domains of TRP channels. In addition, we will discuss what these cryo-EM studies reveal on the importance of screening different types of surfactants towards determining high resolution structures of TRP channels.

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“…Previous studies have identified numerous residues on the ARD finger 2 that are important for TRPV3 channel gating. 44 . In addition, this region of the ARD has been implicated in binding calmodulin (CaM) and ATP, and biochemical and structural studies of isolated ARDs have further identified the conserved residue K169 as being critical for ATP binding [45][46][47] .…”

Section: The Ctd Mediates Inter-protomer Contactsmentioning

confidence: 99%

Conformational ensemble of the human TRPV3 ion channel

Zubcevic¹,

Herzik

et al. 2018

Preprint

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Transient receptor potential vanilloid channel 3 (TRPV3), a member of the thermosensitive TRP (thermoTRPV) channels, is activated by warm temperatures and serves as a key regulator of normal skin physiology through the release of pro-inflammatory messengers.Mutations in trpv3 have been identified as the cause of the congenital skin disorder, Olmsted syndrome. Unlike other members of the thermoTRPV channel family, TRPV3 sensitizes upon repeated simulation, yet a lack of structural information about the channel precludes a molecular-level understanding of TRPV3 sensitization and gating. Here, we present the cryoelectron microscopy structures of apo and sensitized human TRPV3, as well as several structures of TRPV3 in the presence of the common thermoTRPV agonist 2aminoethoxydiphenyl borate (2-APB). Our results show α-to-π-helix transitions in the S6 during sensitization, and suggest a critical role for the S4-S5 linker π-helix during ligand gating.

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Crystal structure of the N-terminal ankyrin repeat domain of TRPV3 reveals unique conformation of finger 3 loop critical for channel function

Cited by 38 publications

References 39 publications

Toward elucidating the heat activation mechanism of the TRPV1 channel gating by molecular dynamics simulation

Toward elucidating the heat activation mechanism of the TRPV1 channel gating by molecular dynamics simulation

Application of Amphipols for Structure–Functional Analysis of TRP Channels

Conformational ensemble of the human TRPV3 ion channel

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