Unfolding of a Temperature-Sensitive Domain Controls Voltage-Gated Channel Activation

Arrigoni, Cristina; Rohaim, Ahmed; Shaya, David; Findeisen, Felix; Stein, Richard A.; Nurva, Shailika; Mishra, Shailendra; Mchaourab, Hassane S.; Minor, Daniel L.

doi:10.1016/j.cell.2016.02.001

Cited by 66 publications

(116 citation statements)

References 53 publications

(156 reference statements)

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“…We also showed that the CC helix unwinds ~25% as temperature is elevated, independent of IP 6 , but that the partial helix unwinding had no detectable impact on coiled-coil tetramerization. This is consistent with the model of partial helix unwinding leading to gating as proposed by Arrigoni et al [35]. Finally, we showed that neither removal of IP 6 , increasing temperature, nor addition of AITC abolished interactions between the coiled-coil and the ARDs.…”

Section: Introductionsupporting

confidence: 93%

Multimerization of Homo sapiens TRPA1 ion channel cytoplasmic domains

Martinez

Gordon

2018

Preprint

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21The transient receptor potential Ankyrin-1 (TRPA1) ion channel is modulated by myriad 22 noxious stimuli that interact with multiple regions of the channel, including cysteine-23 reactive natural extracts from onion and garlic which modify residues in the cytoplasmic 24 domains. The way in which TRPA1 cytoplasmic domain modification is coupled to opening 25 of the ion-conducting pore has yet to be elucidated. The cryo-EM structure of TRPA1 26 revealed a tetrameric C-terminal coiled-coil surrounded by N-terminal ankyrin repeat 27 domains (ARDs), an architecture shared with the canonical transient receptor potential 28 (TRPC) ion channel family. Similarly, structures of the TRP melastatin (TRPM) ion channel 29 family also showed a C-terminal coiled-coil surrounded by N-terminal cytoplasmic 30 domains. This conserved architecture may indicate a common gating mechanism by which 31 modification of cytoplasmic domains can transduce conformational changes to open the 32ion-conducting pore. We developed an in vitro system in which N-terminal ARDs and C-33 terminal coiled-coil domains can be expressed in bacteria and maintain the ability to 34 interact. We tested three gating regulators: temperature; the polyphosphate compound 35 IP 6 ; and the covalent modifier allyl isothiocyanate to determine whether they alter N-and 36 C-terminal interactions. We found that none of the modifiers tested abolished ARD-coiled-37 coil interactions, though there was a significant reduction at 37˚C. We found that coiled-38 coils tetramerize in a concentration dependent manner, with monomers and trimers 39 observed at lower concentrations. Our system provides a method for examining the 40 mechanism of oligomerization of TRPA1 cytoplasmic domains as well as a system to study 41 the transmission of conformational changes resulting from covalent modification. 42 3 43 Introduction 44 The Transient Receptor Potential Ankyrin-1 (TRPA1) ion channel is expressed in 45 nociceptors of the peripheral nervous system [1] where it is activated by a variety of 46 noxious chemical stimuli including electrophilic covalent modifiers [1-3], non-covalent 47 compounds [4], and temperature [5,6]. TRPA1 is also involved in inflammatory signaling [7] 48 and has become an active therapeutic target for treatment of cough [8,9], itch [9,10], and 49 pain [10,11]. 50 Despite the importance of TRPA1 in sensing noxious stimuli, the structural 51 mechanisms of channel activation remain unknown. Since there are multiple channel 52 activators, both covalent and non-covalent, that likely bind to different regions of the 53 channel [3,4,12], it is possible that TRPA1 undergoes different structural rearrangements 54 during activation that depends on the ligand used. Indeed, Cavanaugh, Simkin, and Kim 55 proposed early on that there are different functional states of human TRPA1, one that can 56 be activated by covalent activators in the presence of intracellular polyphosphates and a 57 state that can be activated by Δ 9 -tetra-hydrocannabinol in absence of intracellular 58...

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Section: Introductionsupporting

confidence: 93%

Multimerization of Homo sapiens TRPA1 ion channel cytoplasmic domains

Martinez

Gordon

2018

Preprint

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“…The CTD in this new open structure is very different than the CTDs visible in the closed NavAe1 (Arrigoni et al, 2016) and CavAb structures (Fig. 3, a and b): it consists of a helical extension of the S6 transmembrane helix at the proximal end and a short segment without any canonical secondary structure beginning at residue 234 and ending at residue 240; this is followed by a coiled-coil region that extends to the end of the structure.…”

Section: Structures Of Sodium Channels Represent Different Functionalmentioning

confidence: 69%

Interpreting the functional role of a novel interaction motif in prokaryotic sodium channels

Sula

Wallace

2017

Journal of General Physiology

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“…Whether the core domain senses temperature directly, or allosterically responds to a discrete temperature sensor located elsewhere in the channel (Arrigoni et al 2016), remains to be determined. The squirrel’s transmembrane core differs from rat’s by fifteen amino acids, and transposition of only six of them is sufficient to restore cold sensitivity.…”

Section: Discussionmentioning

confidence: 99%

Molecular Prerequisites for Diminished Cold Sensitivity in Ground Squirrels and Hamsters

et al. 2017

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Summary Thirteen-lined ground squirrels and Syrian hamsters are known for their ability to withstand cold during hibernation. We found that hibernators exhibit cold tolerance even in the active state. Imaging and electrophysiology of squirrel somatosensory neurons reveal a decrease in cold sensitivity of TRPM8-expressing cells. Characterization of squirrel and hamster TRPM8 showed that the channels are chemically-activated, but exhibit poor activation by cold. Cold sensitivity can be re-introduced into squirrel and hamster TRPM8 by transferring the transmembrane domain from the cold sensitive rat orthologue. The same can be achieved in squirrel TRPM8 by mutating only six amino acids. Reciprocal mutations suppress cold sensitivity of the rat orthologue, supporting functional significance of these residues. Our results suggest that ground squirrels and hamsters exhibit reduced cold sensitivity partially due to modifications in the transmembrane domain of TRPM8. Our study reveals molecular adaptations that accompany cold tolerance in two species of mammalian hibernators.

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Unfolding of a Temperature-Sensitive Domain Controls Voltage-Gated Channel Activation

Cited by 66 publications

References 53 publications

Multimerization of Homo sapiens TRPA1 ion channel cytoplasmic domains

Multimerization of Homo sapiens TRPA1 ion channel cytoplasmic domains

Interpreting the functional role of a novel interaction motif in prokaryotic sodium channels

Molecular Prerequisites for Diminished Cold Sensitivity in Ground Squirrels and Hamsters

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