Interaction between the Linker, Pre-S1, and TRP Domains Determines Folding, Assembly, and Trafficking of TRPV Channels

García-Elías, Anna; Berna‐Erro, Alejandro; Rubio-Moscardó, Fanny; Pardo-Pastor, Carlos; Mrkonjic, Sanela; Sepúlveda, Romina V.; Vicente, Rubén; González-Nilo, Fernando D.; Valverde, Miguel A.

doi:10.1016/j.str.2015.05.018

Cited by 21 publications

(20 citation statements)

References 52 publications

(67 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This segment is postulated to play a role in biogenesis, protein folding, and gating of these channels (37)(38)(39)(40)(41)(42)(43)(44)(45). Our NMR spectroscopy and Gd 3ϩ suppression data did not support the presence of a pre-S1 helix in Kv11.1 channels.…”

Section: Role Of S1 In Channel Inactivationcontrasting

confidence: 68%

See 1 more Smart Citation

The S1 helix critically regulates the finely tuned gating of Kv11.1 channels

Phan

David

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

Congenital mutations in the cardiac Kv11.1 channel can cause long QT syndrome type 2 (LQTS2), a heart rhythm disorder associated with sudden cardiac death. Mutations act either by reducing protein expression at the membrane and/or by perturbing the intricate gating properties of Kv11.1 channels. A number of clinical LQTS2-associated mutations have been reported in the first transmembrane segment (S1) of Kv11.1 channels, but the role of this region of the channel is largely unexplored. In part, this is due to problems defining the extent of the S1 helix, as a consequence of its low sequence homology with other Kv family members. Here, we used NMR spectroscopy and electrophysiological characterization to show that the S1 of Kv11.1 channels extends seven helical turns, from Pro-405 to Phe-431, and is flanked by unstructured loops. Functional analysis suggests that pre-S1 loop residues His-402 and Tyr-403 play an important role in regulating the kinetics and voltage dependence of channel activation and deactivation. Multiple residues within the S1 helix also play an important role in finetuning the voltage dependence of activation, regulating slow deactivation, and modulating C-type inactivation of Kv11.1 channels. Analyses of LQTS2-associated mutations in the pre-S1 loop or S1 helix of Kv11.1 channels demonstrate perturbations to both protein expression and most gating transitions. Thus, S1 region mutations would reduce both the action potential repolarizing current passed by Kv11

show abstract

Section: Role Of S1 In Channel Inactivationcontrasting

confidence: 68%

“…Termed the pre-S1, S0, or S0Ј helix, this short helical segment may play a role in the biogenesis, protein-folding, and inter-subunit interactions of TRPV channels (45). In TRPA1 channels, the pre-S1 contains several cysteine and lysine residues that are involved in channel activation by electrophilic agonists (44).…”

mentioning

confidence: 99%

The S1 helix critically regulates the finely tuned gating of Kv11.1 channels

Phan

David

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…To evaluate the stability of the configuration determined by the in silico docking and further explore the interactions between 5′,6′-EET and TRPV4, a 120 ns MD simulation (Fig. 1a ) was performed based on a previously reported TRPV4 model 46 and using the configuration shown in Supplementary Fig. 2 as starting point.…”

Section: Resultsmentioning

confidence: 99%

Structural determinants of 5′,6′-epoxyeicosatrienoic acid binding to and activation of TRPV4 channel

Berna‐Erro

Izquierdo-Serra

Sepúlveda

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

TRPV4 cation channel activation by cytochrome P450-mediated derivatives of arachidonic acid (AA), epoxyeicosatrienoic acids (EETs), constitute a major mechanisms of endothelium-derived vasodilatation. Besides, TRPV4 mechano/osmosensitivity depends on phospholipase A2 (PLA2) activation and subsequent production of AA and EETs. However, the lack of evidence for a direct interaction of EETs with TRPV4 together with claims of EET-independent mechanical activation of TRPV4 has cast doubts on the validity of this mechanism. We now report: 1) The identification of an EET-binding pocket that specifically mediates TRPV4 activation by 5′,6′-EET, AA and hypotonic cell swelling, thereby suggesting that all these stimuli shared a common structural target within the TRPV4 channel; and 2) A structural insight into the gating of TRPV4 by a natural agonist (5′,6′-EET) in which K535 plays a crucial role, as mutant TRPV4-K535A losses binding of and gating by EET, without affecting GSK1016790A, 4α-phorbol 12,13-didecanoate and heat mediated channel activation. Together, our data demonstrates that the mechano- and osmotransducing messenger EET gates TRPV4 by a direct action on a site formed by residues from the S2-S3 linker, S4 and S4-S5 linker.

show abstract

“…Asparagine 855 likely makes key contacts with the TRP domain or nearby residues. Similar interactions between the S4–S5 linker and TRP domain are predicted for other TRP channels ; disrupting the potential interaction results in channel hyperactivity in TRPV4 , and also impairs proper folding in TRPV channels .…”

Section: Trpa1 and Trpv1 Have Very Similar Transmembrane Domainsmentioning

confidence: 66%

How the TRPA1 receptor transmits painful stimuli: Inner workings revealed by electron cryomicroscopy

Brewster

Gaudet

2015

BioEssays

View full text Add to dashboard Cite

Summary A new high-resolution structure of a pain-sensing ion channel, TRPA1, provides a molecular scaffold to understand channel function. Unexpected structural features include a TRP-domain helix similar to TRPV1, a novel ligand-binding site, and an unusual C-terminal coiled coil stabilized by inositol hexakisphosphate (IP6). TRP-domain helices, which structurally act as a nexus for communication between the channel gates and its other domains, may thus be a feature conserved across the entire TRP family and, possibly, other allosterically-gated channels. Similarly, the TRPA1 antagonist-binding site could also represent a druggable location in other ion channels. Combined with known TRPA1 functional properties, the structural role for IP6 leads us to propose that polyphosphate unbinding could act as a molecular kill switch for TRPA1 inactivation. Finally, although packing of the TRPA1 membrane-proximal region hints at a mechanism for electrophile sensing, the details of how TRPA1 responds to noxious reactive electrophiles and temperature await future studies.

show abstract

Interaction between the Linker, Pre-S1, and TRP Domains Determines Folding, Assembly, and Trafficking of TRPV Channels

Cited by 21 publications

References 52 publications

The S1 helix critically regulates the finely tuned gating of Kv11.1 channels

The S1 helix critically regulates the finely tuned gating of Kv11.1 channels

Structural determinants of 5′,6′-epoxyeicosatrienoic acid binding to and activation of TRPV4 channel

How the TRPA1 receptor transmits painful stimuli: Inner workings revealed by electron cryomicroscopy

Contact Info

Product

Resources

About