Side chain flexibility and coupling between the S4‐S5 linker and the TRP domain in thermo‐sensitive TRP channels: Insights from protein modeling

Romero‐Romero, Sergio; Lagunas, Froylan Gomez; Balleza, Daniel

doi:10.1002/prot.25243

Cited by 9 publications

(13 citation statements)

References 95 publications

(237 reference statements)

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“…Interestingly, the TRPV1 channel gating is also accompanied by large entropic and enthalpic changes, which suggest substantial conformation changes in specific zones of the protein [106]. Consistent with this, structural evidence indicates that the`V-sensor´of TRPV1 is virtually static during the closed-to-open transition [28,53], but some reports indicate a high dynamism of the pore and the S4-S5L in those channels [29,56,58,59]. On the other hand, channels considered flexible (as the members of the Shaker-like K V family) or extremely flexible (such as CNGA2) at the S3 segment, exhibit weak dependence on temperature with Q 10 values below 4 [107,108].…”

Section: Discussionmentioning

confidence: 67%

“…In TRP channels, which are weakly voltagesensitive but strongly activated by stimuli as diverse as heat, cold, and several ligands, gating is also achieved through conformational changes facilitated by local flexibility. These motions are associated with specific regions of the VSD, including the S3 segment, as well as linkers S3-S4L and S4-S5L [9,[27][28][29]. In CNG channels, which are virtually voltage-independent, the opening of the pore has evolved in strict dependence on the cyclic nucleotide-binding through conformational changes involving the S4-S5L [30].…”

Section: Introductionmentioning

confidence: 99%

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Voltage vs. Ligand I: Structural basis of the intrinsic flexibility of S3 segment and its significance in ion channel activation

2019

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We systematically predict the internal flexibility of the S3 segment, one of the most mobile elements in the voltage-sensor domain. By analyzing the primary amino acid sequences of V-sensor containing proteins, including Hv1, TPC channels and the voltage-sensing phosphatases, we established correlations between the local flexibility and modes of activation for different members of the VGIC superfamily. Taking advantage of the structural information available, we also assessed structural aspects to understand the role played by the flexibility of S3 during the gating of the pore. We found that S3 flexibility is mainly determined by two specific regions: (1) a short NxxD motif in the N-half portion of the helix (S3a), and (2) a short sequence at the beginning of the so-called paddle motif where the segment has a kink that, in some cases, divide S3 into two distinct helices (S3a and S3b). A good correlation between the flexibility of S3 and the reported sensitivity to temperature and mechanical stretch was found. Thus, if the channel exhibits high sensitivity to heat or membrane stretch, local S3 flexibility is low. On the other hand, high flexibility of S3 is preferentially associated to channels showing poor heat and mechanical sensitivities. In contrast, we did not find any apparent correlation between S3 flexibility and voltage or ligand dependence. Overall, our results provide valuable insights into the dynamics of channel-gating and its modulation.

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Section: Discussionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Voltage vs. Ligand I: Structural basis of the intrinsic flexibility of S3 segment and its significance in ion channel activation

2019

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“…Two of the residues in the P1 patch have been proposed as fundamental to the interaction between the TDh and the TM4-TM5 linker, acting as an allosteric integrator (Taberner et al, 2014; Sierra-Valdez et al, 2018; Romero-Romero et al, 2017; Gregorio-Teruel et al, 2014; Zhao et al, 2020). A third residue in P1 corresponds to a conserved Phe at the lower end of TM1 that is always connected to the other elements of the patch.…”

Section: Discussionmentioning

confidence: 99%

“…The copyright holder for this preprint this version posted September 6, 2021. ; https://doi.org/10.1101/2021.09.06.459056 doi: bioRxiv preprint information from lipids (such as PIP2), the TM4-TM5 linker that reports changes occurring at the transmembrane region and the coupling domain (CD) composed of the pre-S1 helix and a helix-loop-helix (HLH) motif. The high conservation of Phe434 is underscored by the importance of the CD array that couples with all the rest of the cytoplasmic features (Garcia-Elias et al, 2015;Romero-Romero et al, 2017;Hofmann et al, 2017;Yang et al, 2018;Hilton et al, 2019;Yuan, 2019;Zubcevic et al, 2019;Cao, 2020).…”

Section: Sequence Conservation Highlights Structural Featuresmentioning

confidence: 99%

Sequence conservation and structural features that are common within TRP channels

Cabezas-Bratesco

Colenso

Zavala

et al. 2021

Preprint

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TRP proteins are a large family of cation selective channels, surpassed in variety only by voltage-gated potassium channels. Detailed molecular mechanisms governing how membrane voltage, ligand binding, or temperature can induce conformational changes promoting the open state of the channel are still missing for TRP channels. Aiming to unveil distinctive structural features common to the transmembrane domains within the TRP family, we performed bioinformatic analyses over a large set of TRP channel genes. Here we report a discrete and exceptionally conserved set of residues. This fingerprint is composed of eleven residues localized at equivalent three-dimensional positions in TRP channels from the different subtypes. Moreover, these amino acids are arranged in three groups, connected by a set of aromatics located at the core of the transmembrane structure. We hypothesize that differences in the connectivity between these different groups of residues harbors the apparent differences in coupling strategies used by TRP subgroups.

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“…The most profound reduction was caused by the G533A mutation in the S4-S5 linker (Fig. 2A,C), which disrupts a residue that is invariant in all TRPC, TRPV, TRPM, and TRPA1 proteins (Hofmann et al, 2017) and is required for flexibility of the S4-S5 linker (Romero-Romero et al, 2017). In addition, a mutation in the S5px region, D545A, resulted in a dramatic decrease in TRP (,5%; Fig.…”

Section: Residues In S4-s5 Linker S5px and Trp Domain Essential For Expressionmentioning

confidence: 98%

Conserved Modules Required for Drosophila TRP Function in Vivo

et al. 2021

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Transient receptor potential (TRP) channels are broadly required in animals for sensory physiology. To provide insights into regulatory mechanisms, the structures of many TRPs have been solved. This has led to new models, some of which have been tested in vitro. Here, using the classical TRP required for Drosophila visual transduction, we uncovered structural requirements for channel function in photoreceptor cells. Using a combination of molecular genetics, field recordings, protein expression analysis, and molecular modeling, we interrogated roles for the S4-S5 linker and the TRP domain, and revealed mutations in the S4-S5 linker that impair channel opening or closing. We also uncovered differential requirements for the two highly conserved motifs in the TRP domain for activation and protein stability. By performing genetic complementation, we found an intrasubunit interaction between the S4-S5 linker and the S5 segment that contributes to activation. This analysis highlights key structural requirements for TRP channel opening, closing, folding, and for intrasubunit interactions in a native context-Drosophila photoreceptor cells.

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Side chain flexibility and coupling between the S4‐S5 linker and the TRP domain in thermo‐sensitive TRP channels: Insights from protein modeling

Abstract: Taxonomic distribution, repeats and functions of the S1 domain-containing proteins as members of the OB-fold family Evgeniia I. Deryusheva, Andrey V. Machulin, Olga M. Selivanova and Oxana V. Galzitskaya

Cited by 9 publications

References 95 publications

Voltage vs. Ligand I: Structural basis of the intrinsic flexibility of S3 segment and its significance in ion channel activation

Voltage vs. Ligand I: Structural basis of the intrinsic flexibility of S3 segment and its significance in ion channel activation

Sequence conservation and structural features that are common within TRP channels

Conserved Modules Required for Drosophila TRP Function in Vivo

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