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Article ; Online: Anionic omega currents from single countercharge mutants in the voltage-sensing domain of Ci-VSP.

Shen, Rong / Roux, Benoît / Perozo, Eduardo

2023 Volume 156, Issue 1

Abstract: The S4 segment of voltage-sensing domains (VSDs) directly responds to voltage changes by reorienting within the electric field as a permion. A narrow hydrophobic "gasket" or charge transfer center at the core of most VSDs focuses the electric field into ... ...

Abstract	The S4 segment of voltage-sensing domains (VSDs) directly responds to voltage changes by reorienting within the electric field as a permion. A narrow hydrophobic "gasket" or charge transfer center at the core of most VSDs focuses the electric field into a narrow region and catalyzes the sequential and reversible translocation of S4 positive gating charge residues across the electric field while preventing the permeation of physiological ions. Mutating specific S4 gating charges can cause ionic leak currents through the VSDs. These gating pores or omega currents play important pathophysiological roles in many diseases of excitability. Here, we show that mutating D129, a key countercharge residue in the Ciona intestinalis voltage-sensing phosphatase (Ci-VSP), leads to the generation of unique anionic omega currents. Neutralizing D129 causes a dramatic positive shift of activation, facilitates the formation of a continuous water path through the VSD, and creates a positive electrostatic potential landscape inside the VSD that contributes to its unique anionic selectivity. Increasing the population or dwell time of the conducting state by a high external pH or an engineered Cd2+ bridge markedly increases the current magnitude. Our findings uncover a new role of countercharge residues in the impermeable VSD of Ci-VSP and offer insights into mechanisms of the conduction of anionic omega currents linked to countercharge residue mutations.
MeSH term(s)	Animals ; Ciona intestinalis/genetics ; Electricity ; Ion Transport ; Mutation ; Phosphoric Monoester Hydrolases
Chemical Substances	Phosphoric Monoester Hydrolases (EC 3.1.3.2)
Language	English
Publishing date	2023-11-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	3118-5
ISSN	1540-7748 ; 0022-1295
ISSN (online)	1540-7748
ISSN	0022-1295
DOI	10.1085/jgp.202213311
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Article ; Online: Mechanism of voltage gating in the voltage-sensing phosphatase Ci-VSP.

Shen, Rong / Meng, Yilin / Roux, Benoît / Perozo, Eduardo

Proceedings of the National Academy of Sciences of the United States of America

2022 Volume 119, Issue 44, Page(s) e2206649119

Abstract: Conformational changes in voltage-sensing domains (VSDs) are driven by the transmembrane electric field acting on the protein charges. Yet, the overall energetics and detailed mechanism of this process are not fully understood. Here, we determined free ... ...

Abstract	Conformational changes in voltage-sensing domains (VSDs) are driven by the transmembrane electric field acting on the protein charges. Yet, the overall energetics and detailed mechanism of this process are not fully understood. Here, we determined free energy and displacement charge landscapes as well as the major conformations visited during a complete functional gating cycle in the isolated VSD of the phosphatase Ci-VSP (Ci-VSD) comprising four transmembrane helices (segments S1 to S4). Molecular dynamics simulations highlight the extent of S4 movements. In addition to the crystallographically determined activated "Up" and resting "Down" states, the simulations predict two Ci-VSD conformations: a deeper resting state ("down-minus") and an extended activated ("up-plus") state. These additional conformations were experimentally probed via systematic cysteine mutagenesis with metal-ion bridges and the engineering of proton conducting mutants at hyperpolarizing voltages. The present results show that these four states are visited sequentially in a stepwise manner during voltage activation, each step translocating one arginine or the equivalent of ∼1
MeSH term(s)	Ion Channel Gating ; Protons ; Phosphoric Monoester Hydrolases ; Cysteine ; Protein Structure, Secondary ; Arginine
Chemical Substances	Protons ; Phosphoric Monoester Hydrolases (EC 3.1.3.2) ; Cysteine (K848JZ4886) ; Arginine (94ZLA3W45F)
Language	English
Publishing date	2022-10-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2206649119
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Article: Folding of Prestin's Anion-Binding Site and the Mechanism of Outer Hair Cell Electromotility.

Lin, Xiaoxuan / Haller, Patrick / Bavi, Navid / Faruk, Nabil / Perozo, Eduardo / Sosnick, Tobin R

bioRxiv : the preprint server for biology

2023

Abstract: Prestin responds to transmembrane voltage fluctuations by changing its cross-sectional area, a process underlying the electromotility of outer hair cells and cochlear amplification. Prestin belongs to the SLC26 family of anion transporters yet is the ... ...

Abstract	Prestin responds to transmembrane voltage fluctuations by changing its cross-sectional area, a process underlying the electromotility of outer hair cells and cochlear amplification. Prestin belongs to the SLC26 family of anion transporters yet is the only member capable of displaying electromotility. Prestin's voltage-dependent conformational changes are driven by the putative displacement of residue R399 and a set of sparse charged residues within the transmembrane domain, following the binding of a Cl
Language	English
Publishing date	2023-10-01
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.02.27.530320
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Article ; Online: Folding of prestin's anion-binding site and the mechanism of outer hair cell electromotility.

Lin, Xiaoxuan / Haller, Patrick R / Bavi, Navid / Faruk, Nabil / Perozo, Eduardo / Sosnick, Tobin R

eLife

2023 Volume 12

Abstract	Prestin responds to transmembrane voltage fluctuations by changing its cross-sectional area, a process underlying the electromotility of outer hair cells and cochlear amplification. Prestin belongs to the SLC26 family of anion transporters yet is the only member capable of displaying electromotility. Prestin's voltage-dependent conformational changes are driven by the putative displacement of residue R399 and a set of sparse charged residues within the transmembrane domain, following the binding of a Cl
MeSH term(s)	Hair Cells, Auditory, Outer ; Anions ; Binding Sites ; Cochlea ; Lipid Bilayers ; Membrane Transport Proteins
Chemical Substances	Anions ; Lipid Bilayers ; Membrane Transport Proteins
Language	English
Publishing date	2023-12-06
Publishing country	England
Document type	Journal Article
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.89635
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Article ; Online: State-specific morphological deformations of the lipid bilayer explain mechanosensitive gating of MscS ion channels.

Park, Yein Christina / Reddy, Bharat / Bavi, Navid / Perozo, Eduardo / Faraldo-Gómez, José D

eLife

2023 Volume 12

Abstract: The force-from-lipids hypothesis of cellular mechanosensation posits that membrane channels open and close in response to changes in the physical state of the lipid bilayer, induced for example by lateral tension. Here, we investigate the molecular basis ...

Abstract	The force-from-lipids hypothesis of cellular mechanosensation posits that membrane channels open and close in response to changes in the physical state of the lipid bilayer, induced for example by lateral tension. Here, we investigate the molecular basis for this transduction mechanism by studying the mechanosensitive ion channel MscS from Escherichia coli and its eukaryotic homolog MSL1 from Arabidopsis thaliana. First, we use single-particle cryo-electron microscopy to determine the structure of a novel open conformation of wild-type MscS, stabilized in a thinned lipid nanodisc. Compared with the closed state, the structure shows a reconfiguration of helices TM1, TM2, and TM3a, and widening of the central pore. Based on these structures, we examined how the morphology of the membrane is altered upon gating, using molecular dynamics simulations. The simulations reveal that closed-state MscS causes drastic protrusions in the inner leaflet of the lipid bilayer, both in the absence and presence of lateral tension, and for different lipid compositions. These deformations arise to provide adequate solvation to hydrophobic crevices under the TM1-TM2 hairpin, and clearly reflect a high-energy conformation for the membrane, particularly under tension. Strikingly, these protrusions are largely eradicated upon channel opening. An analogous computational study of open and closed MSL1 recapitulates these findings. The gating equilibrium of MscS channels thus appears to be dictated by opposing conformational preferences, namely those of the lipid membrane and of the protein structure. We propose a membrane deformation model of mechanosensation, which posits that tension shifts the gating equilibrium towards the conductive state not because it alters the mode in which channel and lipids interact, but because it increases the energetic cost of the morphological perturbations in the membrane required by the closed state.
MeSH term(s)	Cryoelectron Microscopy ; Escherichia coli/genetics ; Escherichia coli/metabolism ; Escherichia coli Proteins/genetics ; Escherichia coli Proteins/metabolism ; Ion Channels/metabolism ; Lipid Bilayers/chemistry ; Lipid Bilayers/metabolism ; Mechanotransduction, Cellular ; Molecular Dynamics Simulation
Chemical Substances	Escherichia coli Proteins ; Ion Channels ; Lipid Bilayers ; MscS protein, E coli
Language	English
Publishing date	2023-01-30
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.81445
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Mechanism of C-type inactivation in the hERG potassium channel.

Li, Jing / Shen, Rong / Reddy, Bharat / Perozo, Eduardo / Roux, Benoît

Science advances

2021 Volume 7, Issue 5

Abstract: The fast C-type inactivation displayed by the voltage-activated potassium channel hERG plays a critical role in the repolarization of cardiac cells, and malfunction caused by nonspecific binding of drugs or naturally occurring missense mutations ... ...

Abstract	The fast C-type inactivation displayed by the voltage-activated potassium channel hERG plays a critical role in the repolarization of cardiac cells, and malfunction caused by nonspecific binding of drugs or naturally occurring missense mutations affecting inactivation can lead to pathologies. Because of its impact on human health, understanding the molecular mechanism of C-type inactivation in hERG represents an advance of paramount importance. Here, long-time scale molecular dynamics simulations, free energy landscape calculations, and electrophysiological experiments are combined to address the structural and functional impacts of several disease-associated mutations. Results suggest that C-type inactivation in hERG is associated with an asymmetrical constricted-like conformation of the selectivity filter, identifying F627 side-chain rotation and the hydrogen bond between Y616 and N629 as key determinants. Comparison of hERG with other K
Language	English
Publishing date	2021-01-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.abd6203
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Article ; Online: State-specific morphological deformations of the lipid bilayer explain mechanosensitive gating of MscS ion channels

Yein Christina Park / Bharat Reddy / Navid Bavi / Eduardo Perozo / José D Faraldo-Gómez

eLife, Vol

2023 Volume 12

Abstract	The force-from-lipids hypothesis of cellular mechanosensation posits that membrane channels open and close in response to changes in the physical state of the lipid bilayer, induced for example by lateral tension. Here, we investigate the molecular basis for this transduction mechanism by studying the mechanosensitive ion channel MscS from Escherichia coli and its eukaryotic homolog MSL1 from Arabidopsis thaliana. First, we use single-particle cryo-electron microscopy to determine the structure of a novel open conformation of wild-type MscS, stabilized in a thinned lipid nanodisc. Compared with the closed state, the structure shows a reconfiguration of helices TM1, TM2, and TM3a, and widening of the central pore. Based on these structures, we examined how the morphology of the membrane is altered upon gating, using molecular dynamics simulations. The simulations reveal that closed-state MscS causes drastic protrusions in the inner leaflet of the lipid bilayer, both in the absence and presence of lateral tension, and for different lipid compositions. These deformations arise to provide adequate solvation to hydrophobic crevices under the TM1-TM2 hairpin, and clearly reflect a high-energy conformation for the membrane, particularly under tension. Strikingly, these protrusions are largely eradicated upon channel opening. An analogous computational study of open and closed MSL1 recapitulates these findings. The gating equilibrium of MscS channels thus appears to be dictated by opposing conformational preferences, namely those of the lipid membrane and of the protein structure. We propose a membrane deformation model of mechanosensation, which posits that tension shifts the gating equilibrium towards the conductive state not because it alters the mode in which channel and lipids interact, but because it increases the energetic cost of the morphological perturbations in the membrane required by the closed state.
Keywords	mechanosensation ; ion channels ; membrane morphology ; molecular dynamics simulation ; cryo-electron microscopy ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	612
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Folding of prestin’s anion-binding site and the mechanism of outer hair cell electromotility

Xiaoxuan Lin / Patrick R Haller / Navid Bavi / Nabil Faruk / Eduardo Perozo / Tobin R Sosnick

eLife, Vol

2023 Volume 12

Abstract	Prestin responds to transmembrane voltage fluctuations by changing its cross-sectional area, a process underlying the electromotility of outer hair cells and cochlear amplification. Prestin belongs to the SLC26 family of anion transporters yet is the only member capable of displaying electromotility. Prestin’s voltage-dependent conformational changes are driven by the putative displacement of residue R399 and a set of sparse charged residues within the transmembrane domain, following the binding of a Cl− anion at a conserved binding site formed by the amino termini of the TM3 and TM10 helices. However, a major conundrum arises as to how an anion that binds in proximity to a positive charge (R399), can promote the voltage sensitivity of prestin. Using hydrogen–deuterium exchange mass spectrometry, we find that prestin displays an unstable anion-binding site, where folding of the amino termini of TM3 and TM10 is coupled to Cl− binding. This event shortens the TM3–TM10 electrostatic gap, thereby connecting the two helices, resulting in reduced cross-sectional area. These folding events upon anion binding are absent in SLC26A9, a non-electromotile transporter closely related to prestin. Dynamics of prestin embedded in a lipid bilayer closely match that in detergent micelle, except for a destabilized lipid-facing helix TM6 that is critical to prestin’s mechanical expansion. We observe helix fraying at prestin’s anion-binding site but cooperative unfolding of multiple lipid-facing helices, features that may promote prestin’s fast electromechanical rearrangements. These results highlight a novel role of the folding equilibrium of the anion-binding site, and help define prestin’s unique voltage-sensing mechanism and electromotility.
Keywords	mass spectrometry ; hydrogen exchange ; cochlear amplification ; protein folding ; voltage sensing ; cryo-electron microscopy ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	500
Language	English
Publishing date	2023-12-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Molecular determinants of inhibition of the human proton channel hHv1 by the designer peptide C6 and a bivalent derivative.

Zhao, Ruiming / Shen, Rong / Dai, Hui / Perozo, Eduardo / Goldstein, Steve A N

Proceedings of the National Academy of Sciences of the United States of America

2022 Volume 119, Issue 23, Page(s) e2120750119

Abstract: The human voltage-gated proton channel (hHv1) is important for control of intracellular pH. We designed C6, a specific peptide inhibitor of hHv1, to evaluate the roles of the channel in sperm capacitation and in the inflammatory immune response of ... ...

Abstract	The human voltage-gated proton channel (hHv1) is important for control of intracellular pH. We designed C6, a specific peptide inhibitor of hHv1, to evaluate the roles of the channel in sperm capacitation and in the inflammatory immune response of neutrophils [R. Zhao et al., Proc. Natl. Acad. Sci. U.S.A. 115, E11847–E11856 (2018)]. One C6 binds with nanomolar affinity to each of the two S3–S4 voltage-sensor loops in hHv1 in cooperative fashion so that C6-bound channels require greater depolarization to open and do so more slowly. As depolarization drives hHv1 sensors outwardly, C6 affinity decreases, and inhibition is partial. Here, we identified residues essential to C6–hHv1 binding by scanning mutagenesis, five in the hHv1 S3–S4 loops and seven on C6. A structural model of the C6–hHv1 complex was then generated by molecular dynamics simulations and validated by mutant-cycle analysis. Guided by this model, we created a bivalent C6 peptide (C62) that binds simultaneously to both hHv1 subunits and fully inhibits current with picomolar affinity. The results help delineate the structural basis for C6 state-dependent inhibition, support an anionic lipid-mediated binding mechanism, and offer molecular insight into the effectiveness of engineered C6 as a therapeutic agent or lead.
MeSH term(s)	Drug Design ; Humans ; Ion Channels/antagonists & inhibitors ; Ion Channels/chemistry ; Ion Channels/genetics ; Male ; Mutagenesis ; Peptides/chemistry ; Peptides/pharmacology ; Protein Binding ; Protons ; Sperm Capacitation
Chemical Substances	HVCN1 protein, human ; Ion Channels ; Peptides ; Protons
Language	English
Publishing date	2022-06-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2120750119
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Article ; Online: Real time dynamics of Gating-Related conformational changes in CorA.

Rangl, Martina / Schmandt, Nicolaus / Perozo, Eduardo / Scheuring, Simon

eLife

2019 Volume 8

Abstract: CorA, a divalent-selective channel in the metal ion transport superfamily, is the major ... ...

Abstract	CorA, a divalent-selective channel in the metal ion transport superfamily, is the major Mg
MeSH term(s)	Animals ; Bacterial Proteins/chemistry ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Cation Transport Proteins/chemistry ; Cation Transport Proteins/genetics ; Cation Transport Proteins/metabolism ; Crystallography, X-Ray ; Female ; Ion Channel Gating/genetics ; Ion Channel Gating/physiology ; Ion Transport ; Magnesium/metabolism ; Microscopy, Atomic Force ; Molecular Dynamics Simulation ; Oocytes/metabolism ; Oocytes/physiology ; Protein Conformation ; Thermotoga maritima/genetics ; Thermotoga maritima/metabolism ; Xenopus laevis
Chemical Substances	Bacterial Proteins ; Cation Transport Proteins ; Magnesium (I38ZP9992A)
Language	English
Publishing date	2019-11-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.47322
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