Deletion of cytosolic gating ring decreases gate and voltage sensor coupling in BK channels

Zhang, Guohui; Geng, Yanyan; Jin, Yakang; Shi, Jingyi; McFarland, Kelli; Magleby, Karl L.; Salkoff, Lawrence; Cui, Jianmin

doi:10.1085/jgp.201611646

Cited by 27 publications

(52 citation statements)

References 68 publications

(144 reference statements)

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“…Therefore, a rigid body titling of the RCK1 N-lobe may directly or indirectly drive a movement of S6 for channel opening in response to Ca 2+ binding to the RCK1 or the RCK2 while the movement of S4 helices in VSD can in turn exert an effect on the gating ring and the apparent Ca 2+ binding affinity 52–53 . Recent electrophysiological measurements also support the notion that the Ca 2+ -sensitive gating ring facilitates the effective coupling between the VSD and the PD 55 .…”

Section: Slo1 Bkca Channelmentioning

confidence: 61%

“…Recent structural models of the Slo1 BK Ca channels showed that a conserved motif 365 H X DR 368 is 8 Å distant from the former Fe 2+ -binding motif and 4.5 Å away from R514/E902/Y904 near the Ca 2+ RCK1 site while a conserved motif 907 Q XXX C 911 is 6 Å distant from the latter Fe 2+ -binding motif and 3.5 Å away from the Ca 2+ bowl 54–55, 67–68 . Thus, two Fe 2+ can be sandwiched by F391 and H394 via cation-π interactions to form the first putative binuclear Fe 2+ bowl to which H365/D367 or CO or CN − can bind regulating channel gating via the non-swapping interactions of R514 with E902 and Y904 (Figure 4).…”

Section: Slo1 Bkca Channelmentioning

confidence: 99%

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Mechanistic insight into the heme-independent interplay between iron and carbon monoxide in CFTR and Slo1 BK_Ca channels

Wang

2017

Metallomics

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Ion channels have been extensively reported as an effector of carbon monoxide (CO). However, the mechanisms of heme-independent CO action are still missing. Because most of ion channels are heterologously expressed on human embryonic kidney cells which are cultured in Fe3+-containing media, CO may act as a small and strong iron chelator to disrupt a putative iron bridge in ion channels and thus to tune their activity. In this review CFTR and Slo1 BKCa channels are employed to discuss the possible heme-independent interplay between iron and CO. Our recent studies demonstrated a high-affinity Fe3+ site at the interface between the regulatory domain and intracellular loop 3 of CFTR. Because the binding of Fe3+ to CFTR prevents channel opening, the stimulatory effect of CO on the Cl− and HCO3− currents across the apical membrane of rat distal colon may be due to the release of inhibitive Fe3+ by CO. In contrast, CO repeatedly stimulates the human Slo1 BKCa channel opening possibly by binding to an unknown iron site because cyanide prohibits this heme-independent CO stimulation. Here, in silico research on recent structural data of the slo1 BKCa channels indicates two putative binuclear Fe2+-binding motifs in the gating ring in which CO may compete with protein residues to bind to either Fe2+ bowl to disrupt the Fe2+ bridge but not to release Fe2+ from the channel. Thus, these two new regulation models of CO, iron releasing from and retaining in the ion channel, may have significant and extensive implications for other metalloproteins.

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Section: Slo1 Bkca Channelmentioning

confidence: 61%

Section: Slo1 Bkca Channelmentioning

confidence: 99%

Mechanistic insight into the heme-independent interplay between iron and carbon monoxide in CFTR and Slo1 BK_Ca channels

Wang

2017

Metallomics

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“…Left shift of G-V (V0.5 Table 1: C-linker scrambling mutations and measured V0.5 in the full-length and Core-MT BK channels at [Ca 2+ ] = 0 and [Mg 2+ ] = 0. The Core-MT constructs are based on the TMD, C-linker of mSlo1, and an 11-residue tail from KV 1.4 of the mouse Shaker family (19,20). The location of the nearest Tyr to the S6 C-terminal is highlighted in green.…”

Section: Sequence Scrambling Of the C-linker Dramatically Modulates Bmentioning

confidence: 99%

Nonspecific membrane interactions can modulate BK channel activation

Yazdani

Zhang

Jia

et al. 2020

Preprint

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One-sentence summary: The covalent linker between BK intracellular and transmembrane domains is likely a part of the sensing apparatus that regulates the channel activation. # Equal contributions * Corresponding Authors: Jianmin Cui: Phone: (314) 935-8896; AbstractLarge-conductance potassium (BK) channels are transmembrane (TM) proteins that can be synergistically and independently activated by membrane voltage and intracellular Ca 2+ . The only covalent connection between the cytosolic Ca 2+ sensing domain and the TM pore and voltage sensing domains is a 15-residue "C-linker". To determine the linker's role in BK activation, we designed a series of linker sequence scrambling mutants to suppress potential complex interplay of specific interactions with the rest of the protein. The results revealed a surprising sensitivity of BK activation to the linker sequence. Combing atomistic simulations and further mutagenesis experiments, we demonstrated that nonspecific interactions of the linker with membrane alone could directly modulate BK activation. The C-linker thus plays more direct roles in mediating allosteric coupling between BK domains than previously assumed. Our results also suggest that covalent linkers could directly modulate TM protein function and should be considered an integral component of the sensing apparatus.Widely distributed in nerve and muscle cells, large-conductance potassium (BK) channels are characterized by a large single-channel conductance (~ 100 -300 pS) (1-5) and dual activation by both intracellular Ca 2+ and membrane voltage (6-8), thus an ideal model system for understanding the gating and sensor-pore coupling in ion channels. BK channels are involved in numerous vital physiological processes including intracellular ion homeostasis and membrane excitation, and are associated with pathogenesis of many diseases such as epilepsy, stroke, autism and hypertension (9). Functional BK channels are homo-tetramers, each containing three distinct domains (Figure 1a). The voltage sensor domain (VSD) detects membrane potential, the pore-gate domain (PGD) controls the K + selectivity and permeation, and the cytosolic tail domain (CTD) senses various intracellular ligands including Ca 2+ . The VSD and the CTD also form a Mg 2+ binding site for Mg 2+ dependent activation (Yang 2008 NSMB). The tetrameric assembly of CTD domains is also referred to as the "gating ring". VSD and PGD together form the trans-membrane domain (TMD) of BK channels. Previous studies on mouse BK channels (10) and recent atomistic structures of full-length Aplysia californica BK channel (aSlo1) (11, 12) reveal that CTD of each subunit reside beneath the TMD of the neighboring subunit in a surprising domain-swapped arrangement ( Figure S1a).The only covalent connection between CTD and TMD of BK channels is a 15-residue peptide referred to as the "C-linker" (R329 to K343 in the human BK channel, hSlo1) (green in Figure 1a).This linker directly connects the pore lining S6 helices in the PGD (yellow in Figure S1b) to the Nterminus...

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“…45The voltage dependence of Ca 2+ -dependent gating ring rearrangements (Miranda et al, 46 2013(Miranda et al, 46 , 2018 and RCK1 site occupancy (Sweet and Cox, 2008; Savalli et al, 2012; Miranda 47 et al, 2018) as well as the perturbation of VSD movements by Ca 2+ binding (Savalli et al, 48 2012) support the idea that the energetic interaction between both specialized sensors 49 may be crucial to favor BK channel activation. The physical CTD-VSD interface has been 50 suggested to provide the structure capable of mediating the crosstalk between these 51 sensory modules and their synergy in activating the pore domain (Yang et al, 2007; Sun 52 et al, 2013; Tao et al, 2017;Zhang et al, 2017). However, the strength of the interaction 53 between voltage and Ca 2+ sensors and their relevance to BK channel activation is still an 54 unresolved matter (Horrigan and Aldrich, 2002; Carrasquel-Ursulaez et al, 2015).…”

mentioning

confidence: 99%

Calcium-driven regulation of voltage-sensing domains in BK channels

Latorre

Lorenzo-Ceballos

Carrasquel-Ursulaez

et al. 2019

Preprint

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1Allosteric interplays between voltage-sensing domains (VSD), Ca 2+ -binding sites, and the 2 pore domain govern the Ca 2+ -and voltage-activated K + (BK) channel opening. However, 3 the functional relevance of the Ca 2+ -and voltage-sensing mechanisms crosstalk on BK 4 channel gating is still debated. We examined the energetic interaction between Ca 2+ 5 binding and VSD activation measuring and analyzing the effects of internal Ca 2+ on BK 6 channels gating currents. Our results indicate that the Ca 2+ sensors occupancy has a 7 strong impact on the VSD activation through a coordinated interaction mechanism in which 8Ca 2+ binding to a single α-subunit affects all VSDs equally. Moreover, the two distinct high-9affinity Ca 2+ -binding sites contained in the C-terminus domains, RCK1 and RCK2, appear 10 to contribute equally to decrease the free energy necessary to activate the VSD. We 11 conclude that voltage-dependent gating and pore opening in BK channels is modulated to 12 a great extent by the interaction between Ca 2+ sensors and VSDs. 13 BK channels at physiologically relevant voltages necessarily involves the activation of Ca 2+ 39 sensors on the gating ring. The allosteric interplays established between the functional 40 and structural modules (VSD-PD, CTD-PD, and CTD-VSD) are key in enabling BK 41 channels to operate over a dynamic wide-range of internal Ca 2+ and voltage conditions by 42 fine-tuning the channel's gating machinery. Therefore, understanding the structure-43 functional bases that underlie the Ca 2+ and voltage activation mechanisms 44 interrelationship becomes essential. 45The voltage dependence of Ca 2+ -dependent gating ring rearrangements (Miranda et al., 46 2013(Miranda et al., 46 , 2018 and RCK1 site occupancy (Sweet and Cox, 2008; Savalli et al., 2012; Miranda 47 et al., 2018) as well as the perturbation of VSD movements by Ca 2+ binding (Savalli et al., 48 2012) support the idea that the energetic interaction between both specialized sensors 49 may be crucial to favor BK channel activation. The physical CTD-VSD interface has been 50 suggested to provide the structure capable of mediating the crosstalk between these 51 sensory modules and their synergy in activating the pore domain (Yang et al., 2007; Sun 52 et al., 2013; Tao et al., 2017;Zhang et al., 2017). However, the strength of the interaction 53 between voltage and Ca 2+ sensors and their relevance to BK channel activation is still an 54 unresolved matter (Horrigan and Aldrich, 2002; Carrasquel-Ursulaez et al., 2015). Also, 55 the functional role that plays each of the high-affinity Ca 2+ -binding sites on the CTD-VSD 56 allosteric interaction is an open question. The RCK1 and RCK2 Ca 2+ -binding sites have 57 distinct functional properties conferred by their different molecular structures and relative 58 positions within the gating ring (Wu et al., Miranda et al., 2018) and in their 63 5 contribution to allosteric gating mechanism (Yang et al., , 2015. In particular, only 64 the RCK1 site appears to be invol...

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Deletion of cytosolic gating ring decreases gate and voltage sensor coupling in BK channels

Cited by 27 publications

References 68 publications

Mechanistic insight into the heme-independent interplay between iron and carbon monoxide in CFTR and Slo1 BK_Ca channels

Mechanistic insight into the heme-independent interplay between iron and carbon monoxide in CFTR and Slo1 BK_Ca channels

Nonspecific membrane interactions can modulate BK channel activation

Calcium-driven regulation of voltage-sensing domains in BK channels

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Deletion of cytosolic gating ring decreases gate and voltage sensor coupling in BK channels

Cited by 27 publications

References 68 publications

Mechanistic insight into the heme-independent interplay between iron and carbon monoxide in CFTR and Slo1 BKCa channels

Mechanistic insight into the heme-independent interplay between iron and carbon monoxide in CFTR and Slo1 BKCa channels

Nonspecific membrane interactions can modulate BK channel activation

Calcium-driven regulation of voltage-sensing domains in BK channels

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Product

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Mechanistic insight into the heme-independent interplay between iron and carbon monoxide in CFTR and Slo1 BK_Ca channels

Mechanistic insight into the heme-independent interplay between iron and carbon monoxide in CFTR and Slo1 BK_Ca channels