Examining Cooperative Gating Phenomena in Voltage-Dependent Potassium Channels

Yifrach, Ofer; Zandany, Nitzan; Shem-Ad, Tzilhav

doi:10.1016/s0076-6879(09)66008-0

Cited by 15 publications

(18 citation statements)

References 39 publications

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“…The majority of the pH 0.5 > 6.8 residues are nontitratable and must therefore have an indirect effect on pH gating. In any protein structure the most likely effect of a mutation is to destabilize that particular structure (Yifrach et al., 2009). Consequently, the biased effect of these mutations suggests that their disruptive effect is far greater on the open state than on the closed state.…”

Section: Resultsmentioning

confidence: 99%

State-Dependent Network Connectivity Determines Gating in a K+ Channel

et al. 2014

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SummaryX-ray crystallography has provided tremendous insight into the different structural states of membrane proteins and, in particular, of ion channels. However, the molecular forces that determine the thermodynamic stability of a particular state are poorly understood. Here we analyze the different X-ray structures of an inwardly rectifying potassium channel (Kir1.1) in relation to functional data we obtained for over 190 mutants in Kir1.1. This mutagenic perturbation analysis uncovered an extensive, state-dependent network of physically interacting residues that stabilizes the pre-open and open states of the channel, but fragments upon channel closure. We demonstrate that this gating network is an important structural determinant of the thermodynamic stability of these different gating states and determines the impact of individual mutations on channel function. These results have important implications for our understanding of not only K+ channel gating but also the more general nature of conformational transitions that occur in other allosteric proteins.

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Section: Resultsmentioning

confidence: 99%

State-Dependent Network Connectivity Determines Gating in a K+ Channel

et al. 2014

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“…Furthermore, state-dependency of such interactions is the hallmark of structural rearrangements that occur during the thermodynamic transition studied. In the present study, upper interface residue gating sensitivity and state-dependent interactions were assessed by combining electrophysiology recordings of wild type and upper interface mutants of the archetypal Shaker - IR Kv channel, introduced in the context of a tandem-dimer channel construct [15], followed by high-dimensional double-mutant cycle thermodynamic coupling analysis [16]–[18]. Our results reveal that the upper domain interface undergoes moderate structural rearrangements during activation gating but not during the subsequent slow inactivation gating transition.…”

Section: Introductionmentioning

confidence: 99%

Inter-Subunit Interactions across the Upper Voltage Sensing-Pore Domain Interface Contribute to the Concerted Pore Opening Transition of Kv Channels

2013

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The tight electro-mechanical coupling between the voltage-sensing and pore domains of Kv channels lies at the heart of their fundamental roles in electrical signaling. Structural data have identified two voltage sensor pore inter-domain interaction surfaces, thus providing a framework to explain the molecular basis for the tight coupling of these domains. While the contribution of the intra-subunit lower domain interface to the electro-mechanical coupling that underlies channel opening is relatively well understood, the contribution of the inter-subunit upper interface to channel gating is not yet clear. Relying on energy perturbation and thermodynamic coupling analyses of tandem-dimeric Shaker Kv channels, we show that mutation of upper interface residues from both sides of the voltage sensor-pore domain interface stabilizes the closed channel state. These mutations, however, do not affect slow inactivation gating. We, moreover, find that upper interface residues form a network of state-dependent interactions that stabilize the open channel state. Finally, we note that the observed residue interaction network does not change during slow inactivation gating. The upper voltage sensing-pore interaction surface thus only undergoes conformational rearrangements during channel activation gating. We suggest that inter-subunit interactions across the upper domain interface mediate allosteric communication between channel subunits that contributes to the concerted nature of the late pore opening transition of Kv channels.

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confidence: 99%

“…3 Insight into the general principles underlying information transduction along allosteric communication trajectories has been recently gained 5,6 using the prototypical Shaker voltage-activated potassium (Kv) channel model allosteric protein. [7][8][9] Kv channels are pore-forming membrane proteins that control the flow of potassium ions across the membranes of excitable cells and are thus involved in shaping nerve and muscle action potentials. 10 The flow of K + ions through the Kv channel pore is regulated by two distant gates, namely, the activation and the slow (C-type) inactivation gates located at the lower and upper parts of the channel ion conducting pathway, respectively.…”

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confidence: 99%

“…Using doublemutant cycle coupling analysis, 14,15 we found residues spanning the Kv channel allosteric trajectory to be energetically coupled even over long distances (up to 18 Å), 5 where pairwise coupling is typically not expected to prevail. 16 High-dimensional mutant cycle coupling analysis, 9,15 addressing the context dependence of pairwise interactions along the allosteric pathway, revealed the highly synergistic nature of interactions involving two, three, and four trajectory-lining residues. 6 All such residues were found to be interconnected and to assume a hierarchy of cooperative residue interactions of increasing magnitude, thus providing an explanation for the unusual strong couplings observed among residues lying distantly apart.…”

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