The open pore conformation of potassium channels

Jiang, Youxing; Lee, Alice; Chen, Jiayun; Cadène, Martine; Chait, Brian T.; MacKinnon, Roderick

doi:10.1038/417523a

Cited by 1,145 publications

(1,156 citation statements)

References 30 publications

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“…This "imperfection" in a helix would be consistent with the fact that TMD8 has one of the longest (≥20-residue) hydrophobic stretches in PS1, and more importantly, that TMD8 has a completely conserved Gly417 residue in a middle of its sequence. Glycine is known to be a transmembrane helix breaker or a hinge, as has been shown in the structure of Shaker potassium channel (46). Overall, our observations provide biochemical evidence for more detailed structural information about the catalytic component of γ-secretase.…”

Section: Discussionsupporting

confidence: 69%

Deducing the Transmembrane Domain Organization of Presenilin-1 in γ-Secretase by Cysteine Disulfide Cross-Linking

et al. 2006

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Abstractγ-Secretase is a founding member of membrane-embedded aspartyl proteases that cleave substrates within transmembrane domains, and this enzyme is an important target for the development of therapeutics for Alzheimer's disease. The structure of γ-secretase and its precise catalytic mechanism still remain largely unknown. γ-Secretase is a complex of four integral membrane proteins, with presenilin (PS) as the catalytic component. To gain structural and functional information about the 9-transmembrane domain (TMD) presenilin, we employed a cysteine mutagenesis/disulfidecrosslinking approach. Here we report that native Cys92 is close to both Cys410 and Cys419, strongly implying that TMD1 and TMD8 are adjacent to each other. This structural arrangement also suggests that TMD8 is distorted from an ideal helix. Importantly, binding of an active-site directed inhibitor, but not a docking-site directed inhibitor, reduces the ability of the native cysteine pairs of PS1 to crosslink upon oxidation. These findings suggest that the conserved cysteines of TMD1 and TMD8 contribute to or allosterically interact with the active site of γ-secretase.Accumulation of the amyloid β-protein (Aβ) is one of the defining pathological features of Alzheimer's disease. Aβ is produced from the amyloid β-protein precursor (APP) as a result of sequential proteolytic cleavages first by β-secretase (1) and then by γ-secretase (2). γ-Secretase is an aspartyl transmembrane protease that cleaves a number of type I membrane protein substrates, including APP and Notch, in the middle of their transmembrane domains in a poorly understood process of hydrolysis within a hydrophobic environment (3). γ-Secretase is composed of four transmembrane proteins, Aph-1, Pen-2, Nicastrin (NCT) (4-10) and presenilin (PS), which is ostensibly the catalytic component of an unusual aspartyl protease (3,11,12). Despite substantial progress in establishing the full identity of γ-secretase (7-9,13, 14) and the step-wise assembly of the γ-secretase complex (7,15,16), the molecular structure of the protease complex or even any of its individual components remains unknown. PS, as the catalytic component, is of major interest, but only some indirect evidence about its structural arrangement has been reported to date. Indeed, it has only very recently been established that PS1 is a 9-TMD protein (17,18). PS is endoproteolytically processed into an N-terminal fragment (NTF) and C-terminal fragment (CTF) (19). These fragments are metabolically stable, remain associated, and their formation is tightly regulated (20). Also, it is widely † This work was supported by grants to M.S.W. from the National Institutes of Health (NS41355 and AG17574) and the Alzheimer's Association (IIRG-02-4047) and a fellowship to H. L. (Wenner-Gren Foundation in Sweden). An understanding of the mechanism of γ-secretase proteolysis requires a detailed description of the three-dimensional organization of its transmembrane domains. In light of inherent difficulties in obtaining a structure of γ-secr...

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Section: Discussionsupporting

confidence: 69%

Deducing the Transmembrane Domain Organization of Presenilin-1 in γ-Secretase by Cysteine Disulfide Cross-Linking

et al. 2006

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“…Gating properties K ATP channels exhibit fast and long interburst closing kinetics [41][42][43] . The fast gating kinetics of the channels is determined by an intrinsic structure within the pore-loop that is near the selectivity filter of the Kir6.2 subunit [41,44] .…”

Section: Introductionmentioning

confidence: 99%

“…The fast gating kinetics of the channels is determined by an intrinsic structure within the pore-loop that is near the selectivity filter of the Kir6.2 subunit [41,44] . The long last interburst closing kinetics requires ATP binding to the TM2 helices [42,45] . The conformational modeling describes one open and multiple closed states of the channel [36,43] .…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective role of ATP-sensitive potassium channels in cerebral ischemia

Sun

Feng

2012

Acta Pharmacol Sin

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ATP-sensitive potassium (K ATP ) channels are weak, inward rectifiers that couple metabolic status to cell membrane electrical activity, thus modulating many cellular functions. An increase in the ADP/ATP ratio opens K ATP channels, leading to membrane hyperpolarization. K ATP channels are ubiquitously expressed in neurons located in different regions of the brain, including the hippocampus and cortex. Brief hypoxia triggers membrane hyperpolarization in these central neurons. In vivo animal studies confirmed that knocking out the Kir6.2 subunit of the K ATP channels increases ischemic infarction, and overexpression of the Kir6.2 subunit reduces neuronal injury from ischemic insults. These findings provide the basis for a practical strategy whereby activation of endogenous K ATP channels reduces cellular damage resulting from cerebral ischemic stroke. K ATP channel modulators may prove to be clinically useful as part of a combination therapy for stroke management in the future.

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“…As a result, S6 maintains its secondary structure throughout the entire TRPV1 gating cycle, the same residues are facing the pore in the closed and open states, and pore widening is observed at both the S6 bundle crossing and the selectivity filter 18 . On the other hand, K + channels do have a gating hinge in their pore-forming inner helices 26,27 . However, this hinge is formed by a glycine located one residue C-terminally compared to the gating hinge alanine in TRPV6 and permits bending of the inner helices by ~30° without an α-to-π transition.…”

mentioning

confidence: 99%

Opening of the human epithelial calcium channel TRPV6

McGoldrick

Singh

Saotome

et al. 2017

Nature

191

322

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Ca2+-selective transient receptor potential vanilloid subfamily member 6 (TRPV6) channels play a critical role in calcium uptake in epithelial tissues1–4. Altered TRPV6 expression is associated with a variety of human diseases5, including cancers6. TRPV6 channels are constitutively active1,7,8 and their open probability depends on the lipidic composition of the membrane, increasing significantly in the presence of phosphatidylinositol 4,5-bisphosphate (PIP2)7,9. We previously solved crystal structures of detergent-solubilized rat TRPV6 in the closed state10,11. Corroborating previous electrophysiological studies3, these structures demonstrated that the Ca2+ selectivity of TRPV6 arises from a ring of aspartate side chains in the selectivity filter that tightly binds Ca2+. However, it has remained unknown how TRPV6 channels open and close their pores for ion permeation. Here we present cryo-EM structures of human TRPV6 in the open and closed states. The channel selectivity filter adopts similar conformations in both states, consistent with its explicit role in ion permeation. The iris-like channel opening is accompanied by an α-to-π helical transition in the pore-lining S6 helices at an alanine hinge just below the selectivity filter. As a result of this transition, the S6 helices bend and rotate, exposing different residues to the ion channel pore in the open and closed states. This novel gating mechanism, which defines the constitutive activity of TRPV6, is unique for tetrameric ion channels and provides new structural insights for understanding their diverse roles in physiology and disease.

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The open pore conformation of potassium channels

Cited by 1,145 publications

References 30 publications

Deducing the Transmembrane Domain Organization of Presenilin-1 in γ-Secretase by Cysteine Disulfide Cross-Linking

Deducing the Transmembrane Domain Organization of Presenilin-1 in γ-Secretase by Cysteine Disulfide Cross-Linking

Neuroprotective role of ATP-sensitive potassium channels in cerebral ischemia

Opening of the human epithelial calcium channel TRPV6

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