NMR structure of inactivation gates from mammalian voltage-dependent potassium channels

Antz, C.; Geyer, Matthias; Fakler, Bernd; Schott, Markus; Guy, H. Robert; Frank, Rainer; Ruppersberg, J. P.; Kalbitzer, Hans Robert

doi:10.1038/385272a0

Cited by 102 publications

(78 citation statements)

References 21 publications

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“…Although C 13 xxH 16 is located in the very flexible transition between the N-terminal domain and the helix, H35 is in the center of the helix. This observation is consistent with the study by Antz et al (36), where it was shown that a peptide encompassing the inactivation domain of Kv1.4 possesses a highly flexible disordered N terminus and a well-defined helix. Based on CD measurements and NMR data in aqueous solution, Pep61 is even more flexible and disordered at body temperature (37°C) compared with 10°C, and this flexibility enables the distal end to enter the cavity from the intracellular side.…”

Section: Discussionsupporting

confidence: 82%

Heme impairs the ball-and-chain inactivation of potassium channels

Sahoo

Goradia

Ohlenschläger

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Significance Heme, traditionally viewed as a stable protein cofactor such as in hemoglobin, also serves as an acute signaling molecule and is cytotoxic at high concentrations. Here, we show that free intracellular heme potently enhances A-type potassium channel function. Such channels determine action potential frequency in excitable cells, and their dysfunction often contributes to pathological hyperexcitability, such as in pain and epilepsy. Binding of free heme at nanomolar concentrations to the “ball-and-chain” N terminus of A-type potassium channels, which typically closes the channels, introduces a stable structure in the otherwise disordered region and allows for a greater efflux of potassium ions, thus reducing cellular excitability. Heme therefore could be a powerful negative-feedback regulator in brain and muscle function.

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Section: Discussionsupporting

confidence: 82%

Heme impairs the ball-and-chain inactivation of potassium channels

Sahoo

Goradia

Ohlenschläger

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…4A). This structure is similar to the 37 amino acid piece we reported earlier (18) with the exception that the ␣-helix is extended by 2 turns and bent in its center. The C-terminal domain of Kv1.4N-(1-75) equivalent to the stretch harboring ID2 (20) consists of a 2.5-turn ␣-helix between amino acids 41 and 49 connected to a flexible domain formed by residues 50 -75 (Fig.…”

Section: Methodssupporting

confidence: 63%

Solution Structure and Function of the “Tandem Inactivation Domain” of the Neuronal A-type Potassium Channel Kv1.4

Wissmann

Bildl

Oliver

et al. 2003

Journal of Biological Chemistry

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Cumulative inactivation of voltage-gated (Kv) K؉ channels shapes the presynaptic action potential and determines timing and strength of synaptic transmission. Kv1.4 channels exhibit rapid "ball-and-chain"-type inactivation gating. Different from all other Kv␣ subunits, Kv1.4 harbors two inactivation domains at its N terminus. Here we report the solution structure and function of this "tandem inactivation domain" using NMR spectroscopy and patch clamp recordings. Inactivation domain 1 (ID1, residues 1-38) consists of a flexible N terminus anchored at a 5-turn helix, whereas ID2 (residues 40 -50) is a 2.5-turn helix made up of small hydrophobic amino acids. Functional analysis suggests that only ID1 may work as a pore-occluding ball domain, whereas ID2 most likely acts as a "docking domain" that attaches ID1 to the cytoplasmic face of the channel. Deletion of ID2 slows inactivation considerably and largely impairs cumulative inactivation. Together, the concerted action of ID1 and ID2 may promote rapid inactivation of Kv1.4 that is crucial for the channel function in short term plasticity.

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“…The PEVK region is very likely to be structurally disordered and may function as a rubber-like entropic spring that helps to restore over-stretched muscle cells to their natural, relaxed length. 225 K 226,227,228 The timing of this closure is critical to proper nerve cell function and evidently depends on the length and flexibility of the chain. Here we suggest that this flexiblity be recognized as an entropic clock due to its important function as a timing device.…”

Section: Interesting Functions Associated With Disordermentioning

confidence: 99%

Intrinsically disordered protein

Dunker

Lawson

Brown

et al. 2001

Journal of Molecular Graphics and Modelling

2,101

2,085

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Proteins can exist in a trinity of structures: the ordered state, the molten globule and the random coil. Five examples follow which suggest that native protein structure can correspond to any of the three states (not just the ordered state) and that protein function can arise from any of the three states and their transitions. 1. In a process that likely mimics infection, fd phage converts from the ordered into the disordered molten globular state. 2. Nucleosome hyperacetylation is crucial to DNA replication and transcription; this chemical modification greatly increases the net negative charge of the nucleosome core particle. We propose that the increased charge imbalance promotes its conversion to a much less rigid form. 3. Clusterin contains an ordered domain and also a native molten globular region. The molten globular domain likely functions as a proteinaceous detergent for cell remodeling and removal of apoptotic debris. 4. In a critical signaling event, a helix in calcineurin becomes bound and surrounded by calmodulin, thereby turning on calcineurin's serine/threonine phosphatase activity.Locating the calcineurin helix within a region of disorder is essential for enabling calmodulin to surround its target upon binding. 5. Calsequestrin regulates calcium levels in the sarcoplasmic reticulum by binding about 50 ions/molecule. Disordered polyanion tails at the carboxy terminus bind many of these calcium ions, perhaps without adopting a unique structure. In addition to these examples, 16 more proteins with native disorder will be discussed. These disordered regions include molecular recognition domains, protein folding inhibitors, flexible linkers, entropic springs, entropic clocks and entropic bristles.Motivated by such examples of intrinsic disorder, we are studying the relationships between amino acid sequence and order/disorder, and from this information we are predicting intrinsic order/disorder from amino acid sequence.The sequence/structure relationships indicate that disorder is an encoded property, and the predictions strongly suggest that proteins in nature are much richer in intrinsic disorder than are those in the Protein Data Bank. Recent predictions on 29 genomes indicate that proteins from eucaryotes apparently have more intrinsic disorder than those from either bacteria or archaea, with typically > 30 % of eucaryotic proteins having disordered regions of length = 50 consecutive residues.

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NMR structure of inactivation gates from mammalian voltage-dependent potassium channels

Cited by 102 publications

References 21 publications

Heme impairs the ball-and-chain inactivation of potassium channels

Heme impairs the ball-and-chain inactivation of potassium channels

Solution Structure and Function of the “Tandem Inactivation Domain” of the Neuronal A-type Potassium Channel Kv1.4

Intrinsically disordered protein

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