Regulatory role of the extreme C‐terminal end of the S6 inner helix in C‐terminal‐truncated Kv1.2 channel activation

Zhao, Lili; Qi, Zhi T; Zhang, Xian‐En; Bi, Lijun; Jin, Gang

doi:10.1042/cbi20090009

Cited by 10 publications

(12 citation statements)

References 32 publications

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“…This finding highlights that trafficking motifs may not be universal and their importance must be tested for each channel/expression system combination. A similar conclusion can be drawn for the role of the HRET sequence in regulating channel conductance 12 , 49 : in case of Kv1.3 even an alanine substitution of the HRETE sequence restored channel function. Based on this and other recent papers the presence of the C-terminal amino acids adjacent to the activation gate in Kv1.3 are important for maintaining ion conductance, whereas distant C-terminal amino acids govern interactions with other proteins or confer cholesterol sensitivity to the Kv1.3 50 .…”

Section: Discussionsupporting

confidence: 70%

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The C-terminal HRET sequence of Kv1.3 regulates gating rather than targeting of Kv1.3 to the plasma membrane

Vörös

Szilágyi

Balajthy

et al. 2018

Sci Rep

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Kv1.3 channels are expressed in several cell types including immune cells, such as T lymphocytes. The targeting of Kv1.3 to the plasma membrane is essential for T cell clonal expansion and assumed to be guided by the C-terminus of the channel. Using two point mutants of Kv1.3 with remarkably different features compared to the wild-type Kv1.3 (A413V and H399K having fast inactivation kinetics and tetraethylammonium-insensitivity, respectively) we showed that both Kv1.3 channel variants target to the membrane when the C-terminus was truncated right after the conserved HRET sequence and produce currents identical to those with a full-length C-terminus. The truncation before the HRET sequence (NOHRET channels) resulted in reduced membrane-targeting but non-functional phenotypes. NOHRET channels did not display gating currents, and coexpression with wild-type Kv1.3 did not rescue the NOHRET-A413V phenotype, no heteromeric current was observed. Interestingly, mutants of wild-type Kv1.3 lacking HRET(E) (deletion) or substituted with five alanines for the HRET(E) motif expressed current indistinguishable from the wild-type. These results demonstrate that the C-terminal region of Kv1.3 immediately proximal to the S6 helix is required for the activation gating and conduction, whereas the presence of the distal region of the C-terminus is not exclusively required for trafficking of Kv1.3 to the plasma membrane.

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Section: Discussionsupporting

confidence: 70%

“…The HRET(E) is sequence is located in the part of the C-terminal that is proximal to the activation gate or may be part of it 49 . Thus, mutation in this region may profoundly alter activation gating of the channels, the coupling of the voltage-sensor movement to the activation gate or both while leaving the voltage-sensor movement intact.…”

Section: Discussionmentioning

confidence: 99%

The C-terminal HRET sequence of Kv1.3 regulates gating rather than targeting of Kv1.3 to the plasma membrane

Vörös

Szilágyi

Balajthy

et al. 2018

Sci Rep

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“…We note that near the gate there is a histidine (H418 in the 3Lut numbering) on the C terminal end of the pore helix S6, which could affect gating if charged. If this histidine is deleted, the channel stops functioning [ 142 ].…”

Section: Gating Model From the Computationmentioning

confidence: 99%

The Role of Proton Transport in Gating Current in a Voltage Gated Ion Channel, as Shown by Quantum Calculations

Kariev

Green

2018

Sensors

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Over two-thirds of a century ago, Hodgkin and Huxley proposed the existence of voltage gated ion channels (VGICs) to carry Na+ and K+ ions across the cell membrane to create the nerve impulse, in response to depolarization of the membrane. The channels have multiple physiological roles, and play a central role in a wide variety of diseases when they malfunction. The first channel structure was found by MacKinnon and coworkers in 1998. Subsequently, the structure of a number of VGICs was determined in the open (ion conducting) state. This type of channel consists of four voltage sensing domains (VSDs), each formed from four transmembrane (TM) segments, plus a pore domain through which ions move. Understanding the gating mechanism (how the channel opens and closes) requires structures. One TM segment (S4) has an arginine in every third position, with one such segment per domain. It is usually assumed that these arginines are all ionized, and in the resting state are held toward the intracellular side of the membrane by voltage across the membrane. They are assumed to move outward (extracellular direction) when released by depolarization of this voltage, producing a capacitive gating current and opening the channel. We suggest alternate interpretations of the evidence that led to these models. Measured gating current is the total charge displacement of all atoms in the VSD; we propose that the prime, but not sole, contributor is proton motion, not displacement of the charges on the arginines of S4. It is known that the VSD can conduct protons. Quantum calculations on the Kv1.2 potassium channel VSD show how; the key is the amphoteric nature of the arginine side chain, which allows it to transfer a proton. This appears to be the first time the arginine side chain has had its amphoteric character considered. We have calculated one such proton transfer in detail: this proton starts from a tyrosine that can ionize, transferring to the NE of the third arginine on S4; that arginine’s NH then transfers a proton to a glutamate. The backbone remains static. A mutation predicted to affect the proton transfer has been qualitatively confirmed experimentally, from the change in the gating current-voltage curve. The total charge displacement in going from a normal closed potential of −70 mV across the membrane to 0 mV (open), is calculated to be approximately consistent with measured values, although the error limits on the calculation require caution in interpretation.

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“…Although the primary emphasis of this work concerns the relation of water structure to conduction, it also brings implications for gating. In earlier work ( 9) we showed that a residue below the gate, H418, when protonated, rotated toward the gate, with the histidine side-chain moving up almost 3 Å ; we summarized arguments for the importance of protonation, which changes both the potential at the gate and (not yet calculated, but very probably) the arrangement of water all the way from that residue to the gate (a D418 mutant does not function as a channel (36), so it appears that H418 must be important in structuring the channel to allow conduction). From the previous calculation, protonation of H418, and possibly two neighboring glutamates, should close the channel.…”

Section: Implications For Gatingmentioning

confidence: 89%

The Open Gate of the KV1.2 Channel: Quantum Calculations Show the Key Role of Hydration

Kariev

Njau

Green

2014

Biophysical Journal

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The open gate of the Kv1.2 voltage-gated potassium channel can just hold a hydrated K(+) ion. Quantum calculations starting from the x-ray coordinates of the channel confirm this, showing little change from the x-ray coordinates for the protein. Water molecules not in the x-ray coordinates, and the ion itself, are placed by the calculation. The water molecules, including their orientation and hydrogen bonding, with and without an ion, are critical for the path of the ion, from the solution to the gate. A sequence of steps is postulated in which the potential experienced by the ion in the pore is influenced by the position of the ion. The gate structure, with and without the ion, has been optimized. The charges on the atoms and bond lengths have been calculated using natural bond orbital calculations, giving K(+) ~0.77 charges, rather than 1.0. The PVPV hinge sequence has been mutated in silico to PVVV (P407V in the 2A79 numbering). The water structure around the ion becomes discontinuous, separated into two sections, above and below the ion. PVPV conservation closely relates to maintaining the water structure. Finally, these results have implications concerning gating.

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Regulatory role of the extreme C‐terminal end of the S6 inner helix in C‐terminal‐truncated Kv1.2 channel activation

Cited by 10 publications

References 32 publications

The C-terminal HRET sequence of Kv1.3 regulates gating rather than targeting of Kv1.3 to the plasma membrane

The C-terminal HRET sequence of Kv1.3 regulates gating rather than targeting of Kv1.3 to the plasma membrane

The Role of Proton Transport in Gating Current in a Voltage Gated Ion Channel, as Shown by Quantum Calculations

The Open Gate of the KV1.2 Channel: Quantum Calculations Show the Key Role of Hydration

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