BME417HW5 - BME 417 HW5 Transporter or Paddle A Debate on Voltage Sensor Models With the elucidation of the voltage-sensitive KvAP channel

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1 BME 417 HW5 Transporter or Paddle: A Debate on Voltage Sensor Models With the elucidation of the voltage-sensitive KvAP channel structure by MacKinnon’s group, we would expect the voltage sensing model debate to come to a conclusive end. But instead, it introduced a controversial new model that fueled a barrage of debates. Is it transporter or paddle? Both models have strong supporting evidences, and, as a corollary, strong counter evidences. This discussion aims to summarize the evidences for both models, and decide where I would place my money. It all started with a publication by the MacKinnon’s group in 2003, X-ray structure of a voltage-dependent K+ channel and it’s accompanying paper, The principle of gating charge movement in a voltage-dependent K+ channel . In the first paper, a structure of a voltage-dependent K+ channel is presented. To the surprise of everyone, the voltage- sensitive S4 segment is found in an odd position – near the cytoplasmic surface of the membrane. This finding is at odd with previous studies showing that the S4 segment is accessible from the extracellular surface. One possible explanation is that this may not be a natural conformation of the channel, and it is an artifact of the crystallization process. In a subsequent experiment, they produced and isolated only the S1-S4 segment of the channel, and established that the segment is in its natural conformation through a toxin-binding test. Using this shorter segment, they showed that the S4 segment is capable of adopting this new found position naturally. These findings led them to propose a new model for the gating movement of the S4 segment. In the new model, the S4 segment forms a voltage sensitive paddle at the periphery of the channel. The 4 Arg residues responsible for the gating current are located at the moving end of the paddle. The pivoted end is attached to the rest of the channel, close to the
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2 cytoplasmic surface. In the close conformation, the Arg residues are in the lipid bilayer near to the cytoplasmic surface. Upon depolarization of the membrane, the S4 paddle swings through the lipid bilayer, bringing the charged Arg residues to the extracellular surface. Some key features that this model entails are: (1) movement of charges across large distances and (2) charged residues reside within the lipid bilayer. This new model is
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This note was uploaded on 04/30/2008 for the course BIOMEDE 417 taught by Professor Cain during the Winter '07 term at University of Michigan.

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BME417HW5 - BME 417 HW5 Transporter or Paddle A Debate on Voltage Sensor Models With the elucidation of the voltage-sensitive KvAP channel

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