Voltage sensor trapping in the relaxed state
Carlos A. Villalba-Galea: 0000-0002-6489-4651
Conference Title/Conference Publication
Biophysical Society 57th Annual Meeting
February 2-6, 2013
Date of Presentation
2, Supplement 1
The voltage sensitive phosphatase from Ciona intestinalis (Ci-VSP) has constituted an intriguing model for the study of the dynamic of voltage sensing domains (VSD). Four of the five arginines in the fourth (S4) segment of the VSD function as charges sensing the difference in electrical potential across the membrane. The voltage-driven movement of the S4 segment towards the extracellular space triggers relaxation which is characterized by a shift in voltage dependence for the movement of charges to more negative values. The mechanism for relaxation remains unclear. However, it is thought to encompass the rearrangement of the VSD to satisfy the new position of the S4 segment following activation. In this view, changing the membrane potential from negative to positive voltages drives the VSD from the resting to the active state. As the S4 segment moves, the VSD gains potential energy, part of which is dissipated during a voltage-independent transition leading the VSD to the relaxed state. Replacement of the fourth arginine to a histidine (R232H) causes the VSD of Ci-VSP to display a “pump-like” behavior, which differs from the “transporter-like” behavior observed in the mutant R371H of Shaker. The cycling of this “pump” is driven by relaxation. Furthermore, we found that the net sensing charge of the mutant R232H reversibly seemingly decreases over 60% during this process. We concluded that after relaxation, the histidine in position 232 is deprotonated and “trapped” within the VSD without net charge. Similar observations are made using Molecular Dynamics simulation of the Ci-VSP voltage sensor bearing the mutation R232H. We propose electrically driving the VSD back to the resting state is inefficient after neutralizing the histidine R232H. Thus, recovery from relaxation last several seconds, diverging in two orders of magnitude the recovery observed with the native arginine.
Sundarum, Shobana and Villalba-Galea, Carlos A., "Voltage sensor trapping in the relaxed state" (2013). School of Pharmacy Faculty Presentations. 448.