TMEM266 is a functional voltage sensor regulated by extracellular Zn²

Area of Science:

• Biophysics
• Molecular Biology
• Neuroscience

Background:

• Voltage-activated ion channels use S1-S4 domains for voltage sensing and pore gating, essential for electrical signaling.
• Related S1-S4 domains exist in voltage-sensitive phosphatases and proton channels, but lack associated pores.
• hTMEM266, a protein with a predicted S1-S4 domain, has an unknown cellular function.

Purpose of the Study:

• To investigate the functional properties of the S1-S4 domain in the human protein hTMEM266.
• To determine if hTMEM266 acts as a voltage sensor.
• To explore potential applications of hTMEM266 in voltage sensing technologies.

Main Methods:

• Oligomerization studies of hTMEM266.
• Analysis of hTMEM266 structural dynamics across microsecond (µs) and millisecond (ms) timescales in response to voltage.
• Investigation of a zinc (Zn2+) binding site's role in hTMEM266 conformational changes.

Main Results:

• hTMEM266 forms oligomers.
• The protein exhibits voltage-dependent structural rearrangements on both µs and ms timescales.
• A Zn2+ binding site was identified, regulating the slow conformational transition.

Conclusions:

• The S1-S4 domain in hTMEM266 functions as a voltage sensor.
• hTMEM266's voltage-sensing capability suggests roles in uncharacterized cellular processes.
• The rapid voltage response of hTMEM266 is promising for developing genetically encoded voltage indicators.