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Interfacial Binding Sites for Cholesterol on TRP Ion Channels

Anthony G Lee1

  • 1School of Biological Sciences, University of Southampton, Southampton, United Kingdom.

Biophysical Journal
|November 2, 2019
PubMed

Insights

This study reveals how cholesterol binds to Transient Receptor Potential (TRP) channels, identifying specific binding sites within these important ion channels. Findings suggest cholesterol binding may not displace essential phospholipids.

Area of Science:

  • Biophysics
  • Molecular Biology
  • Membrane Protein Research

Background:

  • Transient Receptor Potential (TRP) channels are crucial ion channels embedded in cell membranes.
  • Their function is known to be modulated by membrane cholesterol levels.
  • Understanding cholesterol-TRP interactions is key to elucidating TRP channel regulation.

Purpose of the Study:

  • To investigate and characterize cholesterol binding sites on TRP channels.
  • To determine the precise locations and nature of cholesterol-TRP interactions.
  • To assess the potential impact of cholesterol binding on associated phospholipids.

Main Methods:

  • Utilized a computational docking procedure to scan TRP channel surfaces for potential cholesterol binding sites.
  • Analyzed the spatial distribution of identified cholesterol binding poses.
  • Compared predicted cholesterol binding sites with known phospholipid binding sites on TRP channels.

Main Results:

  • Identified specific hollows and clefts within the tetrameric TRP channel structure as primary cholesterol binding sites.
  • Docking poses accurately predicted 89% of cholesterol hemisuccinate molecules in existing TRP structures (excluding outliers).
  • Cholesterol binding sites largely overlap with or are adjacent to subunit interfaces.

Conclusions:

  • Cholesterol preferentially binds within clefts at the interfaces between TRP channel subunits.
  • The identified binding sites are consistent with structural data, providing a mechanistic view of cholesterol interaction.
  • Cholesterol binding to TRP channels does not necessarily lead to the displacement of phospholipids.

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