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A molecular sensor for cholesterol in the human serotonin1A receptor
G Aditya Kumar1, Parijat Sarkar1, Tomasz Maciej Stepniewski2,3
1CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India.
Science Advances
|July 24, 2021
Summary
Cholesterol affects G protein-coupled receptor (GPCR) function. A key lysine residue (K101) in the serotonin 1A receptor is vital for sensing cholesterol levels, impacting receptor dynamics.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- G protein-coupled receptors (GPCRs) are crucial drug targets.
- GPCR function is known to be modulated by membrane cholesterol levels.
- Specific motifs, like the cholesterol recognition/interaction amino acid consensus (CRAC) motif, mediate cholesterol-receptor interactions.
Purpose of the Study:
- To investigate the molecular mechanisms underlying cholesterol sensitivity in the serotonin 1A receptor.
- To identify key residues and structural features responsible for cholesterol sensing in this GPCR.
Main Methods:
- Site-directed mutagenesis of key residues within CRAC motifs in transmembrane helices (TM2 and TM5) of the serotonin 1A receptor.
- All-atom molecular dynamics simulations to analyze receptor conformational dynamics and cholesterol interactions.
Main Results:
- A specific lysine residue (K101) within a CRAC motif was identified as critical for sensing altered membrane cholesterol levels.
- Cholesterol-sensitive functional states of the serotonin 1A receptor correlate with reduced conformational dynamics in its extracellular loops.
Conclusions:
- The study elucidates the molecular basis of cholesterol sensitivity in the serotonin 1A receptor.
- Identifies a critical lysine residue and links cholesterol sensing to altered receptor dynamics, providing novel insights into GPCR regulation by lipids.
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