Speaker: Prof. Amitabha Chattopadhyay, Ph.D. (Stony Brook)
FTWAS, FRSB, FRSC, FNA, FNASc, FASc
CSIR Bhatnagar Fellow
CSIR-Centre for Cellular & Molecular Biology
Uppal Road, Hyderabad 500 007, India
Title: "Cholesterol and GPCR Function: A Molecular Sensor for
Cholesterol in the Serotonin1A Receptor."
Day and Date: Monday, March 28, 2022
Time: 1600 hrs.
Venue: Room no. 350, Chemistry Department
(Second floor, Annex)
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Hosted by Prof. Rajarshi Chakrabarti
(Zoom Meeting details)
https://zoom.us/j/98623615901?pwd=bWUxdHpOQ3FHY1hOOWFsUG5sSFJSUT09
Meeting ID: 986 2361 5901
Passcode: 050077111
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Abstract G protein-coupled receptors (GPCRs) are the largest class of molecules involved in
signal transduction across membranes, and represent major drug targets in all clinical
areas. The serotonin1A receptor is an important neurotransmitter receptor of the GPCR
superfamily and is implicated in the generation and modulation of various cognitive,
behavioral and developmental functions. In our earlier work, we demonstrated that
membrane cholesterol is necessary for ligand binding, G-protein coupling and signaling of
serotonin1A receptors. In the overall context of high-resolution structures of GPCRs
showing bound cholesterol molecules, we previously reported the presence of cholesterol
recognition/interaction amino acid consensus (CRAC) motifs in the serotonin1A receptor.
In our recent work, we explored the molecular basis of cholesterol sensitivity exhibited by
the serotonin1A receptor by generating mutants of key residues in CRAC motifs in
transmembrane helices (TM) 2 and 5 of the receptor. Our results show that a lysine
residue (K101) in one of the CRAC motifs is crucial for sensing altered membrane
cholesterol levels. These observations are further supported from all-atom molecular
dynamics simulations which reveal a tightly bound cholesterol molecule between TM1 and
TM2 by establishing polar contacts with K101 that leads to stabilization of extracellular
loop 1 (ECL1). Interestingly, the position of this cholesterol molecule is almost identical
to a co-crystallized cholesterol molecule in the recently reported high-resolution cryo-EM
structure of the serotonin1A receptor, thereby strongly validating the molecular mechanism
for cholesterol sensitivity of the serotonin1A receptor proposed by us. These results
constitute one of the first reports comprehensively demonstrating that cholesterol
sensitivity could be knocked out by a single point mutation in a specific cholesterol binding
site. We envision that progress in deciphering molecular details of the nature of GPCRcholesterol interaction would lead to better insight into our overall understanding of GPCR
function in health and disease.