@article {46943,
	title = {Role of cholesterol-mediated effects in GPCR heterodimers},
	journal = {Chemistry and Physics of Lipids},
	volume = {227},
	year = {2020},
	month = {MAR},
	pages = {104852},
	type = {Article},
	abstract = {<p>G protein-coupled receptors (GPCRs) are transmembrane receptors that mediate a large number of cellular responses. The organization of GPCRs into dimers and higher-order oligomers is known to allow a larger repertoire of downstream signaling events. In this context, a crosstalk between the adenosine and dopamine receptors has been reported, indicating the presence of heterodimers that are functionally relevant. In this paper, we explored the effect of membrane cholesterol on the adenosine(2A) (A(2A)) and dopamine D-3 (D-3) receptors using coarse-grain molecular dynamics simulations. We analyzed cholesterol interaction sites on the A(2A) receptor and were able to reproduce the sites indicated by crystallography and previous atomistic simulations. We predict novel cholesterol interaction sites on the D-3 receptor that could be important in the reported cholesterol sensitivity in receptor function. Further, we analyzed the formation of heterodimers between the two receptors. Our results suggest that membrane cholesterol modulates the relative population of several co-existing heterodimer conformations. Both direct receptor-cholesterol interaction and indirect membrane effects contribute toward the modulation of heterodimer conformations. These results constitute one of the first examples of modulation of GPCR hetero-dimerization by membrane cholesterol, and could prove to be useful in designing better therapeutic strategies.</p>
},
	keywords = {Adenosine(2A) receptor, Cholesterol, Dopamine D-3 receptor, G protein-coupled receptors, Heterodimer, MARTINI coarse-grain simulation},
	issn = {0009-3084},
	doi = {10.1016/j.chemphyslip.2019.104852},
	author = {Prasanna, Xavier and Mohole, Madhura and Chattopadhyay, Amitabha and Sengupta, Durba}
}
@article {47098,
	title = {Role of cholesterol in transmembrane dimerization of the ErbB2 growth factor receptor},
	journal = {Journal of Membrane Biology},
	year = {2021},
	month = {JAN},
	type = {Article; Early Access 2021},
	abstract = {<p>The association of ErbB2 growth factor receptors is critical for cell growth and potentiates tumor proliferation in several cancer types. An important aspect in ErbB2 association is the role of lipids such as cholesterol, especially since their metabolism is often reprogrammed in cancer cells. Here, we have coupled metadynamics with coarse-grain simulations to identify cholesterol effects in the transmembrane dimerization of ErbB2 receptors. Overall, cholesterol interactions are observed with the receptor that directly tunes the association energetics. Several dimer conformations are identified both in the presence and absence of cholesterol, although the dimer regime appears to be more favorable in the presence of cholesterol. We observe an overall modulation of the underlying energy profile and the symmetric active and inactive conformational states are not distinguished in the presence of cholesterol. We show that cholesterol binds to the receptor transmembrane domain at a site (CRAC motif) that overlaps with the dimer interface (SmXXXSm motif). The competition between the transmembrane interactions and cholesterol interactions decides the final conformational landscape. Our work is an important step toward characterizing cholesterol effects in ErbB2 membrane receptor function. [GRAPHICS] .</p>
},
	keywords = {Cholesterol, ErbB2 growth factor receptor, Her2 dimer, Juxtamembrane dimer, Martini coarse-grain simulations, Metadynamics},
	issn = {0022-2631},
	doi = {10.1007/s00232-021-00168-z, Early Access Date = JAN 2021},
	author = {Pawar, Aiswarya B. and Sengupta, Durba}
}
