Role of Cholesterol in Transmembrane Dimerization of the ErbB2 Growth Factor Receptor.
Cholesterol
ErbB2 growth factor receptor
Her2 dimer
Juxtamembrane dimer
Martini coarse-grain simulations
Metadynamics
Journal
The Journal of membrane biology
ISSN: 1432-1424
Titre abrégé: J Membr Biol
Pays: United States
ID NLM: 0211301
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
received:
30
09
2020
accepted:
05
01
2021
pubmed:
29
1
2021
medline:
7
4
2022
entrez:
28
1
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33506276
doi: 10.1007/s00232-021-00168-z
pii: 10.1007/s00232-021-00168-z
doi:
Substances chimiques
Cholesterol
97C5T2UQ7J
ERBB2 protein, human
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
301-310Références
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