Journal
CELLULAR AND MOLECULAR LIFE SCIENCES
Volume 68, Issue 7, Pages 1227-1239Publisher
SPRINGER BASEL AG
DOI: 10.1007/s00018-010-0519-z
Keywords
GPCRs; Glycoprotein hormone receptors; Molecular simulations; Computational modeling; Protein structure networks; Intramolecular communication paths; Constitutively active mutants
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Funding
- National Institutes of Health [DK33973, DK69711]
- Telethon-Italy [S00068TELU]
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The luteinizing hormone receptor (LHR) is a G protein-coupled receptor (GPCR) particularly susceptible to spontaneous pathogenic gain-of-function mutations. Protein structure network (PSN) analysis on wild-type LHR and two constitutively active mutants, combined with in vitro mutational analysis, served to identify key amino acids that are part of the regulatory network responsible for propagating communication between the extracellular and intracellular poles of the receptor. Highly conserved amino acids in the rhodopsin family GPCRs participate in the protein structural stability as network hubs in both the inactive and active states. Moreover, they behave as the most recurrent nodes in the communication paths between the extracellular and intracellular sides in both functional states with emphasis on the active one. In this respect, non-conservative loss-of-function mutations of these amino acids is expected to impair the most relevant way of communication between activating mutation sites or hormone-binding domain and G protein recognition regions.
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