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Conserved amino acids participate in the structure networks deputed to intramolecular communication in the lutropin receptor

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Abstract

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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Acknowledgments

This work was supported by grants from the National Institutes of Health, DK33973 and DK69711 (to D.P.) and by a Telethon-Italy grant no. S00068TELU (To F.F.). We thank Judy Gray for her expert technical assistance.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, USA

    Krassimira Angelova, Moon Lee, Manish Patel & David Puett

  2. Department of Chemistry, Dulbecco Telethon Institute, University of Modena and Reggio Emilia, 41125, Modena, Italy

    Angelo Felline & Francesca Fanelli

Authors
  1. Krassimira Angelova
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  2. Angelo Felline
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  3. Moon Lee
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  4. Manish Patel
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  5. David Puett
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  6. Francesca Fanelli
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Corresponding authors

Correspondence to David Puett or Francesca Fanelli.

Additional information

K. Angelova and A. Felline contributed equally to this work.

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Angelova, K., Felline, A., Lee, M. et al. Conserved amino acids participate in the structure networks deputed to intramolecular communication in the lutropin receptor. Cell. Mol. Life Sci. 68, 1227–1239 (2011). https://doi.org/10.1007/s00018-010-0519-z

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  • DOI: https://doi.org/10.1007/s00018-010-0519-z

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