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Model for growth hormone receptor activation based on subunit rotation within a receptor dimer

Nature Structural & Molecular Biology volume 12, pages 814821 (2005) | Download Citation

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Abstract

Growth hormone is believed to activate the growth hormone receptor (GHR) by dimerizing two identical receptor subunits, leading to activation of JAK2 kinase associated with the cytoplasmic domain. However, we have reported previously that dimerization alone is insufficient to activate full-length GHR. By comparing the crystal structure of the liganded and unliganded human GHR extracellular domain, we show here that there is no substantial change in its conformation on ligand binding. However, the receptor can be activated by rotation without ligand by inserting a defined number of alanine residues within the transmembrane domain. Fluorescence resonance energy transfer (FRET), bioluminescence resonance energy transfer (BRET) and coimmunoprecipitation studies suggest that receptor subunits undergo specific transmembrane interactions independent of hormone binding. We propose an activation mechanism involving a relative rotation of subunits within a dimeric receptor as a result of asymmetric placement of the receptor-binding sites on the ligand.

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Acknowledgements

This work was supported by National Health and Medical Research Council (NHMRC; Australia) project grants to M.J.W. and K.A.E. We thank H. Tong and other staff at BioCARS for their help at the Advanced Photon Source (supported by the US Department of Energy, Basic Energy Sciences, Office of Energy Research). The crystallographic work, and use of the BioCARS sector, was supported by the Australian Synchrotron Research Program, funded by the Commonwealth of Australia under the Major National Research Facilities Program. We thank E. Holliday and E. Lim for their skilled assistance. W.J.M. is a NHMRC Industry Fellow and M.W.P. is an NHMRC Senior Principal Research Fellow and M.J.W. and K.A.E. are NHMRC Principal Research Fellows.

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Author notes

    • Richard J Brown
    • , Julian J Adams
    •  & Rebecca A Pelekanos

    These authors contributed equally to this work.

Affiliations

  1. Institute for Molecular Bioscience and School of Biomedical Sciences, University of Queensland, St. Lucia, Queensland, Australia.

    • Richard J Brown
    • , Rebecca A Pelekanos
    • , Yu Wan
    • , Kathryn Palethorpe
    • , Thea A Monks
    •  & Michael J Waters
  2. Biota Structural Biology Laboratory, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.

    • Julian J Adams
    • , William J McKinstry
    •  & Michael W Parker
  3. The University of Western Australia, Western Australian Institute for Medical Research, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.

    • Ruth M Seeber
    •  & Karin A Eidne

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The authors declare no competing financial interests.

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Correspondence to Michael J Waters.

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https://doi.org/10.1038/nsmb977

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