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Publication Detail
Distinct structural features of G protein-coupled receptor kinase 5 (GRK5) regulate its nuclear localization and DNA-binding ability
  • Publication Type:
    Journal article
  • Publication Sub Type:
  • Authors:
    Pitcher JA, Johnson LR, Robinson JR
  • Publication date:
  • Journal:
    PLoS One
  • Volume:
    8 (3)
  • Editors:
    Maki CG
  • Status:
  • Country:
  • Keywords:
    G protein-coupled receptor kinase (GRK),, nucleus, nuclear localization sequence (NLS), nuclear export sequence (NES), DNA-binding
  • Addresses:
    Johnson, LR, Robinson, JR and Pitcher, JA
    University College London
    Gower Street
    WC1E 6BT
G protein-coupled receptor kinases (GRKs) act to desensitize G protein-coupled receptors (GPCRs). In addition to this role at the plasma membrane, a nuclear function for GRK5, a member of the GRK4 subfamily of GRKs, has been reported. GRK5 phosphorylates and promotes the nuclear export of the histone deacetylase, HDAC5. Here we demonstrate that the possession of a nuclear localization sequence (NLS) is a common feature of GRK4 subfamily members (GRKs 4, 5 and 6). However, the location of the NLS and the ability of these GRKs to bind DNA in vitro are different. The NLSs of GRK5 and 6 bind DNA in vitro, whilst the NLS of GRK4 does not. Using mutants of GRK5 we identify the regions of GRK5 required for DNA-binding in vitro and nuclear localization in cells. The DNA-binding ability of GRK5 requires both the NLS and an N-terminal calmodulin (CaM)-binding site. A functional nuclear export sequence (NES), required for CaM-dependent nuclear export of the kinase, is also identified. Based on our observations we propose a model to explain how nuclear localization of GRK5 may be regulated. Notably, the nuclear localization of GRK5 and 6 is differentially regulated. These results suggest subfamily specific nuclear functions for the GRK4 subfamily members. Identification of GRK specific small molecule inhibitors of nuclear localization and/or function for the GRK4 subfamily may thus be an achievable goal.
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