GTP binding controls complex formation by the human ROCO protein MASL1

Authors

  • Sybille Dihanich,

    1. Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
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    • These authors contributed equally to the paper
  • Laura Civiero,

    1. Department of Biology, University of Padova, Italy
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    • These authors contributed equally to the paper
  • Claudia Manzoni,

    1. Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
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  • Adamantios Mamais,

    1. Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
    2. Reta Lila Weston Institute and Queen Square Brain Bank, UCL Institute of Neurology, London, UK
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  • Rina Bandopadhyay,

    1. Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
    2. Reta Lila Weston Institute and Queen Square Brain Bank, UCL Institute of Neurology, London, UK
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  • Elisa Greggio,

    Corresponding author
    1. Department of Biology, University of Padova, Italy
    • Correspondence

      E. Greggio, Department of Biology, University of Padova, Via U. Bassi 58/b, Padova 35121, Italy

      Fax: +39(0)498276300

      Tel: +39(0)498276244

      E-mail: elisa.greggio@unipd.it

      P. A. Lewis, School of Pharmacy, University of Reading, Whiteknights, Reading RG6 6AP, UK

      Fax: +44 (0)118 378 6562

      Tel: +44 (0)118 378 4561

      E-mail: p.a.lewis@reading.ac.uk

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  • Patrick A. Lewis

    Corresponding author
    1. Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
    2. School of Pharmacy, University of Reading, UK
    • Correspondence

      E. Greggio, Department of Biology, University of Padova, Via U. Bassi 58/b, Padova 35121, Italy

      Fax: +39(0)498276300

      Tel: +39(0)498276244

      E-mail: elisa.greggio@unipd.it

      P. A. Lewis, School of Pharmacy, University of Reading, Whiteknights, Reading RG6 6AP, UK

      Fax: +44 (0)118 378 6562

      Tel: +44 (0)118 378 4561

      E-mail: p.a.lewis@reading.ac.uk

    Search for more papers by this author

Abstract

The human ROCO proteins are a family of multi-domain proteins sharing a conserved ROC-COR supra-domain. The family has four members: leucine-rich repeat kinase 1 (LRRK1), leucine-rich repeat kinase 2 (LRRK2), death-associated protein kinase 1 (DAPK1) and malignant fibrous histiocytoma amplified sequences with leucine-rich tandem repeats 1 (MASL1). Previous studies of LRRK1/2 and DAPK1 have shown that the ROC (Ras of complex proteins) domain can bind and hydrolyse GTP, but the cellular consequences of this activity are still unclear. Here, the first biochemical characterization of MASL1 and the impact of GTP binding on MASL1 complex formation are reported. The results demonstrate that MASL1, similar to other ROCO proteins, can bind guanosine nucleotides via its ROC domain. Furthermore, MASL1 exists in two distinct cellular complexes associated with heat shock protein 60, and the formation of a low molecular weight pool of MASL1 is modulated by GTP binding. Finally, loss of GTP enhances MASL1 toxicity in cells. Taken together, these data point to a central role for the ROC/GTPase domain of MASL1 in the regulation of its cellular function.

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