Molecular mechanism of Myosin Va recruitment to dense core secretory granules

Flora Brozzi, Frederique Diraison, Sophie Lajus, Shavanthi Rajatileka, Thomas Philips, Romano Regazzi, Mitsunori Fukuda, Paul Verkade, Elek Molnár, Anikó Váradi

    Research output: Contribution to journalArticle

    29 Citations (Scopus)

    Abstract

    The brain-spliced isoform of Myosin Va (BR-MyoVa) plays an important role in the transport of dense core secretory granules (SGs) to the plasma membrane in hormone and neuropeptide-producing cells. The molecular composition of the protein complex that recruits BR-MyoVa to SGs and regulates its function has not been identified to date. We have identified interaction between SG-associated proteins granuphilin-a/b (Gran-a/b), BR-MyoVa and Rab27a, a member of the Rab family of GTPases. Gran-a/b-BR-MyoVa interaction is direct, involves regions downstream of the Rab27-binding domain, and the C-terminal part of Gran-a determines exon specificity. MyoVa and Gran-a/b are partially colocalised on SGs and disruption of Gran-a/b-BR-MyoVa binding results in a perinuclear accumulation of SGs which augments nutrient-stimulated hormone secretion in pancreatic beta-cells. These results indicate the existence of at least another binding partner of BR-MyoVa that was identified as rabphilin-3A (Rph-3A). BR-MyoVa-Rph-3A interaction is also direct and enhanced when secretion is activated. The BR-MyoVa-Rph-3A and BR-MyoVa-Gran-a/b complexes are linked to a different subset of SGs, and simultaneous inhibition of these complexes nearly completely blocks stimulated hormone release. This study demonstrates that multiple binding partners of BR-MyoVa regulate SG transport, and this molecular mechanism is universally used by neuronal, endocrine and neuroendocrine cells.

    Original languageEnglish
    Pages (from-to)54-69
    Number of pages16
    JournalTraffic
    Volume13
    Issue number1
    DOIs
    Publication statusPublished - 2012 Jan

    Keywords

    • Dense core secretory granules
    • Granuphilin-a/b
    • Hormone secretion
    • Hormone- and neuropeptide-secreting cell
    • Myosin Va
    • Rab27
    • Rabphilin-3A
    • Tripartite complex

    ASJC Scopus subject areas

    • Structural Biology
    • Biochemistry
    • Molecular Biology
    • Genetics
    • Cell Biology

    Fingerprint Dive into the research topics of 'Molecular mechanism of Myosin Va recruitment to dense core secretory granules'. Together they form a unique fingerprint.

  • Cite this

    Brozzi, F., Diraison, F., Lajus, S., Rajatileka, S., Philips, T., Regazzi, R., Fukuda, M., Verkade, P., Molnár, E., & Váradi, A. (2012). Molecular mechanism of Myosin Va recruitment to dense core secretory granules. Traffic, 13(1), 54-69. https://doi.org/10.1111/j.1600-0854.2011.01301.x