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 Molnar, Aniko Varadi*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

32 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/bBR-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/bBR-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-MyoVaRph-3A interaction is also direct and enhanced when secretion is activated. The BR-MyoVaRph-3A and BR-MyoVaGran-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.

Translated title of the contributionMolecular mechanism of myosin Va recruitment to dense core secretory granules
Original languageEnglish
Pages (from-to)54-69
Number of pages16
JournalTraffic
Volume13
Issue number1
Early online date14 Nov 2011
DOIs
Publication statusPublished - Jan 2012

Bibliographical note

Publisher: John Wiley & Sons A/S
Other identifier: 21985333
Other: http://onlinelibrary.wiley.com/doi/10.1111/j.1600-0854.2011.01301.x/abstract

Keywords

  • dense core secretory granules
  • granuphilin-a
  • b
  • hormone- and neuropeptide-secreting cell
  • hormone secretion
  • myosin Va
  • Rab27
  • rabphilin-3A
  • tripartite complex
  • PANCREATIC BETA-CELLS
  • PLASMA-MEMBRANE
  • GRISCELLI-SYNDROME
  • PC12 CELLS
  • F-ACTIN
  • MELANOSOME TRANSPORT
  • CONTROLS EXOCYTOSIS
  • VESICLE EXOCYTOSIS
  • CHROMAFFIN CELLS
  • GLOBULAR TAIL

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