Molecular mechanism of Myosin Va recruitment to dense core secretory granules

Brozzi, Flora; Diraison, Frederique; Lajus, Sophie; Rajatileka, Shavanthi; Philips, Thomas; Regazzi, Romano; Fukuda, Mitsunori; Verkade, Paul; Moln�r, Elek; Varadi, Aniko

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. © 2011 John Wiley & Sons A/S.

Citation

Brozzi, F., Diraison, F., Lajus, S., Rajatileka, S., Philips, T., Regazzi, R., …Varadi, 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

• Journal Article Type: Article
• Publication Date: Jan 1, 2012
• Journal: Traffic
• Print ISSN: 1398-9219
• Electronic ISSN: 1600-0854
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 13
• Issue: 1
• Pages: 54-69
• DOI: https://doi.org/10.1111/j.1600-0854.2011.01301.x
• Keywords: Granuphilin-a/b, Rabphilin-3A, Rab27, dense core secretory granules, hormone secretion, myosin Va, tripartite complex, hormone and neuropeptide secreting cell
• Public URL: https://uwe-repository.worktribe.com/output/958443
• Publisher URL: http://dx.doi.org/10.1111/j.1600-0854.2011.01301.x