title: Molecular mechanism of myosin Va recruitment to dense core secretory granules.
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.
authors: Centre for Research in Biomedicine, Faculty of Health and Life Sciences, University of the West of England, Bristol, UK.
authors: Flora
authors: F
authors: Brozzi
authors: Frederique
authors: F
authors: Diraison
authors: Sophie
authors: S
authors: Lajus
authors: Shavanthi
authors: S
authors: Rajatileka
authors: Thomas
authors: T
authors: Philips
authors: Romano
authors: R
authors: Regazzi
authors: Mitsunori
authors: M
authors: Fukuda
authors: Paul
authors: P
authors: Verkade
authors: Elek
authors: E
authors: Molnár
authors: Anikó
authors: A
authors: Váradi
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D006728:Hormones / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007340:Insulinoma / Q000378:metabolism / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism*; D024701:Myosin Type V / Q000235:genetics / Q000378:metabolism*; D016716:PC12 Cells; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D020033:Protein Isoforms; D021381:Protein Transport; D051381:Rats; D022142:Secretory Vesicles / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000075745:rab27 GTP-Binding Proteins
chemical_list: D006728:Hormones; C513081:Myo5a protein, rat; D020033:Protein Isoforms; C512778:Sytl4 protein, rat; D033921:Vesicular Transport Proteins; D000075745:rab27 GTP-Binding Proteins; D024701:Myosin Type V; C512961:Rab27a protein, rat; D018995:Myosin Heavy Chains; D020691:rab GTP-Binding Proteins