Griscelli Syndrome 1 (GS1, MYO5A, MYO5, MYH12, MYOXIN)

FUNCTION

Ontology

a) Biological process: cytoskeleton organization and biogenesis
b) Biological process: vesicle transport along actin filament
c) Biological process: cytoplasmic mRNA transport
d) Motor activity
e) Component of myosin
f) Component of the acroplaxome of rodent spermatids
g) Actin binding; ATP binding; calmodulin binding.

Location

Cytoskeleton (actin filaments). Anti-MyoVa antibody specifically stained neuronal nuclei from forebrain to cerebellar regions, and more intensely sensory nuclei in adult Wistar rats (Telilli, et al). Immunocytochemical localization of myosin-Va in cultured hippocampal neurons shows that it partially colocalizes with PSD-95 at synapses and is also diffusely localized in cell bodies, dendrites, and axons (Walikonis, et al).

Interaction

Myosin-Va consists of two heavy chains (homodimer), each containing a neck domain with six tandem IQ motifs that bind four to five calmodulins and one to two essential light chains. The N-terminal head region consists of an actin-binding site and an ATP-binding site, with cargo-binding domain at the long neck tail region. Apo-calmodulin acts as the light chain for unconventional myosin V, and treatment with Ca(2+) can cause dissociation of calmodulin from the 6 IQ regions of the myosin heavy chain. Holo-calmodulin forms a high-affinity 1:1 complex with IQ3-IQ4 in a novel mode of interaction, as a "bridged" structure wherein two calmodulin domains interact with adjacent IQ motifs (Martin, et al).

Myosin Va binds Slac2-a/melanophilin and MyRIP ( linker proteins between Rab27A and myosin Va). Slac2-a directly interacts with Rab27a and myosin Va via its N-terminal region (amino acids 1 to 146) and the middle region (amino acids 241 to 405), respectively (Fukuda, et al). The Rab27a interacts with myosin-VIIa and myosin-Va via MyRIP or melanophilin and mediates melanosome binding to actin. The interaction between myosin Va and Rab27a is exon F dependent (Wu, et al). Myosin Va isoforms containing exon F are able to colocalize with and influence melanosome distribution by indirect interaction with rab27a and direct interaction with melanophilin. Isoforms lacking exon F but containing exon D are associated with vesicles near the Golgi area (Westbroek, et al). The MyoVa isoforms lacking exon F are not targeted to the melanosomes, but localized to the perinuclear region instead (Au, et al). The actin-activated ATPase activity of the melanocyte-type myosin Va having exon-F was significantly activated by melanophilin by 4-fold. Although Rab27a binds to myosin Va/melanophilin complex, it did not affect the melanophilin-induced activation of myosin Va. Deletion of the C-terminal actin binding domain and N-terminal Rab binding domain of melanophilin resulted in no change in the activation of the ATPase by melanophilin, indicating that the myosin Va binding domain (MBD) is sufficient for the activation of myosin Va. Among MBDs, the interaction of MBD-2 with exon-F of myosin Va is critical for the binding of myosin Va and melanophilin, whereas MBD-1 interacting with the globular tail of myosin Va plays a more significant role in the activation of myosin Va ATPase activity (Li, et al (2005)). Inhibited myosin Va is in a folded conformation such that the tail domain interacts with and inhibits myosin Va motor activity. The C-terminal globular tail domain (GTD) that directly inhibits the motor activity of myosin Va. A conserved acidic residue in the motor domain (Asp136) and two conserved basic residues in the GTD (Lys1706 and Lys1779) are critical residues for this regulation. It is proposed that binding of the GTD to the motor domain prevents the movement of the converter/lever arm during ATP hydrolysis cycle, thus inhibiting the chemical cycle of the motor domain (Li, et al (2008)).

Melanosomes move along both actin filaments (for short-range, local motility) and microtubules (for long distance movement). The leaden gene product, melanophilin, is required with Rab27a to recruit myosin Va to melanosomes in melanocytes. The reduced levels of myosin Va protein in leaden and ashen melanocytes suggests that myosin Va stability is influenced by the leaden and ashen gene products (Hume, et al). (view diagram of the Myo5a tripartite protein complex and the dynamics of melanosomes here).

Rab27a and MyRIP link neuroendocrine secretory granules to F-actin and control their motion toward release sites through the actin cortex (Desnos, et al (2003)). A reduction of MyoVa protein levels achieved by RNA interference caused a significant decrease in glucose- or depolarization-stimulated insulin secretion (Varadi, et al). Myosin-Va exhibits an unusually high affinity for F-actin in the presence of ATP and induced by Ca(2+) (Tauhata, et al). The actin-based vesicle-transport motor (MyoVA) can interact directly with a microtubule-based transport motor (KhcU) through Myo5a residues 1527-1805 (Huang, et al (1999)). KHC is responsible for plus end-directed microtubule movement. On the other hand, Myo5a directly interacts with Dlc8, one of the dynein light chains (Espindola, et al). The cytoplasmic dynein acts as a minus end-directed microtubule motor. Myosin Va binds to organelles that are transported bi-directionally in axons along microtubules (Bridgman, et al). The coordination of myosin Va and microtubule-dependent motors is required for fast axonal retrograde transport in motor neurons (Lalli, et al). MyoVa inhibition reduces the number of docked granules, leading to reduced secretory responses, indicating that MyoVa directly mediates stable attachment of secretory granules at the plasma membrane (Desnos, et al (2007)). Insulin stimulation leads to Akt-mediated phosphorylation of myosin 5a at serine 1650 to enhance the interaction of myosin 5a with the actin cytoskeleton (Yoshizaki, et al).

Synaptic vesicles are one of the most important cargoes for myosin-Va. Myosin-Va on synaptic vesicles interacts with syntaxin-1A at or above 0.3 microM Ca2+. Interference with formation of the syntaxin-1A-myosin-Va complex reduces the exocytotic frequency in chromaffin cells. The syntaxin-1A-binding site was in the neck, a region that contains calmodulin-binding IQ-motifs. Syntaxin-1A binding by myosin-Va in the presence of Ca2+ depends on the release of calmodulin from the myosin-Va neck, allowing syntaxin-1A to occupy the vacant IQ-motif (Watanabe, et al). Oligodendrocytes express myosin Va and loss of myosin Va function resulted in significantly smaller lamellas and decreased process number, length, and branching of oligodendrocytes. Loss of myosin Va function also blocked distal localization of VAMP2 (Sloane, et al). Myosin Va associates with AMPARs through its cargo binding domain, which is enhanced by active GTP-bound Rab11. Myosin Va mediated the CaMKII-triggered translocation of GluR1 receptors from the dendritic shaft into spines (Correia, et al).

Myo5a drosophila homolog CG2146/didum interaction information shown in CuraGen interaction database.

Pathway

Processive actin-based motor that can move in large steps approximating the 36-nm pseudo-repeat of the actin filament. Involved in melanosome transport. May also be required for some polarization process involved in dendrite formation. Myosin-Va is a molecular motor that may participate in synaptic vesicle cycling and axonal transport.