Cargo Binding Proteins Trigger Myosin VI Dimerization

Among the myosin family, while other myosins move toward the barbed(+) end, myosin VI moves toward the pointed (-) end of the actin filament. This unique feature allows myosin VI to fulfill multiple cellular processes such as clathrin dependant endocytosis when bound to Dab2 or clathrin independant when linked to GiPC, vesicules transport to the Golgi and the perinuclear region, vesicules transition from early endosome to late endosome, AMPA receptor trafficking when bound to SAP-97.Our working model for how myosin VI function in a cell is that the full-length myosin VI molecule primarily exists as a monomer, and folded to form intramolecular interactions involving the cargo-binding domain that block potential dimerization sites. This is consistent with small-angle X-ray scattering data obtained by Spink et al.. Binding to monomeric cargo adaptors leads to an unfolding of the monomers, exposing potential dimerization sites. The unfolded monomers can then be held in close proximity, either via tethering by the adaptor protein and/or via as yet unidentified cargo-binding domain interactions. Alternatively, binding to a dimeric cargo adaptor protein leads to simultaneous unfolding and close opposition of the cargo-binding domains. This distal tethering of two cargo-binding domains allows internal dimerization (likely via coiled coil) to occur at the proximal end of the medial tail, and may include part of the last helix of the three-helix bundle. This internal dimerization causes the three-helix bundle, formerly known as the proximal tail, to unfold, forming an extension of the myosin VI lever arm.Although it has been a controversy whether myosin VI exists as a monomer or dimer, our data and others support the model in which myosin VI exists as monomer in cell but upon binding to cargo binding proteins allows its dimerization and ultimately fulfills its function in cell.