title: Structural basis of the myosin X PH1(N)-PH2-PH1(C) tandem as a specific and acute cellular PI(3,4,5)P(3) sensor.
abstract: Myosin X (MyoX) is an unconventional myosin that is known to induce the formation and elongation of filopodia in many cell types. MyoX-induced filopodial induction requires the three PH domains in its tail region, although with unknown underlying molecular mechanisms. MyoX's first PH domain is split into halves by its second PH domain. We show here that the PH1(N)-PH2-PH1(C) tandem allows MyoX to bind to phosphatidylinositol (3,4,5)-triphosphate [PI(3,4,5)P(3)] with high specificity and cooperativity. We further show that PH2 is responsible for the specificity of the PI(3,4,5)P(3) interaction, whereas PH1 functions to enhance the lipid membrane-binding avidity of the tandem. The structure of the MyoX PH1(N)-PH2-PH1(C) tandem reveals that the split PH1, PH2, and the highly conserved interdomain linker sequences together form a rigid supramodule with two lipid-binding pockets positioned side by side for binding to phosphoinositide membrane bilayers with cooperativity. Finally, we demonstrate that disruption of PH2-mediated binding to PI(3,4,5)P(3) abolishes MyoX's function in inducing filopodial formation and elongation.
authors.affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, Kowloon, Hong Kong, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Lu
authors.forename: Jiang
authors.initials: J
authors.lastname: Yu
authors.forename: Jing
authors.initials: J
authors.lastname: Yan
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Wei
authors.forename: Mingjie
authors.initials: M
authors.lastname: Zhang
mesh_terms: D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D009218:Myosins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011554:Pseudopodia / Q000378:metabolism
chemical_list: C498718:MYO10 protein, human; D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; D009218:Myosins