title: Structural basis of cargo recognition by the myosin-X MyTH4-FERM domain.
abstract: Myosin-X is an important unconventional myosin that is critical for cargo transportation to filopodia tips and is also utilized in spindle assembly by interacting with microtubules. We present a series of structural and biochemical studies of the myosin-X tail domain cassette, consisting of myosin tail homology 4 (MyTH4) and FERM domains in complex with its specific cargo, a netrin receptor DCC (deleted in colorectal cancer). The MyTH4 domain is folded into a helical VHS-like structure and is associated with the FERM domain. We found an unexpected binding mode of the DCC peptide to the subdomain C groove of the FERM domain, which is distinct from previously reported β-β associations found in radixin-adhesion molecule complexes. We also revealed direct interactions between the MyTH4-FERM cassette and tubulin C-terminal acidic tails, and identified a positively charged patch of the MyTH4 domain, which is involved in tubulin binding. We demonstrated that both DCC and integrin bindings interfere with microtubule binding and that DCC binding interferes with integrin binding. Our results provide the molecular basis by which myosin-X facilitates alternative dual binding to cargos and microtubules.
authors.affiliation: Structural Biology Laboratory, Nara Institute of Science and Technology, Nara, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Hirano
authors.forename: Taiki
authors.initials: T
authors.lastname: Hatano
authors.forename: Aya
authors.initials: A
authors.lastname: Takahashi
authors.forename: Michinori
authors.initials: M
authors.lastname: Toriyama
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Inagaki
authors.forename: Toshio
authors.initials: T
authors.lastname: Hakoshima
mesh_terms: D000595:Amino Acid Sequence; D002478:Cells, Cultured; D000075389:DCC Receptor; D006801:Humans; D039641:Integrin beta Chains / Q000235:genetics / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009218:Myosins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D054730:Protein Interaction Domains and Motifs / Q000235:genetics / Q000502:physiology; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary / Q000502:physiology; D021381:Protein Transport / Q000235:genetics / Q000502:physiology; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D000075389:DCC Receptor; C501909:DCC protein, human; D039641:Integrin beta Chains; C498718:MYO10 protein, human; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D009218:Myosins