title: A disorder-to-order structural transition in the COOH-tail of Fz4 determines misfolding of the L501fsX533-Fz4 mutant.
abstract: Frizzled 4 belongs to the superfamily of G protein coupled receptors. The unstructured cytosolic tail of the receptor is essential for its activity. The mutation L501fsX533 in the fz4 gene results in a new COOH-tail of the receptor and causes a form of Familial exudative vitreoretinopathy. Here we show that the mutated tail is structured. Two amphipathic helices, displaying affinity for membranes and resembling the structure of Influenza Hemagglutinin fusion peptide, constitute the new fold. This tail induces the aggregation of the receptor in the Endoplasmic Reticulum and it is sufficient to block the export to the Golgi of a chimeric VSVG protein containing the mutated tail. Affecting the tail's structure, net charge or amphipathicity relocates the mutated Fz4 receptor to the Plasma Membrane. Such disorder-to-order structural transition was never described in GPCRs and opens a new scenario on the possible effect of mutations on unstructured regions of proteins.
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Lemma
authors.forename: Massimo
authors.initials: M
authors.lastname: D'Agostino
authors.forename: Maria Gabriella
authors.initials: MG
authors.lastname: Caporaso
authors.forename: Massimo
authors.initials: M
authors.lastname: Mallardo
authors.forename: Giorgia
authors.initials: G
authors.lastname: Oliviero
authors.forename: Mariano
authors.initials: M
authors.lastname: Stornaiuolo
authors.forename: Stefano
authors.initials: S
authors.lastname: Bonatti
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000080345:Familial Exudative Vitreoretinopathies; D051157:Frizzled Receptors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D040181:Genetic Diseases, X-Linked / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D021381:Protein Transport; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D012996:Solutions; D018630:Vitreoretinopathy, Proliferative / Q000235:genetics
chemical_list: D051157:Frizzled Receptors; D011993:Recombinant Fusion Proteins; D012996:Solutions
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