title: The disease-linked Glu-26-Lys mutant version of Coronin 1A exhibits pleiotropic and pathway-specific signaling defects.
abstract: Coronin 1A (Coro1A) is involved in cytoskeletal and signaling events, including the regulation of Rac1 GTPase- and myosin II-dependent pathways. Mutations that generate truncated or unstable Coro1A proteins cause immunodeficiencies in both humans and rodents. However, in the case of the peripheral T-cell-deficient (Ptcd) mouse strain, the immunodeficiency is caused by a Glu-26-Lys mutation that targets a surface-exposed residue unlikely to affect the intramolecular architecture and stability of the protein. Here we report that this mutation induces pleiotropic effects in Coro1A protein, including the exacerbation of Coro1A-dependent actin-binding and -bundling activities; the formation of large meshworks of Coro1A(E26K)-decorated filaments endowed with unusual organizational, functional, and staining properties; and the elimination of Coro1A functions associated with both Rac1 and myosin II signaling. By contrast, it does not affect the ability of Coro1A to stimulate the nuclear factor of activated T-cells (NF-AT). Coro1A(E26K) is not a dominant-negative mutant, indicating that its pathological effects are derived from the inability to rescue the complete loss of the wild-type counterpart in cells. These results indicate that Coro1A(E26K) behaves as either a recessive gain-of-function or loss-of-function mutant protein, depending on signaling context and presence of the wild-type counterpart in cells.
authors.affiliation: Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas and University of Salamanca, 37007 Salamanca, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Ojeda
authors.affiliation: Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas and University of Salamanca, 37007 Salamanca, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Robles-Valero
authors.affiliation: Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas and University of Salamanca, 37007 Salamanca, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Barreira
authors.affiliation: Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas and University of Salamanca, 37007 Salamanca, Spain xbustelo@usal.es.
authors.forename: Xosé R
authors.initials: XR
authors.lastname: Bustelo
mesh_terms: D008841:Actin Cytoskeleton / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D018929:Cell Culture Techniques; D002522:Chlorocebus aethiops; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D009154:Mutation; D015398:Signal Transduction
chemical_list: D008840:Microfilament Proteins; C072061:coronin proteins