title: All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding.
abstract: Mutations in the inositol 5-phosphatase OCRL are responsible for Lowe syndrome, an X-linked disorder characterized by bilateral cataracts, mental retardation, neonatal hypotonia, and renal Fanconi syndrome, and for Dent disease, another X-linked condition characterized by kidney reabsorption defects. We have previously described an interaction of OCRL with the endocytic adaptor APPL1 that links OCRL to protein networks involved in the disease phenotype. Here, we provide new evidence showing that among the interactions which target OCRL to membranes of the endocytic pathway, binding to APPL1 is the only one abolished by all known disease-causing missense mutations in the ASH-RhoGAP domains of the protein. Furthermore, we demonstrate that APPL1 and rab5 independently contribute to recruit OCRL to enlarged endosomes induced by the expression of constitutively active Rab5. Thus, binding to APPL1 helps localize OCRL at specific cellular sites, and disruption of this interaction may play a role in disease.
authors.affiliation: Department of Cell Biology, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: McCrea
authors.forename: Summer
authors.initials: S
authors.lastname: Paradise
authors.forename: Livia
authors.initials: L
authors.lastname: Tomasini
authors.forename: Maria
authors.initials: M
authors.lastname: Addis
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Melis
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: De Matteis
authors.forename: Pietro
authors.initials: P
authors.lastname: De Camilli
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D051380:GRB2 Adaptor Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D009800:Oculocerebrorenal Syndrome / Q000235:genetics / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: C464801:APPL1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D020690:GTPase-Activating Proteins; C085379:rho GTPase-activating protein; D010744:Phosphoric Monoester Hydrolases; C075695:OCRL protein, human