title: Recognition of the F&H motif by the Lowe syndrome protein OCRL.
abstract: Lowe syndrome and type 2 Dent disease are caused by defects in the inositol 5-phosphatase OCRL. Most missense mutations in the OCRL ASH-RhoGAP domain that are found in affected individuals abolish interactions with the endocytic adaptors APPL1 and Ses (both Ses1 and Ses2), which bind OCRL through a short phenylalanine and histidine (F&H) motif. Using X-ray crystallography, we have identified the F&H motif binding site on the RhoGAP domain of OCRL. Missense mutations associated with disease affected F&H binding indirectly by destabilizing the RhoGAP fold. By contrast, a disease-associated mutation that does not perturb F&H binding and ASH-RhoGAP stability disrupted the interaction of OCRL with Rab5. The F&H binding site of OCRL is conserved even in species that do not have an identified homolog for APPL or Ses. Our study predicts the existence of other OCRL binding partners and shows that the perturbation of OCRL interactions has a crucial role in disease.
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Pirruccello
authors.forename: Laura E
authors.initials: LE
authors.lastname: Swan
authors.forename: Ewa
authors.initials: E
authors.lastname: Folta-Stogniew
authors.forename: Pietro
authors.initials: P
authors.lastname: De Camilli
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001665:Binding Sites; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009800:Oculocerebrorenal Syndrome / Q000235:genetics*; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017510:Protein Folding; D016415:Sequence Alignment; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D010744:Phosphoric Monoester Hydrolases; C075695:OCRL protein, human; D020696:rab5 GTP-Binding Proteins