Recognition of the F&H motif by the Lowe Syndrome protein OCRL

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 found in affected patients abolish interactions with the endocytic adaptors APPL1 and Ses (both Ses1 and Ses2), which bind OCRL through a short F&H motif. Using X-ray crystallography, we have identified the F&H motif binding site on the RhoGAP domain of OCRL. We further show that clinical mutations affect F&H binding indirectly by destabilizing the RhoGAP fold. In contrast, a clinical mutation that does not perturb F&H binding and ASH-RhoGAP stability disrupts OCRL's interaction with Rab5. Additionally, OCRL's F&H binding site is conserved even in species that do not express APPL or Ses. Our study predicts the existence of other OCRL binding partners and demonstrates the critical role of the perturbation of OCRL interactions in disease.