3QIS

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

Summary for 3QIS

• Entry DOI: 10.2210/pdb3qis/pdb
• Descriptor: Inositol polyphosphate 5-phosphatase OCRL-1, Protein FAM109A (3 entities in total)
• Functional Keywords: dent disease, rac1, rab gtpases, appl1, ses2, endocytic pathway, golgi complex, hydrolase-protein binding complex, hydrolase/protein binding
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasmic vesicle, phagosome membrane : Q01968; Early endosome: Q8N4B1
• Total number of polymer chains: 2
• Total formula weight: 44243.66

Authors

Pirruccello, M.,Swan, L.E.,Folta-Stogniew, E.,De Camilli, P. (deposition date: 2011-01-27, release date: 2011-06-15, Last modification date: 2023-09-13)

Primary citation

Pirruccello, M.,Swan, L.E.,Folta-Stogniew, E.,De Camilli, P.
Recognition of the F&H motif by the Lowe syndrome protein OCRL.
Nat.Struct.Mol.Biol., 18:789-795, 2011

PubMed 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.

PubMed: 21666675
DOI: 10.1038/nsmb.2071

Experimental method

X-RAY DIFFRACTION (2.3 Å)