PDBsum entry 3qis

Hydrolase/protein binding

PDB id: 3qis

Contents

Protein chains

293 a.a.

13 a.a.

Waters ×123

PDB id:

3qis

Name:

Hydrolase/protein binding

Title:

Recognition of the f&h motif by the lowe syndrome protein ocrl

Structure:

Inositol polyphosphate 5-phosphatase ocrl-1. Chain: a. Fragment: ash-rhogap (unp residues 536-901). Synonym: lowe oculocerebrorenal syndrome protein. Engineered: yes. Protein fam109a. Chain: b. Fragment: f&h motif (unp residues 223-235). Synonym: ses1.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: inpp5f, ocrl, ocrl1. Expressed in: escherichia coli. Expression_system_taxid: 469008. Synthetic: yes. Organism_taxid: 9606

Resolution:

2.30Å R-factor: 0.198 R-free: 0.238

Authors:

M.Pirruccello,L.E.Swan,E.Folta-Stogniew,P.De Camilli

Key ref:

M.Pirruccello et al. (2011). Recognition of the F&H motif by the Lowe syndrome protein OCRL. Nat Struct Biol, 18, 789-795. PubMed id: 21666675

Date:

27-Jan-11 Release date: 15-Jun-11

Protein chain

Q01968  (OCRL_HUMAN) -  Inositol polyphosphate 5-phosphatase OCRL from Homo sapiens

Seq: 901 a.a.

Struc: 293 a.a.

Protein chain

Q8N4B1  (SESQ1_HUMAN) -  Sesquipedalian-1 from Homo sapiens

Seq: 249 a.a.

Struc: 13 a.a.

Enzyme reactions

• Enzyme class 2: Chain A: E.C.3.1.3.36 - phosphoinositide 5-phosphatase.
• Pathway: 1-Phosphatidyl-myo-inositol Metabolism
• Reaction: a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol 4-phosphate) + phosphate
• Enzyme class 3: Chain A: E.C.3.1.3.56 - inositol-polyphosphate 5-phosphatase.

Pathway:

• Reaction:
  1. 1D-myo-inositol 1,4,5-trisphosphate + H2O = 1D-myo-inositol 1,4- bisphosphate + phosphate
  2. 1D-myo-inositol 1,3,4,5-tetrakisphosphate + H2O = 1D-myo-inositol 1,3,4-trisphosphate + phosphate
• Enzyme class 4: Chain A: E.C.3.1.3.86 - phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase.
• Reaction: a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5-trisphosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4- bisphosphate) + phosphate

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

Nat Struct Biol 18:789-795 (2011)

PubMed id: 21666675

Recognition of the F&H motif by the Lowe syndrome protein OCRL.

M.Pirruccello, L.E.Swan, E.Folta-Stogniew, P.De Camilli.

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.