PDBsum entry 2qv2

Hydrolase

PDB id

2qv2

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Contents

			Protein chain

					305 a.a. *

			Waters ×42

* Residue conservation analysis

PDB id:

2qv2

Links

Name:

Hydrolase

Title:

A role of the lowe syndrome protein ocrl in early steps of the endocytic pathway

Structure:

Inositol polyphosphate 5-phosphatase ocrl-1. Chain: a. Fragment: ash-rhogap-like tandem domains. Synonym: ocrl. Lowe oculocerebrorenal syndrome protein. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ocrl, inpp5f, ocrl1. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.

Resolution:

2.40Å

R-factor:

0.248

R-free:

0.288

Authors:

Y.Mao,K.S.Erdman,H.J.Mccrea,P.De Camilli

Key ref:

K.S.Erdmann et al. (2007). A role of the Lowe syndrome protein OCRL in early steps of the endocytic pathway. Dev Cell, 13, 377-390. PubMed id: 17765681

Date:

07-Aug-07

Release date:

21-Aug-07

PROCHECK

	Headers

	References

Protein chain

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

Seq: Struc:

Seq: Struc:					901 a.a. 305 a.a.

Key:

PfamA domain

Secondary structure

CATH domain



		Enzyme reactions

Enzyme class 1:

E.C.3.1.3.36 - phosphoinositide 5-phosphatase.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

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

1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate)	+	H2O	=	1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol 4-phosphate)	+	phosphate

Enzyme class 2:

E.C.3.1.3.56 - inositol-polyphosphate 5-phosphatase.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

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

1D-myo-inositol 1,4,5-trisphosphate	+	H2O	=	1D-myo-inositol 1,4- bisphosphate	+	phosphate

1D-myo-inositol 1,3,4,5-tetrakisphosphate	+	H2O	=	1D-myo-inositol 1,3,4-trisphosphate	+	phosphate

Enzyme class 3:

E.C.3.1.3.86 - phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

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

1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5-trisphosphate)	+	H2O	=	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

	Dev Cell 13:377-390 (2007)
PubMed id: 17765681

A role of the Lowe syndrome protein OCRL in early steps of the endocytic pathway.
K.S.Erdmann, Y.Mao, H.J.McCrea, R.Zoncu, S.Lee, S.Paradise, J.Modregger, D.Biemesderfer, D.Toomre, P.De Camilli.

ABSTRACT

Mutations in the inositol 5-phosphatase OCRL are responsible for Lowe syndrome, whose manifestations include mental retardation and renal Fanconi syndrome. OCRL has been implicated in membrane trafficking, but disease mechanisms remain unclear. We show that OCRL visits late-stage, endocytic clathrin-coated pits and binds the Rab5 effector APPL1 on peripheral early endosomes. The interaction with APPL1, which is mediated by the ASH-RhoGAP-like domains of OCRL and is abolished by disease mutations, provides a link to protein networks implicated in the reabsorptive function of the kidney and in the trafficking and signaling of growth factor receptors in the brain. Crystallographic studies reveal a role of the ASH-RhoGAP-like domains in positioning the phosphatase domain at the membrane interface and a clathrin box protruding from the RhoGAP-like domain. Our results support a role of OCRL in the early endocytic pathway, consistent with the predominant localization of its preferred substrates, PI(4,5)P(2) and PI(3,4,5)P(3), at the cell surface.

Literature references that cite this PDB file's key reference

PubMed id

Reference

21706022

D.Dambournet, M.Machicoane, L.Chesneau, M.Sachse, M.Rocancourt, A.El Marjou, E.Formstecher, R.Salomon, B.Goud, and A.Echard (2011).
Rab35 GTPase and OCRL phosphatase remodel lipids and F-actin for successful cytokinesis.

Nat Cell Biol, 13, 981-988.

20936522

F.Claverie-Martín, E.Ramos-Trujillo, and V.García-Nieto (2011).
Dent's disease: clinical features and molecular basis.

Pediatr Nephrol, 26, 693-704.

21031565

H.Hichri, J.Rendu, N.Monnier, C.Coutton, O.Dorseuil, R.V.Poussou, G.Baujat, A.Blanchard, F.Nobili, B.Ranchin, M.Remesy, R.Salomon, V.Satre, and J.Lunardi (2011).
From Lowe syndrome to Dent disease: correlations between mutations of the OCRL1 gene and clinical and biochemical phenotypes.

Hum Mutat, 32, 379-388.

21445324

M.J.Taylor, D.Perrais, and C.J.Merrifield (2011).
A high precision survey of the molecular dynamics of mammalian clathrin-mediated endocytosis.

PLoS Biol, 9, e1000604.

21666675

M.Pirruccello, L.E.Swan, E.Folta-Stogniew, and P.De Camilli (2011).
Recognition of the F&H motif by the Lowe syndrome protein OCRL.

Nat Struct Mol Biol, 18, 789-795.

PDB code:

3qis

21249396

V.Tasic, V.J.Lozanovski, P.Korneti, N.Ristoska-Bojkovska, V.Sabolic-Avramovska, Z.Gucev, and M.Ludwig (2011).
Clinical and laboratory features of Macedonian children with OCRL mutations.

Pediatr Nephrol, 26, 557-562.

21378754

X.Hou, N.Hagemann, S.Schoebel, W.Blankenfeldt, R.S.Goody, K.S.Erdmann, and A.Itzen (2011).
A structural basis for Lowe syndrome caused by mutations in the Rab-binding domain of OCRL1.

EMBO J, 30, 1659-1670.

PDB code:

3qbt

20545906

A.Hoffmann, P.N.Dannhauser, S.Groos, L.Hinrichsen, U.Curth, and E.J.Ungewickell (2010).
A comparison of GFP-tagged clathrin light chains with fluorochromated light chains in vivo and in vitro.

Traffic, 11, 1129-1140.

20231409

A.M.Moorhead, J.Y.Jung, A.Smirnov, S.Kaufer, and M.A.Scidmore (2010).
Multiple host proteins that function in phosphatidylinositol-4-phosphate metabolism are recruited to the chlamydial inclusion.

Infect Immun, 78, 1990-2007.

20629659

D.Lasne, G.Baujat, T.Mirault, J.Lunardi, F.Grelac, M.Egot, R.Salomon, and C.Bachelot-Loza (2010).
Bleeding disorders in Lowe syndrome patients: evidence for a link between OCRL mutations and primary haemostasis disorders.

Br J Haematol, 150, 685-688.

20679431

F.Nakatsu, R.M.Perera, L.Lucast, R.Zoncu, J.Domin, F.B.Gertler, D.Toomre, and P.De Camilli (2010).
The inositol 5-phosphatase SHIP2 regulates endocytic clathrin-coated pit dynamics.

J Cell Biol, 190, 307-315.

21115825

G.Ko, S.Paradise, H.Chen, M.Graham, M.Vecchi, F.Bianchi, O.Cremona, P.P.Di Fiore, and P.De Camilli (2010).
Selective high-level expression of epsin 3 in gastric parietal cells, where it is localized at endocytic sites of apical canaliculi.

Proc Natl Acad Sci U S A, 107, 21511-21516.

20814572

H.J.Chial, P.Lenart, and Y.Q.Chen (2010).
APPL proteins FRET at the BAR: direct observation of APPL1 and APPL2 BAR domain-mediated interactions on cell membranes using FRET microscopy.

PLoS One, 5, e12471.

20622009

L.A.Volpicelli-Daley, L.Lucast, L.W.Gong, L.Liu, J.Sasaki, T.Sasaki, C.S.Abrams, Y.Kanaho, and P.De Camilli (2010).
Phosphatidylinositol-4-phosphate 5-kinases and phosphatidylinositol 4,5-bisphosphate synthesis in the brain.

J Biol Chem, 285, 28708-28714.

20133602

L.E.Swan, L.Tomasini, M.Pirruccello, J.Lunardi, and P.De Camilli (2010).
Two closely related endocytic proteins that share a common OCRL-binding motif with APPL1.

Proc Natl Acad Sci U S A, 107, 3511-3516.

20568240

L.Wen, Y.Yang, Y.Wang, A.Xu, D.Wu, and Y.Chen (2010).
Appl1 is essential for the survival of Xenopus pancreas, duodenum, and stomach progenitor cells.

Dev Dyn, 239, 2198-2207.

21115805

M.Bohdanowicz, G.Cosío, J.M.Backer, and S.Grinstein (2010).
Class I and class III phosphoinositide 3-kinases are required for actin polymerization that propels phagosomes.

J Cell Biol, 191, 999.

19924646

M.Jovic, M.Sharma, J.Rahajeng, and S.Caplan (2010).
The early endosome: a busy sorting station for proteins at the crossroads.

Histol Histopathol, 25, 99.

20946626

O.Devuyst, and R.V.Thakker (2010).
Dent's disease.

Orphanet J Rare Dis, 5, 28.

20049615

R.Nielsen, and E.I.Christensen (2010).
Proteinuria and events beyond the slit.

Pediatr Nephrol, 25, 813-822.

19940034

S.Cui, C.J.Guerriero, C.M.Szalinski, C.L.Kinlough, R.P.Hughey, and O.A.Weisz (2010).
OCRL1 function in renal epithelial membrane traffic.

Am J Physiol Renal Physiol, 298, F335-F345.

20872266

S.P.Bothwell, L.W.Farber, A.Hoagland, and R.L.Nussbaum (2010).
Species-specific difference in expression and splice-site choice in Inpp5b, an inositol polyphosphate 5-phosphatase paralogous to the enzyme deficient in Lowe Syndrome.

Mamm Genome, 21, 458-466.

20439739

X.Zhou, L.Wang, H.Hasegawa, P.Amin, B.X.Han, S.Kaneko, Y.He, and F.Wang (2010).
Deletion of PIK3C3/Vps34 in sensory neurons causes rapid neurodegeneration by disrupting the endosomal but not the autophagic pathway.

Proc Natl Acad Sci U S A, 107, 9424-9429.

20040596

Y.Tan, H.You, C.Wu, D.A.Altomare, and J.R.Testa (2010).
Appl1 is dispensable for mouse development, and loss of Appl1 has growth factor-selective effects on Akt signaling in murine embryonic fibroblasts.

J Biol Chem, 285, 6377-6389.

19582483

E.Tosetto, M.Addis, G.Caridi, C.Meloni, F.Emma, G.Vergine, G.Stringini, T.Papalia, G.Barbano, G.M.Ghiggeri, L.Ruggeri, N.Miglietti, A.D Angelo, M.A.Melis, and F.Anglani (2009).
Locus heterogeneity of Dent's disease: OCRL1 and TMEM27 genes in patients with no CLCN5 mutations.

Pediatr Nephrol, 24, 1967-1973.

19666558

H.Chen, G.Ko, A.Zatti, G.Di Giacomo, L.Liu, E.Raiteri, E.Perucco, C.Collesi, W.Min, C.Zeiss, P.De Camilli, and O.Cremona (2009).
Embryonic arrest at midgestation and disruption of Notch signaling produced by the absence of both epsin 1 and epsin 2 in mice.

Proc Natl Acad Sci U S A, 106, 13838-13843.

18647649

J.G.Donaldson, N.Porat-Shliom, and L.A.Cohen (2009).
Clathrin-independent endocytosis: a unique platform for cell signaling and PM remodeling.

Cell Signal, 21, 1-6.

19416712

K.K.Cheng, M.A.Iglesias, K.S.Lam, Y.Wang, G.Sweeney, W.Zhu, P.M.Vanhoutte, E.W.Kraegen, and A.Xu (2009).
APPL1 potentiates insulin-mediated inhibition of hepatic glucose production and alleviates diabetes via Akt activation in mice.

Cell Metab, 9, 417-427.

19686092

M.Banach-Orlowska, I.Pilecka, A.Torun, B.Pyrzynska, and M.Miaczynska (2009).
Functional characterization of the interactions between endosomal adaptor protein APPL1 and the NuRD co-repressor complex.

Biochem J, 423, 389-400.

19508852

P.Mayinger (2009).
Regulation of Golgi function via phosphoinositide lipids.

Semin Cell Dev Biol, 20, 793-800.

19211563

R.Choudhury, C.J.Noakes, E.McKenzie, C.Kox, and M.Lowe (2009).
Differential clathrin binding and subcellular localization of OCRL1 splice isoforms.

J Biol Chem, 284, 9965-9973.

19303853

R.Zoncu, R.M.Perera, D.M.Balkin, M.Pirruccello, D.Toomre, and P.De Camilli (2009).
A phosphoinositide switch controls the maturation and signaling properties of APPL endosomes.

Cell, 136, 1110-1121.

19701229

S.J.Schurman, and S.J.Scheinman (2009).
Inherited cerebrorenal syndromes.

Nat Rev Nephrol, 5, 529-538.

19433865

S.Rashid, I.Pilecka, A.Torun, M.Olchowik, B.Bielinska, and M.Miaczynska (2009).
Endosomal Adaptor Proteins APPL1 and APPL2 Are Novel Activators of {beta}-Catenin/TCF-mediated Transcription.

J Biol Chem, 284, 18115-18128.

18854421

S.S.Deepa, and L.Q.Dong (2009).
APPL1: role in adiponectin signaling and beyond.

Am J Physiol Endocrinol Metab, 296, E22-E36.

19580826

T.Sasaki, S.Takasuga, J.Sasaki, S.Kofuji, S.Eguchi, M.Yamazaki, and A.Suzuki (2009).
Mammalian phosphoinositide kinases and phosphatases.

Prog Lipid Res, 48, 307-343.

18853181

V.Plans, G.Rickheit, and T.J.Jentsch (2009).
Physiological roles of CLC Cl(-)/H (+) exchangers in renal proximal tubules.

Pflugers Arch, 458, 23-37.

19536138

Y.Mao, D.M.Balkin, R.Zoncu, K.S.Erdmann, L.Tomasini, F.Hu, M.M.Jin, M.E.Hodsdon, and P.De Camilli (2009).
A PH domain within OCRL bridges clathrin-mediated membrane trafficking to phosphoinositide metabolism.

EMBO J, 28, 1831-1842.

PDB codes:

2kie 2kig

18455989

A.Schenck, L.Goto-Silva, C.Collinet, M.Rhinn, A.Giner, B.Habermann, M.Brand, and M.Zerial (2008).
The endosomal protein Appl1 mediates Akt substrate specificity and cell survival in vertebrate development.

Cell, 133, 486-497.

18480301

D.Bockenhauer, A.Bokenkamp, W.van't Hoff, E.Levtchenko, J.E.Kist-van Holthe, V.Tasic, and M.Ludwig (2008).
Renal phenotype in Lowe Syndrome: a selective proximal tubular dysfunction.

Clin J Am Soc Nephrol, 3, 1430-1436.

18603546

L.Monnens, and E.Levtchenko (2008).
Evaluation of the proximal tubular function in hereditary renal Fanconi syndrome.

Nephrol Dial Transplant, 23, 2719-2722.

18319245

M.J.Wainszelbaum, A.J.Charron, C.Kong, D.S.Kirkpatrick, P.Srikanth, M.A.Barbieri, S.P.Gygi, and P.D.Stahl (2008).
The hominoid-specific oncogene TBC1D3 activates Ras and modulates epidermal growth factor receptor signaling and trafficking.

J Biol Chem, 283, 13233-13242.

18779366

M.P.McShane, and M.Zerial (2008).
Survival of the weakest: signaling aided by endosomes.

J Cell Biol, 182, 823-825.

18784754

M.Vicinanza, G.D'Angelo, A.Di Campli, and M.A.De Matteis (2008).
Function and dysfunction of the PI system in membrane trafficking.

EMBO J, 27, 2457-2470.

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.