UniProt functional annotation for Q01968



	UniProt functional annotation for Q01968

UniProt code: Q01968.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Catalyzes the hydrolysis of the 4-position phosphate of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and phosphatidylinositol-3,4,5-bisphosphate (PtdIns(3,4,5)P3), with the greatest catalytic activity towards PtdIns(4,5)P2 (PubMed:7761412, PubMed:15474001, PubMed:9430698, PubMed:10764818). Able also to hydrolyzes the 4-phosphate of inositol 1,4,5-trisphosphate and of inositol 1,3,4,5-tetrakisphosphate (PubMed:7761412, PubMed:25869668). Regulates traffic in the endosomal pathway by regulating the specific pool of phosphatidylinositol 4,5-bisphosphate that is associated with endosomes (PubMed:21971085). Involved in primary cilia assembly (PubMed:22228094, PubMed:22543976). Acts as a regulator of phagocytosis, hydrolyzing PtdIns(4,5)P2 to promote phagosome closure, through attenuation of PI3K signaling (PubMed:22072788). {ECO:0000269|PubMed:10764818, ECO:0000269|PubMed:15474001, ECO:0000269|PubMed:21971085, ECO:0000269|PubMed:22072788, ECO:0000269|PubMed:22228094, ECO:0000269|PubMed:22543976, ECO:0000269|PubMed:25869668, ECO:0000269|PubMed:7761412, ECO:0000269|PubMed:9430698}.

Catalytic activity: 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; Xref=Rhea:RHEA:22764, ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:58178, ChEBI:CHEBI:58456; EC=3.1.3.36; Evidence={ECO:0000269|PubMed:10764818, ECO:0000269|PubMed:15474001, ECO:0000269|PubMed:7761412, ECO:0000269|PubMed:9430698}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22765; Evidence={ECO:0000305};

Catalytic activity: 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; Xref=Rhea:RHEA:25528, ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:57658, ChEBI:CHEBI:57836; EC=3.1.3.86; Evidence={ECO:0000269|PubMed:10764818, ECO:0000269|PubMed:15474001}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:25529; Evidence={ECO:0000305};

Catalytic activity: Reaction=1D-myo-inositol 1,3,4,5-tetrakisphosphate + H2O = 1D-myo- inositol 1,3,4-trisphosphate + phosphate; Xref=Rhea:RHEA:11392, ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:57895, ChEBI:CHEBI:58414; EC=3.1.3.56; Evidence={ECO:0000269|PubMed:15474001, ECO:0000269|PubMed:7761412}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:11393; Evidence={ECO:0000305};

Catalytic activity: Reaction=1D-myo-inositol 1,4,5-trisphosphate + H2O = 1D-myo-inositol 1,4-bisphosphate + phosphate; Xref=Rhea:RHEA:19797, ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:58282, ChEBI:CHEBI:203600; EC=3.1.3.56; Evidence={ECO:0000269|PubMed:15474001, ECO:0000269|PubMed:7761412}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19798; Evidence={ECO:0000305};

Biophysicochemical properties: Kinetic parameters: KM=30 uM for Ins(1,3,4,5)P4 {ECO:0000269|PubMed:7761412}; KM=139 uM for PtdIns(3,4,5)P3 {ECO:0000269|PubMed:15474001}; KM=23 uM for PtdIns(4,5)P2 {ECO:0000269|PubMed:15474001}; KM=70 uM for Ins(1,4,5)P3 {ECO:0000269|PubMed:7761412}; Vmax=1.8 umol/min/mg enzyme with Ins(1,3,4,5)P4 as substrate {ECO:0000269|PubMed:7761412}; Vmax=8 umol/min/mg enzyme with Ins(1,4,5)P3 as substrate {ECO:0000269|PubMed:7761412};

Subunit: Interacts with APPL1, FAM109A/SES1 and FAM109B/SES2; APPL1- binding and FAM109A-binding are mutually exclusive. Interacts with clathrin heavy chain. Interacts with several Rab GTPases, at least RAB1B, RAB5A, RAB6A, RAB8A and RAB31; these interactions may play a dual role in targeting OCRL to the specific membranes and stimulating the phosphatase activity. Interaction with RAB8A modulates OCRL recruitment to cilia. Interacts with INPP5F (PubMed:25869668). {ECO:0000269|PubMed:17765681, ECO:0000269|PubMed:19536138, ECO:0000269|PubMed:20133602, ECO:0000269|PubMed:21233288, ECO:0000269|PubMed:21378754, ECO:0000269|PubMed:21666675, ECO:0000269|PubMed:22543976, ECO:0000269|PubMed:25869668}.

Subcellular location: Cytoplasmic vesicle, phagosome membrane {ECO:0000250|UniProtKB:D3ZGS3}. Early endosome membrane {ECO:0000269|PubMed:21971085, ECO:0000269|PubMed:25869668}. Membrane, clathrin-coated pit {ECO:0000269|PubMed:25869668}. Cell projection, cilium, photoreceptor outer segment {ECO:0000269|PubMed:22543976}. Cell projection, cilium {ECO:0000269|PubMed:22543976}. Cytoplasmic vesicle {ECO:0000250|UniProtKB:D3ZGS3}. Endosome {ECO:0000269|PubMed:21971085, ECO:0000269|PubMed:25869668}. Golgi apparatus, trans-Golgi network {ECO:0000250|UniProtKB:D3ZGS3}. Lysosome {ECO:0000269|PubMed:9430698}. Note=Also found on macropinosomes (PubMed:25869668). Colocalized with APPL1 on phagosomes (PubMed:22072788). {ECO:0000269|PubMed:22072788, ECO:0000269|PubMed:25869668}.

Tissue specificity: Brain, skeletal muscle, heart, kidney, lung, placenta and fibroblasts. Expressed in the retina and the retinal pigment epithelium. {ECO:0000269|PubMed:22543976}.

Domain: The ASH (ASPM-SPD2-Hydin) and RhoGAP (Rho GTPase activating) domains form a single folding module. The ASH domain has an immunoglobulin-like fold, the Rho-GAP domain lacks the catalytic arginine and is catalytically inactive. The ASH-RhoGAP module regulates the majority of the protein-protein interactions currently described. The ASH domain mediates association with membrane-targeting Rab GTPases. The Rho-GAP domain interacts with the endocytic adapter APPL1, which is then displaced by FAM109A and FAM109B as endosomes mature. {ECO:0000269|PubMed:19536138}.

Disease: Lowe oculocerebrorenal syndrome (OCRL) [MIM:309000]: X-linked multisystem disorder affecting eyes, nervous system, and kidney. It is characterized by hydrophthalmia, cataract, mental retardation, vitamin D-resistant rickets, aminoaciduria, and reduced ammonia production by the kidney. Ocular abnormalities include cataract, glaucoma, microphthalmos, and decreased visual acuity. Developmental delay, hypotonia, behavior abnormalities, and areflexia are also present. Renal tubular involvement is characterized by impaired reabsorption of bicarbonate, amino acids, and phosphate. Musculoskeletal abnormalities such as joint hypermobility, dislocated hips, and fractures may develop as consequences of renal tubular acidosis and hypophosphatemia. Cataract is the only significant manifestation in carriers and is detected by slit-lamp examination. {ECO:0000269|PubMed:10767176, ECO:0000269|PubMed:10923037, ECO:0000269|PubMed:19168822, ECO:0000269|PubMed:20133602, ECO:0000269|PubMed:21031565, ECO:0000269|PubMed:21233288, ECO:0000269|PubMed:9199559, ECO:0000269|PubMed:9632163, ECO:0000269|PubMed:9682219, ECO:0000269|PubMed:9788721}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Dent disease 2 (DD2) [MIM:300555]: A renal disease belonging to the 'Dent disease complex', a group of disorders characterized by proximal renal tubular defect, hypercalciuria, nephrocalcinosis, and renal insufficiency. The spectrum of phenotypic features is remarkably similar in the various disorders, except for differences in the severity of bone deformities and renal impairment. Characteristic abnormalities include low-molecular-weight proteinuria and other features of Fanconi syndrome, such as glycosuria, aminoaciduria, and phosphaturia, but typically do not include proximal renal tubular acidosis. Progressive renal failure is common, as are nephrocalcinosis and kidney stones. {ECO:0000269|PubMed:15627218, ECO:0000269|PubMed:17384968, ECO:0000269|PubMed:21031565}. Note=The disease is caused by variants affecting the gene represented in this entry.

Similarity: Belongs to the inositol 1,4,5-trisphosphate 5-phosphatase type II family. {ECO:0000305}.

Sequence caution: Sequence=AAA59964.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Catalyzes the hydrolysis of the 4-position phosphate of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and phosphatidylinositol-3,4,5-bisphosphate (PtdIns(3,4,5)P3), with the greatest catalytic activity towards PtdIns(4,5)P2 (PubMed:7761412, PubMed:15474001, PubMed:9430698, PubMed:10764818). Able also to hydrolyzes the 4-phosphate of inositol 1,4,5-trisphosphate and of inositol 1,3,4,5-tetrakisphosphate (PubMed:7761412, PubMed:25869668). Regulates traffic in the endosomal pathway by regulating the specific pool of phosphatidylinositol 4,5-bisphosphate that is associated with endosomes (PubMed:21971085). Involved in primary cilia assembly (PubMed:22228094, PubMed:22543976). Acts as a regulator of phagocytosis, hydrolyzing PtdIns(4,5)P2 to promote phagosome closure, through attenuation of PI3K signaling (PubMed:22072788). {ECO:0000269\|PubMed:10764818, ECO:0000269\|PubMed:15474001, ECO:0000269\|PubMed:21971085, ECO:0000269\|PubMed:22072788, ECO:0000269\|PubMed:22228094, ECO:0000269\|PubMed:22543976, ECO:0000269\|PubMed:25869668, ECO:0000269\|PubMed:7761412, ECO:0000269\|PubMed:9430698}.


Catalytic activity:		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; Xref=Rhea:RHEA:22764, ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:58178, ChEBI:CHEBI:58456; EC=3.1.3.36; Evidence={ECO:0000269\|PubMed:10764818, ECO:0000269\|PubMed:15474001, ECO:0000269\|PubMed:7761412, ECO:0000269\|PubMed:9430698}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22765; Evidence={ECO:0000305};
Catalytic activity:		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; Xref=Rhea:RHEA:25528, ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:57658, ChEBI:CHEBI:57836; EC=3.1.3.86; Evidence={ECO:0000269\|PubMed:10764818, ECO:0000269\|PubMed:15474001}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:25529; Evidence={ECO:0000305};
Catalytic activity:		Reaction=1D-myo-inositol 1,3,4,5-tetrakisphosphate + H2O = 1D-myo- inositol 1,3,4-trisphosphate + phosphate; Xref=Rhea:RHEA:11392, ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:57895, ChEBI:CHEBI:58414; EC=3.1.3.56; Evidence={ECO:0000269\|PubMed:15474001, ECO:0000269\|PubMed:7761412}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:11393; Evidence={ECO:0000305};
Catalytic activity:		Reaction=1D-myo-inositol 1,4,5-trisphosphate + H2O = 1D-myo-inositol 1,4-bisphosphate + phosphate; Xref=Rhea:RHEA:19797, ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:58282, ChEBI:CHEBI:203600; EC=3.1.3.56; Evidence={ECO:0000269\|PubMed:15474001, ECO:0000269\|PubMed:7761412}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19798; Evidence={ECO:0000305};
Biophysicochemical properties:		Kinetic parameters: KM=30 uM for Ins(1,3,4,5)P4 {ECO:0000269\|PubMed:7761412}; KM=139 uM for PtdIns(3,4,5)P3 {ECO:0000269\|PubMed:15474001}; KM=23 uM for PtdIns(4,5)P2 {ECO:0000269\|PubMed:15474001}; KM=70 uM for Ins(1,4,5)P3 {ECO:0000269\|PubMed:7761412}; Vmax=1.8 umol/min/mg enzyme with Ins(1,3,4,5)P4 as substrate {ECO:0000269\|PubMed:7761412}; Vmax=8 umol/min/mg enzyme with Ins(1,4,5)P3 as substrate {ECO:0000269\|PubMed:7761412};
Subunit:		Interacts with APPL1, FAM109A/SES1 and FAM109B/SES2; APPL1- binding and FAM109A-binding are mutually exclusive. Interacts with clathrin heavy chain. Interacts with several Rab GTPases, at least RAB1B, RAB5A, RAB6A, RAB8A and RAB31; these interactions may play a dual role in targeting OCRL to the specific membranes and stimulating the phosphatase activity. Interaction with RAB8A modulates OCRL recruitment to cilia. Interacts with INPP5F (PubMed:25869668). {ECO:0000269\|PubMed:17765681, ECO:0000269\|PubMed:19536138, ECO:0000269\|PubMed:20133602, ECO:0000269\|PubMed:21233288, ECO:0000269\|PubMed:21378754, ECO:0000269\|PubMed:21666675, ECO:0000269\|PubMed:22543976, ECO:0000269\|PubMed:25869668}.
Subcellular location:		Cytoplasmic vesicle, phagosome membrane {ECO:0000250\|UniProtKB:D3ZGS3}. Early endosome membrane {ECO:0000269\|PubMed:21971085, ECO:0000269\|PubMed:25869668}. Membrane, clathrin-coated pit {ECO:0000269\|PubMed:25869668}. Cell projection, cilium, photoreceptor outer segment {ECO:0000269\|PubMed:22543976}. Cell projection, cilium {ECO:0000269\|PubMed:22543976}. Cytoplasmic vesicle {ECO:0000250\|UniProtKB:D3ZGS3}. Endosome {ECO:0000269\|PubMed:21971085, ECO:0000269\|PubMed:25869668}. Golgi apparatus, trans-Golgi network {ECO:0000250\|UniProtKB:D3ZGS3}. Lysosome {ECO:0000269\|PubMed:9430698}. Note=Also found on macropinosomes (PubMed:25869668). Colocalized with APPL1 on phagosomes (PubMed:22072788). {ECO:0000269\|PubMed:22072788, ECO:0000269\|PubMed:25869668}.
Tissue specificity:		Brain, skeletal muscle, heart, kidney, lung, placenta and fibroblasts. Expressed in the retina and the retinal pigment epithelium. {ECO:0000269\|PubMed:22543976}.
Domain:		The ASH (ASPM-SPD2-Hydin) and RhoGAP (Rho GTPase activating) domains form a single folding module. The ASH domain has an immunoglobulin-like fold, the Rho-GAP domain lacks the catalytic arginine and is catalytically inactive. The ASH-RhoGAP module regulates the majority of the protein-protein interactions currently described. The ASH domain mediates association with membrane-targeting Rab GTPases. The Rho-GAP domain interacts with the endocytic adapter APPL1, which is then displaced by FAM109A and FAM109B as endosomes mature. {ECO:0000269\|PubMed:19536138}.
Disease:		Lowe oculocerebrorenal syndrome (OCRL) [MIM:309000]: X-linked multisystem disorder affecting eyes, nervous system, and kidney. It is characterized by hydrophthalmia, cataract, mental retardation, vitamin D-resistant rickets, aminoaciduria, and reduced ammonia production by the kidney. Ocular abnormalities include cataract, glaucoma, microphthalmos, and decreased visual acuity. Developmental delay, hypotonia, behavior abnormalities, and areflexia are also present. Renal tubular involvement is characterized by impaired reabsorption of bicarbonate, amino acids, and phosphate. Musculoskeletal abnormalities such as joint hypermobility, dislocated hips, and fractures may develop as consequences of renal tubular acidosis and hypophosphatemia. Cataract is the only significant manifestation in carriers and is detected by slit-lamp examination. {ECO:0000269\|PubMed:10767176, ECO:0000269\|PubMed:10923037, ECO:0000269\|PubMed:19168822, ECO:0000269\|PubMed:20133602, ECO:0000269\|PubMed:21031565, ECO:0000269\|PubMed:21233288, ECO:0000269\|PubMed:9199559, ECO:0000269\|PubMed:9632163, ECO:0000269\|PubMed:9682219, ECO:0000269\|PubMed:9788721}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Dent disease 2 (DD2) [MIM:300555]: A renal disease belonging to the 'Dent disease complex', a group of disorders characterized by proximal renal tubular defect, hypercalciuria, nephrocalcinosis, and renal insufficiency. The spectrum of phenotypic features is remarkably similar in the various disorders, except for differences in the severity of bone deformities and renal impairment. Characteristic abnormalities include low-molecular-weight proteinuria and other features of Fanconi syndrome, such as glycosuria, aminoaciduria, and phosphaturia, but typically do not include proximal renal tubular acidosis. Progressive renal failure is common, as are nephrocalcinosis and kidney stones. {ECO:0000269\|PubMed:15627218, ECO:0000269\|PubMed:17384968, ECO:0000269\|PubMed:21031565}. Note=The disease is caused by variants affecting the gene represented in this entry.
Similarity:		Belongs to the inositol 1,4,5-trisphosphate 5-phosphatase type II family. {ECO:0000305}.
Sequence caution:		Sequence=AAA59964.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};