3qis

From Proteopedia

(Difference between revisions)

Revision as of 11:01, 19 December 2014

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

Structural highlights

3qis is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Gene:	INPP5F, OCRL, OCRL1 (Homo sapiens)
Activity:	Phosphoinositide 5-phosphatase, with EC number 3.1.3.36
Resources:	FirstGlance, OCA, RCSB, PDBsum

Disease

[OCRL_HUMAN] Defects in OCRL are the cause of Lowe oculocerebrorenal syndrome (OCRL) [MIM:309000]. It is an 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.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] Defects in OCRL are the cause of Dent disease type 2 (DD2) [MIM:300555]. DD2 is 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.^[11] ^[12] ^[13]

Function

[OCRL_HUMAN] Converts phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 4-phosphate. Also converts inositol 1,4,5-trisphosphate to inositol 1,4-bisphosphate and inositol 1,3,4,5-tetrakisphosphate to inositol 1,3,4-trisphosphate. May function in lysosomal membrane trafficking by regulating the specific pool of phosphatidylinositol 4,5-bisphosphate that is associated with lysosomes. Involved in primary cilia assembly.^[14] ^[15]

Publication Abstract from PubMed

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.

Recognition of the F&H motif by the Lowe syndrome protein OCRL.,Pirruccello M, Swan LE, Folta-Stogniew E, De Camilli P Nat Struct Mol Biol. 2011 Jun 12. doi: 10.1038/nsmb.2071. PMID:21666675^[16]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Swan LE, Tomasini L, Pirruccello M, Lunardi J, De Camilli P. Two closely related endocytic proteins that share a common OCRL-binding motif with APPL1. Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3511-6. doi:, 10.1073/pnas.0914658107. Epub 2010 Feb 2. PMID:20133602 doi:10.1073/pnas.0914658107
↑ Noakes CJ, Lee G, Lowe M. The PH domain proteins IPIP27A and B link OCRL1 to receptor recycling in the endocytic pathway. Mol Biol Cell. 2011 Mar 1;22(5):606-23. doi: 10.1091/mbc.E10-08-0730. Epub 2011, Jan 13. PMID:21233288 doi:10.1091/mbc.E10-08-0730
↑ Lin T, Orrison BM, Leahey AM, Suchy SF, Bernard DJ, Lewis RA, Nussbaum RL. Spectrum of mutations in the OCRL1 gene in the Lowe oculocerebrorenal syndrome. Am J Hum Genet. 1997 Jun;60(6):1384-8. PMID:9199559 doi:10.1086/515471
↑ Lin T, Orrison BM, Suchy SF, Lewis RA, Nussbaum RL. Mutations are not uniformly distributed throughout the OCRL1 gene in Lowe syndrome patients. Mol Genet Metab. 1998 May;64(1):58-61. PMID:9682219 doi:S1096-7192(98)92687-7
↑ Kawano T, Indo Y, Nakazato H, Shimadzu M, Matsuda I. Oculocerebrorenal syndrome of Lowe: three mutations in the OCRL1 gene derived from three patients with different phenotypes. Am J Med Genet. 1998 Jun 5;77(5):348-55. PMID:9632163
↑ Kubota T, Sakurai A, Arakawa K, Shimazu M, Wakui K, Furihata K, Fukushima Y. Identification of two novel mutations in the OCRL1 gene in Japanese families with Lowe syndrome. Clin Genet. 1998 Sep;54(3):199-202. PMID:9788721
↑ Monnier N, Satre V, Lerouge E, Berthoin F, Lunardi J. OCRL1 mutation analysis in French Lowe syndrome patients: implications for molecular diagnosis strategy and genetic counseling. Hum Mutat. 2000;16(2):157-65. PMID:10923037 doi:<157::AID-HUMU8>3.0.CO;2-9 10.1002/1098-1004(200008)16:2<157::AID-HUMU8>3.0.CO;2-9
↑ Roschinger W, Muntau AC, Rudolph G, Roscher AA, Kammerer S. Carrier assessment in families with lowe oculocerebrorenal syndrome: novel mutations in the OCRL1 gene and correlation of direct DNA diagnosis with ocular examination. Mol Genet Metab. 2000 Mar;69(3):213-22. PMID:10767176 doi:10.1006/mgme.1999.2955
↑ Yuksel A, Karaca E, Albayram MS. Magnetic resonance imaging, magnetic resonance spectroscopy, and facial dysmorphism in a case of Lowe syndrome with novel OCRL1 gene mutation. J Child Neurol. 2009 Jan;24(1):93-6. doi: 10.1177/0883073808321047. PMID:19168822 doi:10.1177/0883073808321047
↑ Hichri H, Rendu J, Monnier N, Coutton C, Dorseuil O, Poussou RV, Baujat G, Blanchard A, Nobili F, Ranchin B, Remesy M, Salomon R, Satre V, Lunardi J. From Lowe syndrome to Dent disease: correlations between mutations of the OCRL1 gene and clinical and biochemical phenotypes. Hum Mutat. 2011 Apr;32(4):379-88. doi: 10.1002/humu.21391. Epub 2011 Mar 10. PMID:21031565 doi:10.1002/humu.21391
↑ Hichri H, Rendu J, Monnier N, Coutton C, Dorseuil O, Poussou RV, Baujat G, Blanchard A, Nobili F, Ranchin B, Remesy M, Salomon R, Satre V, Lunardi J. From Lowe syndrome to Dent disease: correlations between mutations of the OCRL1 gene and clinical and biochemical phenotypes. Hum Mutat. 2011 Apr;32(4):379-88. doi: 10.1002/humu.21391. Epub 2011 Mar 10. PMID:21031565 doi:10.1002/humu.21391
↑ Hoopes RR Jr, Shrimpton AE, Knohl SJ, Hueber P, Hoppe B, Matyus J, Simckes A, Tasic V, Toenshoff B, Suchy SF, Nussbaum RL, Scheinman SJ. Dent Disease with mutations in OCRL1. Am J Hum Genet. 2005 Feb;76(2):260-7. Epub 2004 Dec 30. PMID:15627218 doi:10.1086/427887
↑ Sekine T, Nozu K, Iyengar R, Fu XJ, Matsuo M, Tanaka R, Iijima K, Matsui E, Harita Y, Inatomi J, Igarashi T. OCRL1 mutations in patients with Dent disease phenotype in Japan. Pediatr Nephrol. 2007 Jul;22(7):975-80. Epub 2007 Mar 24. PMID:17384968 doi:10.1007/s00467-007-0454-x
↑ Luo N, West CC, Murga-Zamalloa CA, Sun L, Anderson RM, Wells CD, Weinreb RN, Travers JB, Khanna H, Sun Y. OCRL localizes to the primary cilium: a new role for cilia in Lowe syndrome. Hum Mol Genet. 2012 Aug 1;21(15):3333-44. doi: 10.1093/hmg/dds163. Epub 2012 Apr , 27. PMID:22543976 doi:10.1093/hmg/dds163
↑ Coon BG, Hernandez V, Madhivanan K, Mukherjee D, Hanna CB, Barinaga-Rementeria Ramirez I, Lowe M, Beales PL, Aguilar RC. The Lowe syndrome protein OCRL1 is involved in primary cilia assembly. Hum Mol Genet. 2012 Apr 15;21(8):1835-47. doi: 10.1093/hmg/ddr615. Epub 2012 Jan , 6. PMID:22228094 doi:10.1093/hmg/ddr615
↑ Pirruccello M, Swan LE, Folta-Stogniew E, De Camilli P. Recognition of the F&H motif by the Lowe syndrome protein OCRL. Nat Struct Mol Biol. 2011 Jun 12. doi: 10.1038/nsmb.2071. PMID:21666675 doi:10.1038/nsmb.2071

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3qis"

@@ Line 1: / Line 1: @@
-{{STRUCTURE_3qis|  PDB=3qis  |  SCENE=  }}
+==Recognition of the F&H motif by the Lowe Syndrome protein OCRL==
-===Recognition of the F&H motif by the Lowe Syndrome protein OCRL===
+<StructureSection load='3qis' size='340' side='right' caption='[[3qis]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
-{{ABSTRACT_PUBMED_21666675}}
+== Structural highlights ==
+<table><tr><td colspan='2'>[[3qis]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QIS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3QIS FirstGlance]. <br>
+</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">INPP5F, OCRL, OCRL1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
+<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Phosphoinositide_5-phosphatase Phosphoinositide 5-phosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.36 3.1.3.36] </span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3qis FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qis OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3qis RCSB], [http://www.ebi.ac.uk/pdbsum/3qis PDBsum]</span></td></tr>
+</table>
+== Disease ==
+[[http://www.uniprot.org/uniprot/OCRL_HUMAN OCRL_HUMAN]] Defects in OCRL are the cause of Lowe oculocerebrorenal syndrome (OCRL) [MIM:[http://omim.org/entry/309000 309000]]. It is an 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.<ref>PMID:20133602</ref> <ref>PMID:21233288</ref> <ref>PMID:9199559</ref> <ref>PMID:9682219</ref> <ref>PMID:9632163</ref> <ref>PMID:9788721</ref> <ref>PMID:10923037</ref> <ref>PMID:10767176</ref> <ref>PMID:19168822</ref> <ref>PMID:21031565</ref>   Defects in OCRL are the cause of Dent disease type 2 (DD2) [MIM:[http://omim.org/entry/300555 300555]]. DD2 is 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.<ref>PMID:21031565</ref> <ref>PMID:15627218</ref> <ref>PMID:17384968</ref>
+== Function ==
+[[http://www.uniprot.org/uniprot/OCRL_HUMAN OCRL_HUMAN]] Converts phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 4-phosphate. Also converts inositol 1,4,5-trisphosphate to inositol 1,4-bisphosphate and inositol 1,3,4,5-tetrakisphosphate to inositol 1,3,4-trisphosphate. May function in lysosomal membrane trafficking by regulating the specific pool of phosphatidylinositol 4,5-bisphosphate that is associated with lysosomes. Involved in primary cilia assembly.<ref>PMID:22543976</ref> <ref>PMID:22228094</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+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&amp;H) motif. Using X-ray crystallography, we have identified the F&amp;H motif binding site on the RhoGAP domain of OCRL. Missense mutations associated with disease affected F&amp;H binding indirectly by destabilizing the RhoGAP fold. By contrast, a disease-associated mutation that does not perturb F&amp;H binding and ASH-RhoGAP stability disrupted the interaction of OCRL with Rab5. The F&amp;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.
-==Disease==
+Recognition of the F&amp;H motif by the Lowe syndrome protein OCRL.,Pirruccello M, Swan LE, Folta-Stogniew E, De Camilli P Nat Struct Mol Biol. 2011 Jun 12. doi: 10.1038/nsmb.2071. PMID:21666675<ref>PMID:21666675</ref>
-[[http://www.uniprot.org/uniprot/OCRL_HUMAN OCRL_HUMAN]] Defects in OCRL are the cause of Lowe oculocerebrorenal syndrome (OCRL) [MIM:[http://omim.org/entry/309000 309000]]. It is an 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.<ref>PMID:20133602</ref><ref>PMID:21233288</ref><ref>PMID:9199559</ref><ref>PMID:9682219</ref><ref>PMID:9632163</ref><ref>PMID:9788721</ref><ref>PMID:10923037</ref><ref>PMID:10767176</ref><ref>PMID:19168822</ref><ref>PMID:21031565</ref>  Defects in OCRL are the cause of Dent disease type 2 (DD2) [MIM:[http://omim.org/entry/300555 300555]]. DD2 is 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.<ref>PMID:21031565</ref><ref>PMID:15627218</ref><ref>PMID:17384968</ref>
-==Function==
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[http://www.uniprot.org/uniprot/OCRL_HUMAN OCRL_HUMAN]] Converts phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 4-phosphate. Also converts inositol 1,4,5-trisphosphate to inositol 1,4-bisphosphate and inositol 1,3,4,5-tetrakisphosphate to inositol 1,3,4-trisphosphate. May function in lysosomal membrane trafficking by regulating the specific pool of phosphatidylinositol 4,5-bisphosphate that is associated with lysosomes. Involved in primary cilia assembly.<ref>PMID:22543976</ref><ref>PMID:22228094</ref>
+</div>
+== References ==
-==About this Structure==
+<references/>
-[[3qis]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QIS OCA].
+__TOC__
+</StructureSection>
-==Reference==
-<ref group="xtra">PMID:021666675</ref><references group="xtra"/><references/>
 [[Category: Homo sapiens]]
 [[Category: Phosphoinositide 5-phosphatase]]
-[[Category: Camilli, P De.]]
+[[Category: Camilli, P De]]
-[[Category: Folta-Stogniew, E.]]
+[[Category: Folta-Stogniew, E]]
-[[Category: Pirruccello, M.]]
+[[Category: Pirruccello, M]]
-[[Category: Swan, L E.]]
+[[Category: Swan, L E]]
 [[Category: Appl1]]
 [[Category: Dent disease]]

3qis

From Proteopedia

Revision as of 11:01, 19 December 2014

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

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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