3irt

From Proteopedia

(Difference between revisions)

Current revision

Crystal Structure of the I93M Mutant of Ubiquitin Carboxy-terminal Hydrolase L1

Structural highlights

3irt 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.
Method:	X-ray diffraction, Resolution 2.799Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

UCHL1_HUMAN Defects in UCHL1 are the cause of Parkinson disease type 5 (PARK5) [MIM:613643; also known as Parkinson disease autosomal dominant 5. PARK5 is a complex neurodegenerative disorder with manifestations ranging from typical Parkinson disease to dementia with Lewy bodies. Clinical features include parkinsonian symptoms (resting tremor, rigidity, postural instability and bradykinesia), dementia, diffuse Lewy body pathology, autonomic dysfunction, hallucinations and paranoia.^[1] ^[2] ^[3] ^[4]

Function

UCHL1_HUMAN Ubiquitin-protein hydrolase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins. This enzyme is a thiol protease that recognizes and hydrolyzes a peptide bond at the C-terminal glycine of ubiquitin. Also binds to free monoubiquitin and may prevent its degradation in lysosomes. The homodimer may have ATP-independent ubiquitin ligase activity.^[5] ^[6] ^[7]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a Parkinson disease-associated, putative cysteine protease found abundantly and selectively expressed in neurons. The crystal structure of apo UCHL1 showed that the active-site residues are not aligned in a canonical form, with the nucleophilic cysteine being 7.7 A from the general base histidine, an arrangement consistent with an inactive form of the enzyme. Here we report the crystal structures of the wild type and two Parkinson disease-associated variants of the enzyme, S18Y and I93M, bound to a ubiquitin-based suicide substrate, ubiquitin vinyl methyl ester. These structures reveal that ubiquitin vinyl methyl ester binds primarily at two sites on the enzyme, with its carboxy terminus at the active site and with its amino-terminal beta-hairpin at the distal site-a surface-exposed hydrophobic crevice 17 A away from the active site. Binding at the distal site initiates a cascade of side-chain movements in the enzyme that starts at a highly conserved, surface-exposed phenylalanine and is relayed to the active site resulting in the reorientation and proximal placement of the general base within 4 A of the catalytic cysteine, an arrangement found in productive cysteine proteases. Mutation of the distal-site, surface-exposed phenylalanine to alanine reduces ubiquitin binding and severely impairs the catalytic activity of the enzyme. These results suggest that the activity of UCHL1 may be regulated by its own substrate.

Ubiquitin vinyl methyl ester binding orients the misaligned active site of the ubiquitin hydrolase UCHL1 into productive conformation.,Boudreaux DA, Maiti TK, Davies CW, Das C Proc Natl Acad Sci U S A. 2010 May 18;107(20):9117-22. Epub 2010 May 3. PMID:20439756^[8]

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

References

↑ Liu Y, Fallon L, Lashuel HA, Liu Z, Lansbury PT Jr. The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility. Cell. 2002 Oct 18;111(2):209-18. PMID:12408865
↑ Leroy E, Boyer R, Auburger G, Leube B, Ulm G, Mezey E, Harta G, Brownstein MJ, Jonnalagada S, Chernova T, Dehejia A, Lavedan C, Gasser T, Steinbach PJ, Wilkinson KD, Polymeropoulos MH. The ubiquitin pathway in Parkinson's disease. Nature. 1998 Oct 1;395(6701):451-2. PMID:9774100 doi:10.1038/26652
↑ Nishikawa K, Li H, Kawamura R, Osaka H, Wang YL, Hara Y, Hirokawa T, Manago Y, Amano T, Noda M, Aoki S, Wada K. Alterations of structure and hydrolase activity of parkinsonism-associated human ubiquitin carboxyl-terminal hydrolase L1 variants. Biochem Biophys Res Commun. 2003 Apr 25;304(1):176-83. PMID:12705903
↑ Healy DG, Abou-Sleiman PM, Casas JP, Ahmadi KR, Lynch T, Gandhi S, Muqit MM, Foltynie T, Barker R, Bhatia KP, Quinn NP, Lees AJ, Gibson JM, Holton JL, Revesz T, Goldstein DB, Wood NW. UCHL-1 is not a Parkinson's disease susceptibility gene. Ann Neurol. 2006 Apr;59(4):627-33. PMID:16450370 doi:10.1002/ana.20757
↑ Wada H, Kito K, Caskey LS, Yeh ET, Kamitani T. Cleavage of the C-terminus of NEDD8 by UCH-L3. Biochem Biophys Res Commun. 1998 Oct 29;251(3):688-92. PMID:9790970 doi:S0006-291X(98)99532-8
↑ Liu Y, Fallon L, Lashuel HA, Liu Z, Lansbury PT Jr. The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility. Cell. 2002 Oct 18;111(2):209-18. PMID:12408865
↑ Kyratzi E, Pavlaki M, Stefanis L. The S18Y polymorphic variant of UCH-L1 confers an antioxidant function to neuronal cells. Hum Mol Genet. 2008 Jul 15;17(14):2160-71. doi: 10.1093/hmg/ddn115. Epub 2008 Apr, 14. PMID:18411255 doi:10.1093/hmg/ddn115
↑ Boudreaux DA, Maiti TK, Davies CW, Das C. Ubiquitin vinyl methyl ester binding orients the misaligned active site of the ubiquitin hydrolase UCHL1 into productive conformation. Proc Natl Acad Sci U S A. 2010 May 18;107(20):9117-22. Epub 2010 May 3. PMID:20439756

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 See Also
7 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

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

Categories: Homo sapiens | Large Structures | Das C | Davies CW | Maiti TK

@@ Line 1: / Line 1: @@
 ==Crystal Structure of the I93M Mutant of Ubiquitin Carboxy-terminal Hydrolase L1==
-<StructureSection load='3irt' size='340' side='right' caption='[[3irt]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
+<StructureSection load='3irt' size='340' side='right'caption='[[3irt]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3irt]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3IRT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3IRT FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3irt]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3IRT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3IRT FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.799&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2etl|2etl]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PGP9.5, UCHL1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3irt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3irt OCA], [https://pdbe.org/3irt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3irt RCSB], [https://www.ebi.ac.uk/pdbsum/3irt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3irt ProSAT]</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=3irt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3irt OCA], [http://pdbe.org/3irt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3irt RCSB], [http://www.ebi.ac.uk/pdbsum/3irt PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3irt ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://www.uniprot.org/uniprot/UCHL1_HUMAN UCHL1_HUMAN]] Defects in UCHL1 are the cause of Parkinson disease type 5 (PARK5) [MIM:[http://omim.org/entry/613643 613643]]; also known as Parkinson disease autosomal dominant 5. PARK5 is a complex neurodegenerative disorder with manifestations ranging from typical Parkinson disease to dementia with Lewy bodies. Clinical features include parkinsonian symptoms (resting tremor, rigidity, postural instability and bradykinesia), dementia, diffuse Lewy body pathology, autonomic dysfunction, hallucinations and paranoia.<ref>PMID:12408865</ref> <ref>PMID:9774100</ref> <ref>PMID:12705903</ref> <ref>PMID:16450370</ref>
+[https://www.uniprot.org/uniprot/UCHL1_HUMAN UCHL1_HUMAN] Defects in UCHL1 are the cause of Parkinson disease type 5 (PARK5) [MIM:[https://omim.org/entry/613643 613643]; also known as Parkinson disease autosomal dominant 5. PARK5 is a complex neurodegenerative disorder with manifestations ranging from typical Parkinson disease to dementia with Lewy bodies. Clinical features include parkinsonian symptoms (resting tremor, rigidity, postural instability and bradykinesia), dementia, diffuse Lewy body pathology, autonomic dysfunction, hallucinations and paranoia.<ref>PMID:12408865</ref> <ref>PMID:9774100</ref> <ref>PMID:12705903</ref> <ref>PMID:16450370</ref>
 == Function ==
-[[http://www.uniprot.org/uniprot/UCHL1_HUMAN UCHL1_HUMAN]] Ubiquitin-protein hydrolase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins. This enzyme is a thiol protease that recognizes and hydrolyzes a peptide bond at the C-terminal glycine of ubiquitin. Also binds to free monoubiquitin and may prevent its degradation in lysosomes. The homodimer may have ATP-independent ubiquitin ligase activity.<ref>PMID:9790970</ref> <ref>PMID:12408865</ref> <ref>PMID:18411255</ref>
+[https://www.uniprot.org/uniprot/UCHL1_HUMAN UCHL1_HUMAN] Ubiquitin-protein hydrolase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins. This enzyme is a thiol protease that recognizes and hydrolyzes a peptide bond at the C-terminal glycine of ubiquitin. Also binds to free monoubiquitin and may prevent its degradation in lysosomes. The homodimer may have ATP-independent ubiquitin ligase activity.<ref>PMID:9790970</ref> <ref>PMID:12408865</ref> <ref>PMID:18411255</ref>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 34: / Line 33: @@
 ==See Also==
-*[[Thioesterase|Thioesterase]]
+*[[Thioesterase 3D structures|Thioesterase 3D structures]]
-*[[Ubiquitin|Ubiquitin]]
+*[[3D structures of ubiquitin|3D structures of ubiquitin]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
-[[Category: Das, C]]
+[[Category: Large Structures]]
-[[Category: Davies, C W]]
+[[Category: Das C]]
-[[Category: Maiti, T K]]
+[[Category: Davies CW]]
-[[Category: Cytoplasm]]
+[[Category: Maiti TK]]
-[[Category: Disease mutation]]
-[[Category: Glycoprotein]]
-[[Category: Hydrolase]]
-[[Category: Ligase]]
-[[Category: Oxidation]]
-[[Category: Parkinson's disease mutant]]
-[[Category: Polymorphism]]
-[[Category: Protease]]
-[[Category: Thiol protease]]
-[[Category: Ubiquitin hydrolase]]
-[[Category: Ubl conjugation pathway]]

3irt

From Proteopedia

Current revision

Crystal Structure of the I93M Mutant of Ubiquitin Carboxy-terminal Hydrolase L1

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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