3b3a
From Proteopedia
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|PDB= 3b3a |SIZE=350|CAPTION= <scene name='initialview01'>3b3a</scene>, resolution 1.50Å | |PDB= 3b3a |SIZE=350|CAPTION= <scene name='initialview01'>3b3a</scene>, resolution 1.50Å | ||
|SITE= <scene name='pdbsite=AC1:Cl+Binding+Site+For+Residue+A+190'>AC1</scene>, <scene name='pdbsite=AC2:Edo+Binding+Site+For+Residue+A+191'>AC2</scene>, <scene name='pdbsite=AC3:Edo+Binding+Site+For+Residue+A+192'>AC3</scene> and <scene name='pdbsite=AC4:Edo+Binding+Site+For+Residue+A+193'>AC4</scene> | |SITE= <scene name='pdbsite=AC1:Cl+Binding+Site+For+Residue+A+190'>AC1</scene>, <scene name='pdbsite=AC2:Edo+Binding+Site+For+Residue+A+191'>AC2</scene>, <scene name='pdbsite=AC3:Edo+Binding+Site+For+Residue+A+192'>AC3</scene> and <scene name='pdbsite=AC4:Edo+Binding+Site+For+Residue+A+193'>AC4</scene> | ||
| - | |LIGAND= <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene> | + | |LIGAND= <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene> |
|ACTIVITY= | |ACTIVITY= | ||
|GENE= PARK7 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= PARK7 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[2rk3|2RK3]], [[2rk4|2RK4]], [[2rk6|2RK6]], [[2b36|2B36]], [[2b38|2B38]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3b3a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3b3a OCA], [http://www.ebi.ac.uk/pdbsum/3b3a PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=3b3a RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
A number of missense mutations in the oxidative stress response protein DJ-1 are implicated in rare forms of familial Parkinsonism. The best-characterized Parkinsonian DJ-1 missense mutation, L166P, disrupts homodimerization and results in a poorly folded protein. The molecular basis by which the other Parkinsonism-associated mutations disrupt the function of DJ-1, however, is incompletely understood. In this study we show that three different Parkinsonism-associated DJ-1 missense mutations (A104T, E163K, and M26I) reduce the thermal stability of DJ-1 in solution by subtly perturbing the structure of DJ-1 without causing major folding defects or loss of dimerization. Atomic resolution X-ray crystallography shows that the A104T substitution introduces water and a discretely disordered residue into the core of the protein, E163K disrupts a key salt bridge with R145, and M26I causes packing defects in the core of the dimer. The deleterious effect of each Parkinsonism-associated mutation on DJ-1 is dissected by analysis of engineered substitutions (M26L, A104V, and E163K/R145E) that partially alleviate each of the defects introduced by the A104T, E163K and M26I mutations. In total, our results suggest that the protective function of DJ-1 can be compromised by diverse perturbations in its structural integrity, particularly near the junctions of secondary structural elements. | A number of missense mutations in the oxidative stress response protein DJ-1 are implicated in rare forms of familial Parkinsonism. The best-characterized Parkinsonian DJ-1 missense mutation, L166P, disrupts homodimerization and results in a poorly folded protein. The molecular basis by which the other Parkinsonism-associated mutations disrupt the function of DJ-1, however, is incompletely understood. In this study we show that three different Parkinsonism-associated DJ-1 missense mutations (A104T, E163K, and M26I) reduce the thermal stability of DJ-1 in solution by subtly perturbing the structure of DJ-1 without causing major folding defects or loss of dimerization. Atomic resolution X-ray crystallography shows that the A104T substitution introduces water and a discretely disordered residue into the core of the protein, E163K disrupts a key salt bridge with R145, and M26I causes packing defects in the core of the dimer. The deleterious effect of each Parkinsonism-associated mutation on DJ-1 is dissected by analysis of engineered substitutions (M26L, A104V, and E163K/R145E) that partially alleviate each of the defects introduced by the A104T, E163K and M26I mutations. In total, our results suggest that the protective function of DJ-1 can be compromised by diverse perturbations in its structural integrity, particularly near the junctions of secondary structural elements. | ||
| + | |||
| + | ==Disease== | ||
| + | Known disease associated with this structure: Amyotrophic lateral sclerosis-Parkinsonism/dementia complex 2 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602533 602533]], Parkinson disease 7, autosomal recessive early-onset OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602533 602533]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Wilson, M A.]] | [[Category: Wilson, M A.]] | ||
[[Category: Zhou, W.]] | [[Category: Zhou, W.]] | ||
| - | [[Category: CL]] | ||
| - | [[Category: EDO]] | ||
[[Category: chaperone]] | [[Category: chaperone]] | ||
[[Category: cytoplasm]] | [[Category: cytoplasm]] | ||
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[[Category: ubl conjugation]] | [[Category: ubl conjugation]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 05:22:43 2008'' |
Revision as of 02:22, 31 March 2008
| |||||||
| , resolution 1.50Å | |||||||
|---|---|---|---|---|---|---|---|
| Sites: | , , and | ||||||
| Ligands: | , | ||||||
| Gene: | PARK7 (Homo sapiens) | ||||||
| Related: | 2RK3, 2RK4, 2RK6, 2B36, 2B38
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Structure of E163K/R145E DJ-1
Contents |
Overview
A number of missense mutations in the oxidative stress response protein DJ-1 are implicated in rare forms of familial Parkinsonism. The best-characterized Parkinsonian DJ-1 missense mutation, L166P, disrupts homodimerization and results in a poorly folded protein. The molecular basis by which the other Parkinsonism-associated mutations disrupt the function of DJ-1, however, is incompletely understood. In this study we show that three different Parkinsonism-associated DJ-1 missense mutations (A104T, E163K, and M26I) reduce the thermal stability of DJ-1 in solution by subtly perturbing the structure of DJ-1 without causing major folding defects or loss of dimerization. Atomic resolution X-ray crystallography shows that the A104T substitution introduces water and a discretely disordered residue into the core of the protein, E163K disrupts a key salt bridge with R145, and M26I causes packing defects in the core of the dimer. The deleterious effect of each Parkinsonism-associated mutation on DJ-1 is dissected by analysis of engineered substitutions (M26L, A104V, and E163K/R145E) that partially alleviate each of the defects introduced by the A104T, E163K and M26I mutations. In total, our results suggest that the protective function of DJ-1 can be compromised by diverse perturbations in its structural integrity, particularly near the junctions of secondary structural elements.
Disease
Known disease associated with this structure: Amyotrophic lateral sclerosis-Parkinsonism/dementia complex 2 OMIM:[602533], Parkinson disease 7, autosomal recessive early-onset OMIM:[602533]
About this Structure
3B3A is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Structural Impact of Three Parkinsonism-Associated Missense Mutations on Human DJ-1(,)., Lakshminarasimhan M, Maldonado MT, Zhou W, Fink AL, Wilson MA, Biochemistry. 2008 Feb 5;47(5):1381-92. Epub 2008 Jan 9. PMID:18181649
Page seeded by OCA on Mon Mar 31 05:22:43 2008
Categories: Homo sapiens | Single protein | Fink, A L. | Lakshminarasimhan, M. | Maldonado, M T. | Wilson, M A. | Zhou, W. | Chaperone | Cytoplasm | Disease mutation | Nucleus | Oncogene | Oxidation | Parkinson disease | Parkinson's disease | Pfpi | Phosphorylation | Polymorphism | Thij | Ubl conjugation
