3b36: Difference between revisions
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|PDB= 3b36 |SIZE=350|CAPTION= <scene name='initialview01'>3b36</scene>, resolution 1.50Å | |PDB= 3b36 |SIZE=350|CAPTION= <scene name='initialview01'>3b36</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>, <scene name='pdbsite=AC4:Edo+Binding+Site+For+Residue+A+193'>AC4</scene>, <scene name='pdbsite=AC5:Edo+Binding+Site+For+Residue+A+194'>AC5</scene>, <scene name='pdbsite=AC6:Edo+Binding+Site+For+Residue+A+195'>AC6</scene>, <scene name='pdbsite=AC7:Edo+Binding+Site+For+Residue+A+196'>AC7</scene>, <scene name='pdbsite=AC8:Edo+Binding+Site+For+Residue+A+197'>AC8</scene> and <scene name='pdbsite=AC9:Edo+Binding+Site+For+Residue+A+198'>AC9</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>, <scene name='pdbsite=AC4:Edo+Binding+Site+For+Residue+A+193'>AC4</scene>, <scene name='pdbsite=AC5:Edo+Binding+Site+For+Residue+A+194'>AC5</scene>, <scene name='pdbsite=AC6:Edo+Binding+Site+For+Residue+A+195'>AC6</scene>, <scene name='pdbsite=AC7:Edo+Binding+Site+For+Residue+A+196'>AC7</scene>, <scene name='pdbsite=AC8:Edo+Binding+Site+For+Residue+A+197'>AC8</scene> and <scene name='pdbsite=AC9:Edo+Binding+Site+For+Residue+A+198'>AC9</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]] | |||
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3b36 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3b36 OCA], [http://www.ebi.ac.uk/pdbsum/3b36 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=3b36 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: 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 05:22:40 2008'' | ||