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3b3a
From Proteopedia
(New page: 200px<br /><applet load="3b3a" size="350" color="white" frame="true" align="right" spinBox="true" caption="3b3a, resolution 1.50Å" /> '''Structure of E163K/R...) |
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caption="3b3a, resolution 1.50Å" /> | caption="3b3a, resolution 1.50Å" /> | ||
'''Structure of E163K/R145E DJ-1'''<br /> | '''Structure of E163K/R145E DJ-1'''<br /> | ||
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| + | ==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. | ||
==About this Structure== | ==About this Structure== | ||
| - | 3B3A is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=CL:'>CL</scene> and <scene name='pdbligand=EDO:'>EDO</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3B3A OCA]. | + | 3B3A is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=CL:'>CL</scene> and <scene name='pdbligand=EDO:'>EDO</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Known structural/functional Sites: <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>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3B3A 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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=18181649 18181649] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Fink, A | + | [[Category: Fink, A L.]] |
[[Category: Lakshminarasimhan, M.]] | [[Category: Lakshminarasimhan, M.]] | ||
| - | [[Category: Maldonado, M | + | [[Category: Maldonado, M T.]] |
| - | [[Category: Wilson, M | + | [[Category: Wilson, M A.]] |
[[Category: Zhou, W.]] | [[Category: Zhou, W.]] | ||
[[Category: CL]] | [[Category: CL]] | ||
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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 Thu Feb 21 19:03:03 2008'' |
Revision as of 17:03, 21 February 2008
|
Structure of E163K/R145E DJ-1
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.
About this Structure
3B3A is a Single protein structure of sequence from Homo sapiens with and as ligands. Known structural/functional Sites: , , and . 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 Thu Feb 21 19:03:03 2008
Categories: Homo sapiens | Single protein | Fink, A L. | Lakshminarasimhan, M. | Maldonado, M T. | Wilson, M A. | Zhou, W. | CL | EDO | Chaperone | Cytoplasm | Disease mutation | Nucleus | Oncogene | Oxidation | Parkinson disease | Parkinson's disease | Pfpi | Phosphorylation | Polymorphism | Thij | Ubl conjugation
