3b36: Difference between revisions
New page: left|200px<br /><applet load="3b36" size="350" color="white" frame="true" align="right" spinBox="true" caption="3b36, resolution 1.50Å" /> '''Structure of M26L DJ... |
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'''Structure of M26L DJ-1'''<br /> | '''Structure of M26L DJ-1'''<br /> | ||
==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== | ||
3B36 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=3B36 OCA]. | 3B36 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>, <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>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3B36 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 19:02:59 2008'' | ||
Revision as of 20:02, 21 February 2008
|
Structure of M26L DJ-1
OverviewOverview
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 StructureAbout this Structure
3B36 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.
ReferenceReference
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
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