1pu0
From Proteopedia
(New page: 200px<br /> <applet load="1pu0" size="450" color="white" frame="true" align="right" spinBox="true" caption="1pu0, resolution 1.70Å" /> '''Structure of Human ...) |
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| - | [[Image:1pu0.gif|left|200px]]<br /> | + | [[Image:1pu0.gif|left|200px]]<br /><applet load="1pu0" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1pu0" size=" | + | |
caption="1pu0, resolution 1.70Å" /> | caption="1pu0, resolution 1.70Å" /> | ||
'''Structure of Human Cu,Zn Superoxide Dismutase'''<br /> | '''Structure of Human Cu,Zn Superoxide Dismutase'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Many point mutations in human Cu,Zn superoxide dismutase (SOD) cause | + | Many point mutations in human Cu,Zn superoxide dismutase (SOD) cause familial amyotrophic lateral sclerosis (FALS), a fatal neurodegenerative disorder in heterozygotes. Here we show that these mutations cluster in protein regions influencing architectural integrity. Furthermore, crystal structures of SOD wild-type and FALS mutant H43R proteins uncover resulting local framework defects. Characterizations of beta-barrel (H43R) and dimer interface (A4V) FALS mutants reveal reduced stability and drastically increased aggregation propensity. Moreover, electron and atomic force microscopy indicate that these defects promote the formation of filamentous aggregates. The filaments resemble those seen in neurons of FALS patients and bind both Congo red and thioflavin T, suggesting the presence of amyloid-like, stacked beta-sheet interactions. These results support free-cysteine-independent aggregation of FALS mutant SOD as an integral part of FALS pathology. They furthermore provide a molecular basis for the single FALS disease phenotype resulting from mutations of diverse side-chains throughout the protein: many FALS mutations reduce structural integrity, lowering the energy barrier for fibrous aggregation. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1PU0 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 CU1, ZN and SO4 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Superoxide_dismutase Superoxide dismutase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.15.1.1 1.15.1.1] Full crystallographic information is available from [http:// | + | 1PU0 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=CU1:'>CU1</scene>, <scene name='pdbligand=ZN:'>ZN</scene> and <scene name='pdbligand=SO4:'>SO4</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Superoxide_dismutase Superoxide dismutase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.15.1.1 1.15.1.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1PU0 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Superoxide dismutase]] | [[Category: Superoxide dismutase]] | ||
| - | [[Category: Bruns, C | + | [[Category: Bruns, C K.]] |
| - | [[Category: Cardoso, R | + | [[Category: Cardoso, R M.F.]] |
[[Category: Craig, L.]] | [[Category: Craig, L.]] | ||
[[Category: DiDonato, M.]] | [[Category: DiDonato, M.]] | ||
| - | [[Category: Getzoff, E | + | [[Category: Getzoff, E D.]] |
| - | [[Category: Huff, M | + | [[Category: Huff, M E.]] |
| - | [[Category: Kassmann, C | + | [[Category: Kassmann, C J.]] |
| - | [[Category: Kelly, J | + | [[Category: Kelly, J W.]] |
| - | [[Category: Lo, T | + | [[Category: Lo, T P.]] |
| - | [[Category: Powers, E | + | [[Category: Powers, E T.]] |
| - | [[Category: Tainer, J | + | [[Category: Tainer, J A.]] |
| - | [[Category: Thayer, M | + | [[Category: Thayer, M M.]] |
[[Category: CU1]] | [[Category: CU1]] | ||
[[Category: SO4]] | [[Category: SO4]] | ||
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[[Category: lou gehrig's disease]] | [[Category: lou gehrig's disease]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:32:31 2008'' |
Revision as of 12:32, 21 February 2008
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Structure of Human Cu,Zn Superoxide Dismutase
Contents |
Overview
Many point mutations in human Cu,Zn superoxide dismutase (SOD) cause familial amyotrophic lateral sclerosis (FALS), a fatal neurodegenerative disorder in heterozygotes. Here we show that these mutations cluster in protein regions influencing architectural integrity. Furthermore, crystal structures of SOD wild-type and FALS mutant H43R proteins uncover resulting local framework defects. Characterizations of beta-barrel (H43R) and dimer interface (A4V) FALS mutants reveal reduced stability and drastically increased aggregation propensity. Moreover, electron and atomic force microscopy indicate that these defects promote the formation of filamentous aggregates. The filaments resemble those seen in neurons of FALS patients and bind both Congo red and thioflavin T, suggesting the presence of amyloid-like, stacked beta-sheet interactions. These results support free-cysteine-independent aggregation of FALS mutant SOD as an integral part of FALS pathology. They furthermore provide a molecular basis for the single FALS disease phenotype resulting from mutations of diverse side-chains throughout the protein: many FALS mutations reduce structural integrity, lowering the energy barrier for fibrous aggregation.
Disease
Known disease associated with this structure: Amyotrophic lateral sclerosis, due to SOD1 deficiency OMIM:[147450]
About this Structure
1PU0 is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as Superoxide dismutase, with EC number 1.15.1.1 Full crystallographic information is available from OCA.
Reference
ALS mutants of human superoxide dismutase form fibrous aggregates via framework destabilization., DiDonato M, Craig L, Huff ME, Thayer MM, Cardoso RM, Kassmann CJ, Lo TP, Bruns CK, Powers ET, Kelly JW, Getzoff ED, Tainer JA, J Mol Biol. 2003 Sep 19;332(3):601-15. PMID:12963370
Page seeded by OCA on Thu Feb 21 14:32:31 2008
Categories: Homo sapiens | Single protein | Superoxide dismutase | Bruns, C K. | Cardoso, R M.F. | Craig, L. | DiDonato, M. | Getzoff, E D. | Huff, M E. | Kassmann, C J. | Kelly, J W. | Lo, T P. | Powers, E T. | Tainer, J A. | Thayer, M M. | CU1 | SO4 | ZN | Als | Fals | Lou gehrig's disease
