1n19
From Proteopedia
(New page: 200px<br /> <applet load="1n19" size="450" color="white" frame="true" align="right" spinBox="true" caption="1n19, resolution 1.86Å" /> '''Structure of the HS...) |
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| - | [[Image:1n19.gif|left|200px]]<br /> | + | [[Image:1n19.gif|left|200px]]<br /><applet load="1n19" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1n19" size=" | + | |
caption="1n19, resolution 1.86Å" /> | caption="1n19, resolution 1.86Å" /> | ||
'''Structure of the HSOD A4V mutant'''<br /> | '''Structure of the HSOD A4V mutant'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Mutations in human superoxide dismutase (HSOD) have been linked to the | + | Mutations in human superoxide dismutase (HSOD) have been linked to the familial form of amyotrophic lateral sclerosis (FALS). Amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) is one of the most common neurodegenerative disorders in humans. In ALS patients, selective killing of motor neurons leads to progressive paralysis and death within one to five years of onset. The most frequent FALS mutation in HSOD, Ala4-->Val, is associated with the most rapid disease progression. Here we identify and characterize key differences in the stability between the A4V mutant protein and its thermostable parent (HSOD-AS), in which free cysteine residues were mutated to eliminate interferences from cysteine oxidation. Denaturation studies reveal that A4V unfolds at a guanidine-HCl concentration 1M lower than HSOD-AS, revealing that A4V is significantly less stable than HSOD-AS. Determination and analysis of the crystallographic structures of A4V and HSOD-AS reveal structural features likely responsible for the loss of architectural stability of A4V observed in the denaturation experiments. The combined structural and biophysical results presented here argue that architectural destabilization of the HSOD protein may underlie the toxic function of the many HSOD FALS mutations. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1N19 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:// | + | 1N19 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=1N19 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: DiDonato, M.]] | [[Category: DiDonato, M.]] | ||
| - | [[Category: Getzoff, E | + | [[Category: Getzoff, E D.]] |
| - | [[Category: Lo, T | + | [[Category: Lo, T P.]] |
| - | [[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: greek key beta-barrel]] | [[Category: greek key beta-barrel]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:01:07 2008'' |
Revision as of 12:01, 21 February 2008
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Structure of the HSOD A4V mutant
Contents |
Overview
Mutations in human superoxide dismutase (HSOD) have been linked to the familial form of amyotrophic lateral sclerosis (FALS). Amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) is one of the most common neurodegenerative disorders in humans. In ALS patients, selective killing of motor neurons leads to progressive paralysis and death within one to five years of onset. The most frequent FALS mutation in HSOD, Ala4-->Val, is associated with the most rapid disease progression. Here we identify and characterize key differences in the stability between the A4V mutant protein and its thermostable parent (HSOD-AS), in which free cysteine residues were mutated to eliminate interferences from cysteine oxidation. Denaturation studies reveal that A4V unfolds at a guanidine-HCl concentration 1M lower than HSOD-AS, revealing that A4V is significantly less stable than HSOD-AS. Determination and analysis of the crystallographic structures of A4V and HSOD-AS reveal structural features likely responsible for the loss of architectural stability of A4V observed in the denaturation experiments. The combined structural and biophysical results presented here argue that architectural destabilization of the HSOD protein may underlie the toxic function of the many HSOD FALS mutations.
Disease
Known disease associated with this structure: Amyotrophic lateral sclerosis, due to SOD1 deficiency OMIM:[147450]
About this Structure
1N19 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
Insights into Lou Gehrig's disease from the structure and instability of the A4V mutant of human Cu,Zn superoxide dismutase., Cardoso RM, Thayer MM, DiDonato M, Lo TP, Bruns CK, Getzoff ED, Tainer JA, J Mol Biol. 2002 Nov 22;324(2):247-56. PMID:12441104
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