2gbv: Difference between revisions
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==Overview== | ==Overview== | ||
The gain of neurotoxic function in amyotrophic lateral sclerosis (ALS) has | The gain of neurotoxic function in amyotrophic lateral sclerosis (ALS) has been linked to misfolding of the homodimeric enzyme Cu/Zn superoxide dismutase (SOD). Here, we present the crystal structure of fully cysteine-depleted human SOD (SOD(CallA)), representing a reduced, marginally stable intermediate on the folding pathway in vivo that has also been implicated as neurotoxic precursor state. A hallmark of this species is that it fails to dimerize and becomes trapped as a monomer in the absence of the active-site metals. The crystallographic data show that removal of the C57-C146 disulphide bond sets free the interface loop IV in the apo protein, whereas the same loop remains unaffected in the holo protein. Thus, the low dimerisation propensity of disulphide-reduced apoSOD seems to be of entropic origin due to increased loop flexibility in the monomeric state: in the disulphide-reduced holo protein this gain in configurational entropy upon splitting of the dimer interface is reduced by the metal coordination. | ||
==Disease== | ==Disease== | ||
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[[Category: Superoxide dismutase]] | [[Category: Superoxide dismutase]] | ||
[[Category: Hornberg, A.]] | [[Category: Hornberg, A.]] | ||
[[Category: Logan, D | [[Category: Logan, D T.]] | ||
[[Category: Marklund, S | [[Category: Marklund, S L.]] | ||
[[Category: Oliveberg, M.]] | [[Category: Oliveberg, M.]] | ||
[[Category: CU1]] | [[Category: CU1]] | ||
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[[Category: oxidoreductase]] | [[Category: oxidoreductase]] | ||
''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 17:30:11 2008'' | ||
Revision as of 18:30, 21 February 2008
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C6A/C111A/C57A/C146A holo CuZn Superoxide dismutase
OverviewOverview
The gain of neurotoxic function in amyotrophic lateral sclerosis (ALS) has been linked to misfolding of the homodimeric enzyme Cu/Zn superoxide dismutase (SOD). Here, we present the crystal structure of fully cysteine-depleted human SOD (SOD(CallA)), representing a reduced, marginally stable intermediate on the folding pathway in vivo that has also been implicated as neurotoxic precursor state. A hallmark of this species is that it fails to dimerize and becomes trapped as a monomer in the absence of the active-site metals. The crystallographic data show that removal of the C57-C146 disulphide bond sets free the interface loop IV in the apo protein, whereas the same loop remains unaffected in the holo protein. Thus, the low dimerisation propensity of disulphide-reduced apoSOD seems to be of entropic origin due to increased loop flexibility in the monomeric state: in the disulphide-reduced holo protein this gain in configurational entropy upon splitting of the dimer interface is reduced by the metal coordination.
DiseaseDisease
Known disease associated with this structure: Amyotrophic lateral sclerosis, due to SOD1 deficiency OMIM:[147450]
About this StructureAbout this Structure
2GBV 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.
ReferenceReference
The coupling between disulphide status, metallation and dimer interface strength in Cu/Zn superoxide dismutase., Hornberg A, Logan DT, Marklund SL, Oliveberg M, J Mol Biol. 2007 Jan 12;365(2):333-42. Epub 2006 Sep 23. PMID:17070542
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