Document Detail


Flavinylation and assembly of succinate dehydrogenase are dependent on the C-terminal tail of the flavoprotein subunit.
MedLine Citation:
PMID:  23043141     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Succinate dehydrogenase (SDH) requires a covalent addition of FAD for catalytic function.
RESULTS: Mutational analyses of Sdh1 implicate C-terminal region Arg residues involvement in covalent flavinylation and SDH assembly.
CONCLUSION: SDH assembly is dependent on FAD binding to Sdh1 but not covalent binding.
SIGNIFICANCE: These results document the basis for the SDH deficiency and pathology seen with mutations in human Sdh1. The enzymatic function of succinate dehydrogenase (SDH) is dependent on covalent attachment of FAD on the ~70-kDa flavoprotein subunit Sdh1. We show presently that flavinylation of the Sdh1 subunit of succinate dehydrogenase is dependent on a set of two spatially close C-terminal arginine residues that are distant from the FAD binding site. Mutation of Arg(582) in yeast Sdh1 precludes flavinylation as well as assembly of the tetrameric enzyme complex. Mutation of Arg(638) compromises SDH function only when present in combination with a Cys(630) substitution. Mutations of either Arg(582) or Arg(638)/Cys(630) do not markedly destabilize the Sdh1 polypeptide; however, the steady-state level of Sdh5 is markedly attenuated in the Sdh1 mutant cells. With each mutant Sdh1, second-site Sdh1 suppressor mutations were recovered in Sdh1 permitting flavinylation, stabilization of Sdh5 and SDH tetramer assembly. SDH assembly appears to require FAD binding but not necessarily covalent FAD attachment. The Arg residues may be important not only for Sdh5 association but also in the recruitment and/or guidance of FAD and or succinate to the substrate site for the flavinylation reaction. The impaired assembly of SDH with the C-terminal Sdh1 mutants suggests that FAD binding is important to stabilize the Sdh1 conformation enabling association with Sdh2 and the membrane anchor subunits.
Authors:
Hyung J Kim; Mi-Young Jeong; Un Na; Dennis R Winge
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-10-07
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-27     Completed Date:  2013-02-28     Revised Date:  2013-12-04    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  40670-9     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Binding Sites
Flavins / metabolism*
Flavoproteins / chemistry,  genetics,  metabolism
Humans
Models, Molecular
Protein Binding
Protein Multimerization
Protein Structure, Tertiary
Saccharomyces cerevisiae / chemistry,  enzymology*,  genetics
Saccharomyces cerevisiae Proteins / chemistry,  genetics,  metabolism*
Succinate Dehydrogenase / chemistry*,  genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
ES03817/ES/NIEHS NIH HHS; P30 CA042014/CA/NCI NIH HHS; R24DK092784-01/DK/NIDDK NIH HHS; T32 DK007115/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Flavins; 0/Flavoproteins; 0/Saccharomyces cerevisiae Proteins; EC 1.3.99.1/Succinate Dehydrogenase
Comments/Corrections

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