Publication Date:
2011-12-14
Description:
3-Methylcrotonyl-CoA carboxylase (MCC), a member of the biotin-dependent carboxylase superfamily, is essential for the metabolism of leucine, and deficient mutations in this enzyme are linked to methylcrotonylglycinuria (MCG) and other serious diseases in humans. MCC has strong sequence conservation with propionyl-CoA carboxylase (PCC), and their holoenzymes are both 750-kilodalton (kDa) alpha(6)beta(6) dodecamers. Therefore the architecture of the MCC holoenzyme is expected to be highly similar to that of PCC. Here we report the crystal structures of the Pseudomonas aeruginosa MCC (PaMCC) holoenzyme, alone and in complex with coenzyme A. Surprisingly, the structures show that the architecture and overall shape of PaMCC are markedly different when compared to PCC. The alpha-subunits show trimeric association in the PaMCC holoenzyme, whereas they have no contacts with each other in PCC. Moreover, the positions of the two domains in the beta-subunit of PaMCC are swapped relative to those in PCC. This structural information establishes a foundation for understanding the disease-causing mutations of MCC and provides new insights into the catalytic mechanism and evolution of biotin-dependent carboxylases. The large structural differences between MCC and PCC also have general implications for the relationship between sequence conservation and structural similarity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3271731/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3271731/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Christine S -- Ge, Peng -- Zhou, Z Hong -- Tong, Liang -- DK067238/DK/NIDDK NIH HHS/ -- GM071940/GM/NIGMS NIH HHS/ -- GM08281/GM/NIGMS NIH HHS/ -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 DK067238/DK/NIDDK NIH HHS/ -- R01 DK067238-08/DK/NIDDK NIH HHS/ -- R01 GM071940/GM/NIGMS NIH HHS/ -- R01 GM071940-08/GM/NIGMS NIH HHS/ -- T32 GM008281/GM/NIGMS NIH HHS/ -- T32 GM008281-25/GM/NIGMS NIH HHS/ -- England -- Nature. 2011 Dec 11;481(7380):219-23. doi: 10.1038/nature10691.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Sciences, Columbia University, New York, New York 10027, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22158123" target="_blank"〉PubMed〈/a〉
Keywords:
Binding Sites
;
Biocatalysis
;
Carbon-Carbon Ligases/*chemistry/genetics/metabolism/ultrastructure
;
Coenzyme A/chemistry/metabolism
;
Crystallography, X-Ray
;
Disease/genetics
;
Holoenzymes/chemistry/metabolism
;
Humans
;
Methylmalonyl-CoA Decarboxylase/chemistry
;
Models, Molecular
;
Mutation/genetics
;
Protein Binding
;
Protein Structure, Tertiary
;
Protein Subunits/chemistry/genetics/metabolism
;
Pseudomonas aeruginosa/*enzymology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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