1x80: Difference between revisions
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'''Crystal structure of the human mitochondrial branched-chain alpha-ketoacid dehydrogenase'''<br /> | '''Crystal structure of the human mitochondrial branched-chain alpha-ketoacid dehydrogenase'''<br /> | ||
==Overview== | ==Overview== | ||
The human mitochondrial branched-chain alpha-ketoacid dehydrogenase | The human mitochondrial branched-chain alpha-ketoacid dehydrogenase complex (BCKDC) is a 4 MDa macromolecular machine comprising three catalytic components (E1b, E2b, and E3), a kinase, and a phosphatase. The BCKDC overall activity is tightly regulated by phosphorylation in response to hormonal and dietary stimuli. We report that phosphorylation of Ser292-alpha in the E1b active site channel results in an order-to-disorder transition of the conserved phosphorylation loop carrying the phosphoryl serine. The conformational change is triggered by steric clashes of the phosphoryl group with invariant His291-alpha that serves as an indispensable anchor for the phosphorylation loop through bound thiamin diphosphate. Phosphorylation of Ser292-alpha does not severely impede the E1b-dependent decarboxylation of alpha-ketoacids. However, the disordered loop conformation prevents phosphorylated E1b from binding the E2b lipoyl-bearing domain, which effectively shuts off the E1b-catalyzed reductive acylation reaction and therefore completely inactivates BCKDC. This mechanism provides a paradigm for regulation of mitochondrial alpha-ketoacid dehydrogenase complexes by phosphorylation. | ||
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
1X80 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with K, MN, CL, TDP and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/3-methyl-2-oxobutanoate_dehydrogenase_(2-methylpropanoyl-transferring) 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.2.4.4 1.2.4.4] Full crystallographic information is available from [http:// | 1X80 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=K:'>K</scene>, <scene name='pdbligand=MN:'>MN</scene>, <scene name='pdbligand=CL:'>CL</scene>, <scene name='pdbligand=TDP:'>TDP</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/3-methyl-2-oxobutanoate_dehydrogenase_(2-methylpropanoyl-transferring) 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.2.4.4 1.2.4.4] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1X80 OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: Chuang, D | [[Category: Chuang, D T.]] | ||
[[Category: Chuang, J | [[Category: Chuang, J L.]] | ||
[[Category: Kato, M.]] | [[Category: Kato, M.]] | ||
[[Category: Li, J.]] | [[Category: Li, J.]] | ||
[[Category: Machius, M.]] | [[Category: Machius, M.]] | ||
[[Category: Tomchick, D | [[Category: Tomchick, D R.]] | ||
[[Category: Wynn, R | [[Category: Wynn, R M.]] | ||
[[Category: CL]] | [[Category: CL]] | ||
[[Category: GOL]] | [[Category: GOL]] | ||
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[[Category: thiamin diphosphate]] | [[Category: thiamin diphosphate]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:51:55 2008'' | ||
Revision as of 13:51, 21 February 2008
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Crystal structure of the human mitochondrial branched-chain alpha-ketoacid dehydrogenase
Overview
The human mitochondrial branched-chain alpha-ketoacid dehydrogenase complex (BCKDC) is a 4 MDa macromolecular machine comprising three catalytic components (E1b, E2b, and E3), a kinase, and a phosphatase. The BCKDC overall activity is tightly regulated by phosphorylation in response to hormonal and dietary stimuli. We report that phosphorylation of Ser292-alpha in the E1b active site channel results in an order-to-disorder transition of the conserved phosphorylation loop carrying the phosphoryl serine. The conformational change is triggered by steric clashes of the phosphoryl group with invariant His291-alpha that serves as an indispensable anchor for the phosphorylation loop through bound thiamin diphosphate. Phosphorylation of Ser292-alpha does not severely impede the E1b-dependent decarboxylation of alpha-ketoacids. However, the disordered loop conformation prevents phosphorylated E1b from binding the E2b lipoyl-bearing domain, which effectively shuts off the E1b-catalyzed reductive acylation reaction and therefore completely inactivates BCKDC. This mechanism provides a paradigm for regulation of mitochondrial alpha-ketoacid dehydrogenase complexes by phosphorylation.
Disease
Known diseases associated with this structure: Maple syrup urine disease, type Ia OMIM:[608348], Maple syrup urine disease, type Ib OMIM:[248611]
About this Structure
1X80 is a Protein complex structure of sequences from Homo sapiens with K, MN, CL, TDP and GOL as ligands. Active as 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring), with EC number 1.2.4.4 Full crystallographic information is available from OCA.
Reference
Molecular mechanism for regulation of the human mitochondrial branched-chain alpha-ketoacid dehydrogenase complex by phosphorylation., Wynn RM, Kato M, Machius M, Chuang JL, Li J, Tomchick DR, Chuang DT, Structure. 2004 Dec;12(12):2185-96. PMID:15576032
Page seeded by OCA on Thu Feb 21 15:51:55 2008
Proteopedia Page Contributors and Editors (what is this?)
- Pages with broken file links
- 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring)
- Homo sapiens
- Protein complex
- Chuang, D T.
- Chuang, J L.
- Kato, M.
- Li, J.
- Machius, M.
- Tomchick, D R.
- Wynn, R M.
- CL
- GOL
- K
- MN
- TDP
- Acylation
- Branched-chain
- Flavoprotein
- Ketoacid dehydrogenase
- Multi-enzyme complex
- Oxidative decarboxylation maple syrup urine disease
- Oxidoreductase
- Phosphorylation
- Thiamin diphosphate
