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1u5b

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==Overview==
==Overview==
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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.
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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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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Protein complex]]
[[Category: Protein complex]]
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[[Category: Chuang, D.T.]]
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[[Category: Chuang, D T.]]
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[[Category: Chuang, J.L.]]
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[[Category: Chuang, J L.]]
[[Category: Kato, M.]]
[[Category: Kato, M.]]
[[Category: Li, J.]]
[[Category: Li, J.]]
[[Category: Machius, M.]]
[[Category: Machius, M.]]
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[[Category: Tomchick, D.R.]]
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[[Category: Tomchick, D R.]]
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[[Category: Wynn, R.M.]]
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[[Category: Wynn, R M.]]
[[Category: GOL]]
[[Category: GOL]]
[[Category: K]]
[[Category: K]]
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[[Category: thiamin diphosphate]]
[[Category: thiamin diphosphate]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Feb 15 16:59:20 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:20:42 2008''

Revision as of 13:20, 21 February 2008

Image:1u5b.jpg

1u5b, resolution 1.83Å

Drag the structure with the mouse to rotate

Crystal structure of the human mitochondrial branched-chain alpha-ketoacid dehydrogenase

Contents

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

1U5B is a Protein complex structure of sequences from Homo sapiens with , , and 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

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