1X80

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

Summary for 1X80

• Entry DOI: 10.2210/pdb1x80/pdb
• Related: 1U5B 1X7W 1X7X 1X7Y 1X7Z
• Descriptor: 2-oxoisovalerate dehydrogenase alpha subunit, 2-oxoisovalerate dehydrogenase beta subunit, POTASSIUM ION, ... (8 entities in total)
• Functional Keywords: oxidoreductase, ketoacid dehydrogenase, branched-chain, multi-enzyme complex, acylation, oxidative decarboxylation maple syrup urine disease, thiamin diphosphate, phosphorylation, flavoprotein
• Biological source: Homo sapiens (human); More
• Cellular location: Mitochondrion matrix: P12694 P21953
• Total number of polymer chains: 2
• Total formula weight: 84239.34

Authors

Wynn, R.M.,Kato, M.,Machius, M.,Chuang, J.L.,Li, J.,Tomchick, D.R.,Chuang, D.T. (deposition date: 2004-08-16, release date: 2004-11-23, Last modification date: 2024-10-30)

Primary citation

Wynn, R.M.,Kato, M.,Machius, M.,Chuang, J.L.,Li, J.,Tomchick, D.R.,Chuang, D.T.
Molecular mechanism for regulation of the human mitochondrial branched-chain alpha-ketoacid dehydrogenase complex by phosphorylation
Structure, 12:2185-2196, 2004

PubMed Abstract: 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.

PubMed: 15576032
DOI: 10.1016/j.str.2004.09.013

Experimental method

X-RAY DIFFRACTION (2 Å)