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391 a.a.
329 a.a.
__K
_MN
 3-methyl-2-oxobutanoate |
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[dihydrolipoyllysine-residue (2- methylpropanoyl)transferase] lipoyllysine |
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[dihydrolipoyllysine-residue (2-methylpropanoyl)transferase] S-(2-methylpropanoyl)dihydrolipoyllysine |
+ |
 CO(2) |
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Bound ligand (Het Group name = TDP) corresponds exactly |
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Key reference
DOI no: 10.1016/j.str.2004.09.013 Structure 12:2185-2196 (2004) PubMed id: 15576032
Molecular mechanism for regulation of the human mitochondrial branched-chain alpha-ketoacid dehydrogenase complex by phosphorylation. R.M.Wynn, M.Kato, M.Machius, J.L.Chuang, J.Li, D.R.Tomchick, D.T.Chuang. 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.
Selected figure(s)
Figure 6.
Figure 6. Predicted Steric Clashes in Phosphorylated, S292E-a, and S292Q-a E1b Structures(A-D) In the (A) phosphorylated, (B) S292E-a, (C) S292N-a, and (D) S292Q-a structures, modeled van der Waals surfaces for the phosphoryl group or substituted residues, which predict steric clashes with His291-a, except Asn292-a, are based on coordinates of the wild-type structure in Figure 5A. These steric clashes result in the destabilization of the hydrogen bond network and therefore disorder the loop. Conformations for ThDP, Arg114-a, and the Cl - ion that coordinates to the 4' amino group on the aminopyrimidine ring of ThDP, His146-b', and Tyr113-a are derived from 2F[o] - F[c] electron densities.The above figure is reprinted by permission from Cell Press: Structure (2004, 12, 2185-2196) copyright 2004. Figure was selected by the author.
Literature references that cite this PDB file's key reference
PubMed id Reference
18385140 M.J.Rardin, S.E.Wiley, A.N.Murphy, D.J.Pagliarini, and J.E.Dixon (2008).
Dual specificity phosphatases 18 and 21 target to opposing sides of the mitochondrial inner membrane.J Biol Chem, 283, 15440-15450.
18767075 N.Bisek, S.Wetzel, H.D.Arndt, and H.Waldmann (2008).
Synthesis and conformational analysis of stevastelin C3 analogues and their activity against the dual-specific vaccina H1-related phosphatase.Chemistry, 14, 8847-8860.
17329260 J.Li, M.Machius, J.L.Chuang, R.M.Wynn, and D.T.Chuang (2007).
The two active sites in human branched-chain alpha-keto acid dehydrogenase operate independently without an obligatory alternating-site mechanism.J Biol Chem, 282, 11904-11913.
PDB code: 2j9f
17314104 M.M.Islam, R.Wallin, R.M.Wynn, M.Conway, H.Fujii, J.A.Mobley, D.T.Chuang, and S.M.Hutson (2007).
A novel branched-chain amino acid metabolon. Protein-protein interactions in a supramolecular complex.J Biol Chem, 282, 11893-11903.
16436377 L.G.Korotchkina, S.Sidhu, and M.S.Patel (2006).
Characterization of testis-specific isoenzyme of human pyruvate dehydrogenase.J Biol Chem, 281, 9688-9696. The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.
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