Structures of the human pyruvate dehydrogenase complex cores: a highly conserved catalytic center with flexible N-terminal domains.
Dihydrolipoyl acetyltransferase (E2) is the central component of pyruvate dehydrogenase complex (PDC), which converts pyruvate to acetyl-CoA. Structural comparison by cryo-electron microscopy (cryo-EM) of the human full-length and truncated E2 (tE2) cores revealed flexible linkers emanating from the edges of trimers of the internal catalytic domains. Using the secondary structure constraints revealed in our 8 A cryo-EM reconstruction and the prokaryotic tE2 atomic structure as a template, we derived a pseudo atomic model of human tE2. The active sites are conserved between prokaryotic tE2 and human tE2. However, marked structural differences are apparent in the hairpin domain and in the N-terminal helix connected to the flexible linker. These permutations away from the catalytic center likely impart structures needed to integrate a second component into the inner core and provide a sturdy base for the linker that holds the pyruvate dehydrogenase for access by the E2-bound regulatory kinase/phosphatase components in humans.
Yu
Xuekui
X
Department of Pathology and Laboratory Medicine, The University of Texas Medical School at Houston, Houston, TX 77030, USA.
Hiromasa
Yasuaki
Y
Tsen
Hua
H
Stoops
James K
JK
Roche
Thomas E
TE
Zhou
Z Hong
ZH
D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry; D001665:Binding Sites; D017124:Conserved Sequence; D020285:Cryoelectron Microscopy; D001411:Geobacillus stearothermophilus / Q000201:enzymology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry*; D011487:Protein Conformation; D011768:Pyruvate Dehydrogenase Complex / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D013314:Stress, Mechanical
D001426:Bacterial Proteins; D010446:Peptide Fragments; D011768:Pyruvate Dehydrogenase Complex