title: Structures of the human pyruvate dehydrogenase complex cores: a highly conserved catalytic center with flexible N-terminal domains.
abstract: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, The University of Texas Medical School at Houston, Houston, TX 77030, USA.
authors.forename: Xuekui
authors.initials: X
authors.lastname: Yu
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Hiromasa
authors.forename: Hua
authors.initials: H
authors.lastname: Tsen
authors.forename: James K
authors.initials: JK
authors.lastname: Stoops
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Roche
authors.forename: Z Hong
authors.initials: ZH
authors.lastname: Zhou
mesh_terms: 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
chemical_list: D001426:Bacterial Proteins; D010446:Peptide Fragments; D011768:Pyruvate Dehydrogenase Complex