Stoichiometry and architecture of the human pyruvate dehydrogenase complex.

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  • Additional Information
    • Source:
      Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101653440 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2375-2548 (Electronic) Linking ISSN: 23752548 NLM ISO Abbreviation: Sci Adv Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : American Association for the Advancement of Science, [2015]-
    • Subject Terms:
      Pyruvate Dehydrogenase Complex*/metabolism ; Pyruvate Dehydrogenase Complex*/chemistry ; Cryoelectron Microscopy*; Humans ; Models, Molecular ; Dihydrolipoamide Dehydrogenase/metabolism ; Dihydrolipoamide Dehydrogenase/chemistry ; Protein Multimerization ; Protein Binding ; Protein Subunits/metabolism ; Protein Subunits/chemistry ; Dihydrolipoyllysine-Residue Acetyltransferase/metabolism ; Dihydrolipoyllysine-Residue Acetyltransferase/chemistry
    • Abstract:
      The pyruvate dehydrogenase complex (PDHc) is a key megaenzyme linking glycolysis with the citric acid cycle. In mammalian PDHc, dihydrolipoamide acetyltransferase (E2) and the dihydrolipoamide dehydrogenase-binding protein (E3BP) form a 60-subunit core that associates with the peripheral subunits pyruvate dehydrogenase (E1) and dihydrolipoamide dehydrogenase (E3). The structure and stoichiometry of the fully assembled, mammalian PDHc or its core remained elusive. Here, we demonstrate that the human PDHc core is formed by 48 E2 copies that bind 48 E1 heterotetramers and 12 E3BP copies that bind 12 E3 homodimers. Cryo-electron microscopy, together with native and cross-linking mass spectrometry, confirmed a core model in which 8 E2 homotrimers and 12 E2-E2-E3BP heterotrimers assemble into a pseudoicosahedral particle such that the 12 E3BP molecules form six E3BP-E3BP intertrimer interfaces distributed tetrahedrally within the 60-subunit core. The even distribution of E3 subunits in the peripheral shell of PDHc guarantees maximum enzymatic activity of the megaenzyme.
    • References:
      Nat Methods. 2019 Nov;16(11):1153-1160. (PMID: 31591578)
      J Biol Chem. 2013 May 24;288(21):15402-17. (PMID: 23580650)
      J Comput Chem. 2010 Jan 15;31(1):133-43. (PMID: 19421996)
      Clin Biochem Rev. 2003;24(1):3-12. (PMID: 18568044)
      Acta Crystallogr Sect F Struct Biol Cryst Commun. 2010 Mar 1;66(Pt 3):225-8. (PMID: 20208148)
      Biochem J. 2001 Aug 15;358(Pt 1):69-77. (PMID: 11485553)
      Sci Adv. 2024 Feb 9;10(6):eadj6358. (PMID: 38324697)
      Sci Adv. 2020 Nov 6;6(45):. (PMID: 33158864)
      J Biol Chem. 2009 May 8;284(19):13086-98. (PMID: 19240034)
      Biochemistry. 1991 Sep 3;30(35):8501-12. (PMID: 1888719)
      Adv Enzyme Regul. 2002;42:249-59. (PMID: 12123719)
      Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):14802-7. (PMID: 11752427)
      Methods Enzymol. 2013;526:189-217. (PMID: 23791102)
      Nat Methods. 2008 Jan;5(1):53-5. (PMID: 18157137)
      Nat Biotechnol. 2012 Oct;30(10):918-20. (PMID: 23051804)
      Methods Enzymol. 2010;481:109-26. (PMID: 20887855)
      Cell Mol Life Sci. 2014 Jul;71(14):2577-604. (PMID: 24363178)
      Methods Enzymol. 1999;309:605-32. (PMID: 10507051)
      Biophys J. 2000 Mar;78(3):1606-19. (PMID: 10692345)
      J Biol Chem. 1963 Jan;238:30-9. (PMID: 14034257)
      J Comput Chem. 2004 Oct;25(13):1605-12. (PMID: 15264254)
      Adv Exp Med Biol. 1982;148:231-41. (PMID: 6751042)
      Nat Methods. 2017 Mar;14(3):290-296. (PMID: 28165473)
      Biochemistry. 2018 Apr 24;57(16):2325-2334. (PMID: 29608861)
      J Biol Chem. 1995 Jun 16;270(24):14297-304. (PMID: 7782287)
      Structure. 2008 Dec 10;16(12):1849-59. (PMID: 19081061)
      Nat Methods. 2012 Sep;9(9):901-3. (PMID: 22772729)
      Acta Crystallogr D Biol Crystallogr. 2010 Jan;66(Pt 1):12-21. (PMID: 20057044)
      J Biol Chem. 2001 Jun 15;276(24):21704-13. (PMID: 11285267)
      Anal Chem. 2019 Jul 2;91(13):8564-8573. (PMID: 31141659)
      J Biol Chem. 1990 Jun 5;265(16):8971-4. (PMID: 2188967)
      FASEB J. 1990 Nov;4(14):3224-33. (PMID: 2227213)
      Mol Genet Metab. 2011 Dec;104(4):507-16. (PMID: 21914562)
      Structure. 2019 Jul 2;27(7):1124-1136.e4. (PMID: 31130485)
      Nat Commun. 2020 Oct 15;11(1):5208. (PMID: 33060581)
      Cell. 2009 Aug 21;138(4):628-44. (PMID: 19703392)
      Acta Crystallogr D Struct Biol. 2018 Jun 1;74(Pt 6):531-544. (PMID: 29872004)
      Nature. 2021 Aug;596(7873):583-589. (PMID: 34265844)
      Nucleic Acids Res. 2022 Jan 7;50(D1):D439-D444. (PMID: 34791371)
      Science. 1992 Mar 20;255(5051):1544-50. (PMID: 1549782)
      Protein Sci. 2021 Jan;30(1):70-82. (PMID: 32881101)
      Trends Biochem Sci. 2016 Jan;41(1):20-32. (PMID: 26654279)
      J Mol Biol. 2007 Sep 21;372(3):774-97. (PMID: 17681537)
      J Mol Biol. 2010 May 28;399(1):71-93. (PMID: 20361979)
      Biol Proced Online. 2004;6:23-34. (PMID: 15103397)
      Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501. (PMID: 20383002)
      J Biol Chem. 2001 Oct 19;276(42):38329-36. (PMID: 11477096)
      Nat Methods. 2008 Apr;5(4):315-8. (PMID: 18327264)
      J Struct Biol. 2010 Jun;170(3):427-38. (PMID: 20338243)
      J Struct Biol. 2021 Mar;213(1):107677. (PMID: 33307178)
      Nature. 2014 Jan 23;505(7484):515-9. (PMID: 24362565)
      Anal Chem. 2022 Sep 13;94(36):12435-12443. (PMID: 36049221)
      Acta Crystallogr D Struct Biol. 2019 Oct 1;75(Pt 10):861-877. (PMID: 31588918)
      J Biol Chem. 2014 Mar 21;289(12):8312-25. (PMID: 24515115)
      Biochem J. 1988 May 1;251(3):817-23. (PMID: 3415648)
      Elife. 2018 Nov 09;7:. (PMID: 30412051)
      J Biol Chem. 1989 Mar 5;264(7):3655-7. (PMID: 2917967)
      J Biol Chem. 1990 Dec 25;265(36):22402-8. (PMID: 2266132)
      Nat Protoc. 2014 Jan;9(1):120-37. (PMID: 24356771)
      Mol Genet Metab. 2012 Jan;105(1):34-43. (PMID: 22079328)
      Acta Crystallogr D Struct Biol. 2017 Jun 1;73(Pt 6):496-502. (PMID: 28580911)
      J Biol Chem. 2003 Jun 6;278(23):21240-6. (PMID: 12651851)
      Nucleic Acids Res. 2022 Jan 7;50(D1):D543-D552. (PMID: 34723319)
      Genes Nutr. 2019 Sep 09;14:27. (PMID: 31516637)
      Nat Methods. 2017 Apr;14(4):331-332. (PMID: 28250466)
      Nat Biotechnol. 2007 Oct;25(10):1145-7. (PMID: 17873865)
      Structure. 2006 Mar;14(3):611-21. (PMID: 16442803)
      J Biol Chem. 2014 Jun 13;289(24):16615-23. (PMID: 24798336)
      ACS Omega. 2017 Mar 31;2(3):1134-1145. (PMID: 30023628)
      Protein Sci. 2018 Jan;27(1):14-25. (PMID: 28710774)
      J Biol Chem. 1989 Feb 5;264(4):2221-7. (PMID: 2914903)
      J Mol Biol. 2003 Jun 27;330(1):129-35. (PMID: 12818207)
      Anal Biochem. 2003 Sep 1;320(1):104-24. (PMID: 12895474)
      Methods Enzymol. 2015;562:109-33. (PMID: 26412649)
      J Biol Chem. 2004 Feb 20;279(8):6921-33. (PMID: 14638692)
    • Accession Number:
      0 (Pyruvate Dehydrogenase Complex)
      EC 1.8.1.4 (Dihydrolipoamide Dehydrogenase)
      0 (Protein Subunits)
      EC 2.3.1.12 (Dihydrolipoyllysine-Residue Acetyltransferase)
    • Publication Date:
      Date Created: 20240717 Date Completed: 20240717 Latest Revision: 20240719
    • Publication Date:
      20240719
    • Accession Number:
      PMC466950
    • Accession Number:
      10.1126/sciadv.adn4582
    • Accession Number:
      39018392