Proteopedia

3exh

Crystal structure of the pyruvate dehydrogenase (E1p) component of human pyruvate dehydrogenase complexCrystal structure of the pyruvate dehydrogenase (E1p) component of human pyruvate dehydrogenase complex

Structural highlights

3exh is a 8 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.444Å
Ligands:, , , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

ODPA_HUMAN Defects in PDHA1 are a cause of pyruvate dehydrogenase E1-alpha deficiency (PDHAD) [MIM:312170. An enzymatic defect causing primary lactic acidosis in children. It is associated with a broad clinical spectrum ranging from fatal lactic acidosis in the newborn to chronic neurologic dysfunction with structural abnormalities in the central nervous system without systemic acidosis.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] Defects in PDHA1 are the cause of X-linked Leigh syndrome (X-LS) [MIM:308930. X-LS is an early-onset progressive neurodegenerative disorder with a characteristic neuropathology consisting of focal, bilateral lesions in one or more areas of the central nervous system, including the brainstem, thalamus, basal ganglia, cerebellum, and spinal cord. The lesions are areas of demyelination, gliosis, necrosis, spongiosis, or capillary proliferation. Clinical symptoms depend on which areas of the central nervous system are involved. The most common underlying cause is a defect in oxidative phosphorylation. LS may be a feature of a deficiency of any of the mitochondrial respiratory chain complexes.[15] [16] [17] [18] [19]

Function

ODPA_HUMAN The pyruvate dehydrogenase complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and thereby links the glycolytic pathway to the tricarboxylic cycle.[20] [21]

Evolutionary Conservation

 

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

We report the crystal structures of the phosporylated pyruvate dehydrogenase (E1p) component of the human pyruvate dehydrogenase complex (PDC). The complete phosphorylation at Ser264-alpha (site 1) of a variant E1p protein was achieved using robust pyruvate dehydrogenase kinase 4 free of the PDC core. We show that unlike its unmodified counterpart, the presence of a phosphoryl group at Ser264-alpha prevents the cofactor thiamine diphosphate-induced ordering of the two loops carrying the three phosphorylation sites. The disordering of these phosphorylation loops is caused by a previously unrecognized steric clash between the phosphoryl group at site 1 and a nearby Ser266-alpha, which nullifies a hydrogen-bonding network essential for maintaining the loop conformations. The disordered phosphorylation loops impede the binding of lipoyl domains of the PDC core to E1p, negating the reductive acetylation step. This results in the disruption of the substrate channeling in the PDC, leading to the inactivation of this catalytic machine.

Structural basis for inactivation of the human pyruvate dehydrogenase complex by phosphorylation: role of disordered phosphorylation loops.,Kato M, Wynn RM, Chuang JL, Tso SC, Machius M, Li J, Chuang DT Structure. 2008 Dec 10;16(12):1849-59. PMID:19081061[22]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Ito M, Huq AH, Naito E, Saijo T, Takeda E, Kuroda Y. Mutation of E1 alpha gene in a female patient with pyruvate dehydrogenase deficiency due to rapid degradation of E1 protein. J Inherit Metab Dis. 1992;15(6):848-56. PMID:1338114
  2. ↑ Hansen LL, Brown GK, Kirby DM, Dahl HH. Characterization of the mutations in three patients with pyruvate dehydrogenase E1 alpha deficiency. J Inherit Metab Dis. 1991;14(2):140-51. PMID:1909401
  3. ↑ De Meirleir L, Lissens W, Vamos E, Liebaers I. Pyruvate dehydrogenase (PDH) deficiency caused by a 21-base pair insertion mutation in the E1 alpha subunit. Hum Genet. 1992 Mar;88(6):649-52. PMID:1551669
  4. ↑ Dahl HH, Hansen LL, Brown RM, Danks DM, Rogers JG, Brown GK. X-linked pyruvate dehydrogenase E1 alpha subunit deficiency in heterozygous females: variable manifestation of the same mutation. J Inherit Metab Dis. 1992;15(6):835-47. PMID:1293379
  5. ↑ Chun K, MacKay N, Petrova-Benedict R, Robinson BH. Mutations in the X-linked E1 alpha subunit of pyruvate dehydrogenase leading to deficiency of the pyruvate dehydrogenase complex. Hum Mol Genet. 1993 Apr;2(4):449-54. PMID:8504306
  6. ↑ Matthews PM, Brown RM, Otero LJ, Marchington DR, LeGris M, Howes R, Meadows LS, Shevell M, Scriver CR, Brown GK. Pyruvate dehydrogenase deficiency. Clinical presentation and molecular genetic characterization of five new patients. Brain. 1994 Jun;117 ( Pt 3):435-43. PMID:8032855
  7. ↑ Hansen LL, Horn N, Dahl HH, Kruse TA. Pyruvate dehydrogenase deficiency caused by a 33 base pair duplication in the PDH E1 alpha subunit. Hum Mol Genet. 1994 Jun;3(6):1021-2. PMID:7545958
  8. ↑ Awata H, Endo F, Tanoue A, Kitano A, Matsuda I. Characterization of a point mutation in the pyruvate dehydrogenase E1 alpha gene from two boys with primary lactic acidaemia. J Inherit Metab Dis. 1994;17(2):189-95. PMID:7967473
  9. ↑ Chun K, MacKay N, Petrova-Benedict R, Federico A, Fois A, Cole DE, Robertson E, Robinson BH. Mutations in the X-linked E1 alpha subunit of pyruvate dehydrogenase: exon skipping, insertion of duplicate sequence, and missense mutations leading to the deficiency of the pyruvate dehydrogenase complex. Am J Hum Genet. 1995 Mar;56(3):558-69. PMID:7887409
  10. ↑ Takakubo F, Cartwright P, Hoogenraad N, Thorburn DR, Collins F, Lithgow T, Dahl HH. An amino acid substitution in the pyruvate dehydrogenase E1 alpha gene, affecting mitochondrial import of the precursor protein. Am J Hum Genet. 1995 Oct;57(4):772-80. PMID:7573035
  11. ↑ Hemalatha SG, Kerr DS, Wexler ID, Lusk MM, Kaung M, Du Y, Kolli M, Schelper RL, Patel MS. Pyruvate dehydrogenase complex deficiency due to a point mutation (P188L) within the thiamine pyrophosphate binding loop of the E1 alpha subunit. Hum Mol Genet. 1995 Feb;4(2):315-8. PMID:7757088
  12. ↑ Lissens W, De Meirleir L, Seneca S, Benelli C, Marsac C, Poll-The BT, Briones P, Ruitenbeek W, van Diggelen O, Chaigne D, Ramaekers V, Liebaers I. Mutation analysis of the pyruvate dehydrogenase E1 alpha gene in eight patients with a pyruvate dehydrogenase complex deficiency. Hum Mutat. 1996;7(1):46-51. PMID:8664900 doi:<46::AID-HUMU6>3.0.CO;2-N 10.1002/(SICI)1098-1004(1996)7:1<46::AID-HUMU6>3.0.CO;2-N
  13. ↑ Tripatara A, Kerr DS, Lusk MM, Kolli M, Tan J, Patel MS. Three new mutations of the pyruvate dehydrogenase alpha subunit: a point mutation (M181V), 3 bp deletion (-R282), and 16 bp insertion/frameshift (K358SVS-->TVDQS). Hum Mutat. 1996;8(2):180-2. PMID:8844217 doi:<180::AID-HUMU11>3.0.CO;2-Z 10.1002/(SICI)1098-1004(1996)8:2<180::AID-HUMU11>3.0.CO;2-Z
  14. ↑ Otero LJ, Brown RM, Brown GK. Arginine 302 mutations in the pyruvate dehydrogenase E1alpha subunit gene: identification of further patients and in vitro demonstration of pathogenicity. Hum Mutat. 1998;12(2):114-21. PMID:9671272 doi:<114::AID-HUMU6>3.0.CO;2-# 10.1002/(SICI)1098-1004(1998)12:2<114::AID-HUMU6>3.0.CO;2-#
  15. ↑ Hansen LL, Brown GK, Kirby DM, Dahl HH. Characterization of the mutations in three patients with pyruvate dehydrogenase E1 alpha deficiency. J Inherit Metab Dis. 1991;14(2):140-51. PMID:1909401
  16. ↑ Chun K, MacKay N, Petrova-Benedict R, Federico A, Fois A, Cole DE, Robertson E, Robinson BH. Mutations in the X-linked E1 alpha subunit of pyruvate dehydrogenase: exon skipping, insertion of duplicate sequence, and missense mutations leading to the deficiency of the pyruvate dehydrogenase complex. Am J Hum Genet. 1995 Mar;56(3):558-69. PMID:7887409
  17. ↑ Matthews PM, Marchington DR, Squier M, Land J, Brown RM, Brown GK. Molecular genetic characterization of an X-linked form of Leigh's syndrome. Ann Neurol. 1993 Jun;33(6):652-5. PMID:8498846 doi:http://dx.doi.org/10.1002/ana.410330616
  18. ↑ Dahl HH, Brown GK. Pyruvate dehydrogenase deficiency in a male caused by a point mutation (F205L) in the E1 alpha subunit. Hum Mutat. 1994;3(2):152-5. PMID:8199595 doi:http://dx.doi.org/10.1002/humu.1380030210
  19. ↑ Naito E, Ito M, Yokota I, Saijo T, Matsuda J, Osaka H, Kimura S, Kuroda Y. Biochemical and molecular analysis of an X-linked case of Leigh syndrome associated with thiamin-responsive pyruvate dehydrogenase deficiency. J Inherit Metab Dis. 1997 Aug;20(4):539-48. PMID:9266390
  20. ↑ Korotchkina LG, Patel MS. Mutagenesis studies of the phosphorylation sites of recombinant human pyruvate dehydrogenase. Site-specific regulation. J Biol Chem. 1995 Jun 16;270(24):14297-304. PMID:7782287
  21. ↑ Kato M, Wynn RM, Chuang JL, Tso SC, Machius M, Li J, Chuang DT. Structural basis for inactivation of the human pyruvate dehydrogenase complex by phosphorylation: role of disordered phosphorylation loops. Structure. 2008 Dec 10;16(12):1849-59. PMID:19081061 doi:10.1016/j.str.2008.10.010
  22. ↑ Kato M, Wynn RM, Chuang JL, Tso SC, Machius M, Li J, Chuang DT. Structural basis for inactivation of the human pyruvate dehydrogenase complex by phosphorylation: role of disordered phosphorylation loops. Structure. 2008 Dec 10;16(12):1849-59. PMID:19081061 doi:10.1016/j.str.2008.10.010

3exh, resolution 2.44Å

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