skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Structural Basis for Inactivation of the Human Pyruvate Dehydrogenase Complex by Phosphorylation: Role of Disordered Phosphorylation Loops

Abstract

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.

Authors:
; ; ; ; ; ;  [1]
  1. UTSMC
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1007113
Resource Type:
Journal Article
Journal Name:
Structure
Additional Journal Information:
Journal Volume: 16; Journal Issue: (12) ; 12, 2008
Country of Publication:
United States
Language:
ENGLISH
Subject:
36 MATERIALS SCIENCE; ACETYLATION; CHANNELING; CRYSTAL STRUCTURE; INACTIVATION; OXIDOREDUCTASES; PHOSPHORYLATION; PHOSPHOTRANSFERASES; PROTEINS; SUBSTRATES; THIAMINE

Citation Formats

Kato, Masato, Wynn, R Max, Chuang, Jacinta L, Tso, Shih-Chia, Machius, Mischa, Li, Jun, and Chuang, David T. Structural Basis for Inactivation of the Human Pyruvate Dehydrogenase Complex by Phosphorylation: Role of Disordered Phosphorylation Loops. United States: N. p., 2009. Web. doi:10.1016/j.str.2008.10.010.
Kato, Masato, Wynn, R Max, Chuang, Jacinta L, Tso, Shih-Chia, Machius, Mischa, Li, Jun, & Chuang, David T. Structural Basis for Inactivation of the Human Pyruvate Dehydrogenase Complex by Phosphorylation: Role of Disordered Phosphorylation Loops. United States. https://doi.org/10.1016/j.str.2008.10.010
Kato, Masato, Wynn, R Max, Chuang, Jacinta L, Tso, Shih-Chia, Machius, Mischa, Li, Jun, and Chuang, David T. 2009. "Structural Basis for Inactivation of the Human Pyruvate Dehydrogenase Complex by Phosphorylation: Role of Disordered Phosphorylation Loops". United States. https://doi.org/10.1016/j.str.2008.10.010.
@article{osti_1007113,
title = {Structural Basis for Inactivation of the Human Pyruvate Dehydrogenase Complex by Phosphorylation: Role of Disordered Phosphorylation Loops},
author = {Kato, Masato and Wynn, R Max and Chuang, Jacinta L and Tso, Shih-Chia and Machius, Mischa and Li, Jun and Chuang, David T},
abstractNote = {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.},
doi = {10.1016/j.str.2008.10.010},
url = {https://www.osti.gov/biblio/1007113}, journal = {Structure},
number = (12) ; 12, 2008,
volume = 16,
place = {United States},
year = {Fri Sep 11 00:00:00 EDT 2009},
month = {Fri Sep 11 00:00:00 EDT 2009}
}