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Elife. 2016 Dec 15;5. pii: e20198. doi: 10.7554/eLife.20198.

Relief of autoinhibition by conformational switch explains enzyme activation by a catalytically dead paralog.

Author information

1
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States.
2
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States.
3
Howard Hughes Medical Institute,University of Texas Southwestern Medical Center, Dallas, United States.
4
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States.

Abstract

Catalytically inactive enzyme paralogs occur in many genomes. Some regulate their active counterparts but the structural principles of this regulation remain largely unknown. We report X-ray structures of Trypanosoma brucei S-adenosylmethionine decarboxylase alone and in functional complex with its catalytically dead paralogous partner, prozyme. We show monomeric TbAdoMetDC is inactive because of autoinhibition by its N-terminal sequence. Heterodimerization with prozyme displaces this sequence from the active site through a complex mechanism involving a cis-to-trans proline isomerization, reorganization of a β-sheet, and insertion of the N-terminal α-helix into the heterodimer interface, leading to enzyme activation. We propose that the evolution of this intricate regulatory mechanism was facilitated by the acquisition of the dimerization domain, a single step that can in principle account for the divergence of regulatory schemes in the AdoMetDC enzyme family. These studies elucidate an allosteric mechanism in an enzyme and a plausible scheme by which such complex cooperativity evolved.

KEYWORDS:

Trypanosome brucei; allostery; biochemistry; biophysics; polyamines; pseudo enzymes; structural biology

PMID:
27977001
PMCID:
PMC5201418
DOI:
10.7554/eLife.20198
[Indexed for MEDLINE]
Free PMC Article

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