Relief of autoinhibition by conformational switch explains enzyme activation by a catalytically dead paralog
- University of Texas Southwestern Medical Center, 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 evolution of this intricate regulatory mechanism was facilitated by 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.
Article and author information
Author details
Margaret A Phillips
Funding
National Institute of Allergy and Infectious Diseases (2R37AI034432)
- Margaret A Phillips
National Institute of Allergy and Infectious Diseases (R01AI090599)
- Margaret A Phillips
Welch Foundation (I-1257)
- Margaret A Phillips
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2016, Volkov et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Relief of autoinhibition by conformational switch explains enzyme activation by a catalytically dead paralog
eLife 5:e20198.
https://doi.org/10.7554/eLife.20198
