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

Oleg A. Volkov, Lisa Kinch, Carson Ariagno, Xiaoyi Deng, Shihua Zhong, Nick Grishin, Diana R. Tomchick, Zhe Chen, Margaret A. Phillips

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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 b-sheet, and insertion of the N-terminal a-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.

Original languageEnglish (US)
Article numbere20198
JournaleLife
Volume5
Issue numberDECEMBER2016
DOIs
StatePublished - Dec 15 2016

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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