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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosylmethionine Decarboxylase / chemistry*
  • Adenosylmethionine Decarboxylase / metabolism*
  • Allosteric Regulation
  • Crystallography, X-Ray
  • Enzyme Activation*
  • Gene Expression Regulation, Enzymologic*
  • Models, Molecular
  • Protein Conformation
  • Protein Multimerization
  • Protozoan Proteins / chemistry
  • Protozoan Proteins / metabolism
  • Trypanosoma brucei brucei / enzymology*


  • Protozoan Proteins
  • Adenosylmethionine Decarboxylase