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.DOI:
http://dx.doi.org/10.7554/eLife.20198.001
Pseudoenzymes are known to functionally regulate their active counterparts. We present a case study of such a regulation in Trypanosoma brucei S-adenosylmeyhionine decarboxylase (TbAdoMetDC), which is 1000-fold activated by heterodimerization with its catalytically dead paralog, prozyme.To gain insight into the activation mechanism, we solved crystal structures of both the low-activity monomeric TbAdoMetDC and fully active heterodimeric TbAdoMetDC/prozyme.The structures reveal that TbAdoMetDC monomer activity is low due to autoinhibition, and that prozyme allosterically activates the complex by inducing intricate conformational changes that result in a relief of autoinhibition.We were able to identify key segments of movement that facilitate long-range control of the TbAdoMetDC active site from the dimerization interface: (1) flipping and slipping of betastrands, (2) disordered-to-ordered transitioning of a loop, and (3) prolyl peptide bond cis-to-trans isomerization. These concerted changes lead to a stable active confirmation.
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