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

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 -adenosylmethionine decarboxylase alone and in functional complex with its catalytically dead paralogous partner， prozyme. We show monomeric AdoMetDC 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 -to- 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.