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 journalArticle

10 Citations (Scopus)

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

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Enzyme Activation
Chemical activation
Switches
Enzymes
Adenosylmethionine Decarboxylase
Trypanosoma brucei brucei
Dimerization
Proline
Catalytic Domain
Isomerization
X-Rays
Genome
Genes
X rays

ASJC Scopus subject areas

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

Cite this

Relief of autoinhibition by conformational switch explains enzyme activation by a catalytically dead paralog. / Volkov, Oleg A.; Kinch, Lisa; Ariagno, Carson; Deng, Xiaoyi; Zhong, Shihua; Grishin, Nick; Tomchick, Diana R.; Chen, Zhe; Phillips, Margaret A.

In: eLife, Vol. 5, No. DECEMBER2016, e20198, 15.12.2016.

Research output: Contribution to journalArticle

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AU - Grishin, Nick

AU - Tomchick, Diana R.

AU - Chen, Zhe

AU - Phillips, Margaret A.

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