title: Relief of autoinhibition by conformational switch explains enzyme activation by a catalytically dead paralog.
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 ofTrypanosoma brucei S-adenosylmethionine decarboxylase alone and in functional complex with its catalytically dead paralogous partner, prozyme. We show monomericTbAdoMetDC 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 acis-to-transproline 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.
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Oleg A
authors.initials: OA
authors.lastname: Volkov
authors.affiliation: Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Lisa
authors.initials: L
authors.lastname: Kinch
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Carson
authors.initials: C
authors.lastname: Ariagno
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Deng
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Shihua
authors.initials: S
authors.lastname: Zhong
authors.affiliation: Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States.|Howard Hughes Medical Institute,University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Nick
authors.initials: N
authors.lastname: Grishin
authors.affiliation: Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Diana R
authors.identifier: 0000-0002-7529-4643
authors.initials: DR
authors.lastname: Tomchick
authors.affiliation: Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States.|Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Margaret A
authors.identifier: 0000-0001-5250-5578
authors.initials: MA
authors.lastname: Phillips
mesh_terms: D012437:Adenosylmethionine Decarboxylase / Q000737:chemistry* / Q000378:metabolism*; D000494:Allosteric Regulation; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D008958:Models, Molecular; D011487:Protein Conformation; D055503:Protein Multimerization; D015800:Protozoan Proteins / Q000737:chemistry / Q000378:metabolism; D014346:Trypanosoma brucei brucei / Q000201:enzymology*
chemical_list: D015800:Protozoan Proteins; D012437:Adenosylmethionine Decarboxylase
keywords: Trypanosome brucei; allostery; biochemistry; biophysics; polyamines; pseudo enzymes; structural biology