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 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 evolution of this intricate regulatory mechanism was facilitated by 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.

Article and author information

Author details

  1. Oleg A Volkov

    Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Lisa N Kinch

    Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Carson Ariagno

    Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Xiaoyi Deng

    Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Shihua Zhong

    Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Nick V Grishin

    Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Diana R Tomchick

    Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7529-4643
  8. Zhe Chen

    Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Margaret A Phillips

    Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    margaret.phillips@utsouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5250-5578

Funding

National Institute of Allergy and Infectious Diseases (2R37AI034432)

  • Margaret A Phillips

National Institute of Allergy and Infectious Diseases (R01AI090599)

  • Margaret A Phillips

Welch Foundation (I-1257)

  • Margaret A Phillips

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. John Kuriyan, Howard Hughes Medical Institute, University of California, Berkeley, United States

Version history

  1. Received: July 30, 2016
  2. Accepted: December 11, 2016
  3. Accepted Manuscript published: December 15, 2016 (version 1)
  4. Version of Record published: December 30, 2016 (version 2)

Copyright

© 2016, Volkov et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Oleg A Volkov
  2. Lisa N Kinch
  3. Carson Ariagno
  4. Xiaoyi Deng
  5. Shihua Zhong
  6. Nick V Grishin
  7. Diana R Tomchick
  8. Zhe Chen
  9. Margaret A Phillips
(2016)
Relief of autoinhibition by conformational switch explains enzyme activation by a catalytically dead paralog
eLife 5:e20198.
https://doi.org/10.7554/eLife.20198

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https://doi.org/10.7554/eLife.20198

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