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Structure–function study of a Ca2+-independent metacaspase involved in lateral root emergence

Simon Stael (UGent) , Igor Sabljić, Dominique Audenaert (UGent) , Thilde Andersson, Liana Tsiatsiani (UGent) , Robert P. Kumpf, Andreu Vidal-Albalat, Cecilia Lindgren, Dominique Vercammen, Silke Jacques (UGent) , et al.
(2023) PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 120(22).
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Abstract
Metacaspases are part of an evolutionarily broad family of multifunctional cysteine pro -teases, involved in disease and normal development. As the structure-function relation-ship of metacaspases remains poorly understood, we solved the X-ray crystal structure of an Arabidopsis thaliana type II metacaspase (AtMCA-IIf) belonging to a particular subgroup not requiring calcium ions for activation. To study metacaspase activity in plants, we developed an in vitro chemical screen to identify small molecule metacaspase inhibitors and found several hits with a minimal thioxodihydropyrimidine-dione structure, of which some are specific AtMCA-IIf inhibitors. We provide mechanistic insight into the basis of inhibition by the TDP-containing compounds through molecular docking onto the AtMCA-IIf crystal structure. Finally, a TDP-containing compound (TDP6) effectively hampered lateral root emergence in vivo, probably through inhibition of metacaspases specifically expressed in the endodermal cells overlying developing lateral root primordia. In the future, the small compound inhibitors and crystal structure of AtMCA-IIf can be used to study metacaspases in other species, such as important human pathogens, including those causing neglected diseases.
Keywords
Multidisciplinary, small chemical inhibitor, metacaspase, lateral root development, cysteine protease, AtMCA-IIf crystal structure

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MLA
Stael, Simon, et al. “Structure–Function Study of a Ca2+-Independent Metacaspase Involved in Lateral Root Emergence.” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 120, no. 22, Proceedings of the National Academy of Sciences, 2023, doi:10.1073/pnas.2303480120.
APA
Stael, S., Sabljić, I., Audenaert, D., Andersson, T., Tsiatsiani, L., Kumpf, R. P., … Van Breusegem, F. (2023). Structure–function study of a Ca2+-independent metacaspase involved in lateral root emergence. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 120(22). https://doi.org/10.1073/pnas.2303480120
Chicago author-date
Stael, Simon, Igor Sabljić, Dominique Audenaert, Thilde Andersson, Liana Tsiatsiani, Robert P. Kumpf, Andreu Vidal-Albalat, et al. 2023. “Structure–Function Study of a Ca2+-Independent Metacaspase Involved in Lateral Root Emergence.” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 120 (22). https://doi.org/10.1073/pnas.2303480120.
Chicago author-date (all authors)
Stael, Simon, Igor Sabljić, Dominique Audenaert, Thilde Andersson, Liana Tsiatsiani, Robert P. Kumpf, Andreu Vidal-Albalat, Cecilia Lindgren, Dominique Vercammen, Silke Jacques, Long Nguyen, Maria Njo, Álvaro Daniel Fernández Fernández, Tine Beunens, Evy Timmerman, Kris Gevaert, Marc Van Montagu, Jerry Ståhlberg, Peter V. Bozhkov, Anna Linusson, Tom Beeckman, and Frank Van Breusegem. 2023. “Structure–Function Study of a Ca2+-Independent Metacaspase Involved in Lateral Root Emergence.” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 120 (22). doi:10.1073/pnas.2303480120.
Vancouver
1.
Stael S, Sabljić I, Audenaert D, Andersson T, Tsiatsiani L, Kumpf RP, et al. Structure–function study of a Ca2+-independent metacaspase involved in lateral root emergence. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 2023;120(22).
IEEE
[1]
S. Stael et al., “Structure–function study of a Ca2+-independent metacaspase involved in lateral root emergence,” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 120, no. 22, 2023.
@article{01H1BBT35J1JZDAM2WQF7EAVEJ,
  abstract     = {{Metacaspases are part of an evolutionarily broad family of multifunctional cysteine pro -teases, involved in disease and normal development. As the structure-function relation-ship of metacaspases remains poorly understood, we solved the X-ray crystal structure of an Arabidopsis thaliana type II metacaspase (AtMCA-IIf) belonging to a particular subgroup not requiring calcium ions for activation. To study metacaspase activity in plants, we developed an in vitro chemical screen to identify small molecule metacaspase inhibitors and found several hits with a minimal thioxodihydropyrimidine-dione structure, of which some are specific AtMCA-IIf inhibitors. We provide mechanistic insight into the basis of inhibition by the TDP-containing compounds through molecular docking onto the AtMCA-IIf crystal structure. Finally, a TDP-containing compound (TDP6) effectively hampered lateral root emergence in vivo, probably through inhibition of metacaspases specifically expressed in the endodermal cells overlying developing lateral root primordia. In the future, the small compound inhibitors and crystal structure of AtMCA-IIf can be used to study metacaspases in other species, such as important human pathogens, including those causing neglected diseases.}},
  articleno    = {{e2303480120}},
  author       = {{Stael, Simon and Sabljić, Igor and Audenaert, Dominique and Andersson, Thilde and Tsiatsiani, Liana and Kumpf, Robert P. and Vidal-Albalat, Andreu and Lindgren, Cecilia and Vercammen, Dominique and Jacques, Silke and Nguyen, Long and Njo, Maria and Fernández Fernández, Álvaro Daniel and Beunens, Tine and Timmerman, Evy and Gevaert, Kris and Van Montagu, Marc and Ståhlberg, Jerry and Bozhkov, Peter V. and Linusson, Anna and Beeckman, Tom and Van Breusegem, Frank}},
  issn         = {{0027-8424}},
  journal      = {{PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA}},
  keywords     = {{Multidisciplinary,small chemical inhibitor,metacaspase,lateral root development,cysteine protease,AtMCA-IIf crystal structure}},
  language     = {{eng}},
  number       = {{22}},
  pages        = {{12}},
  publisher    = {{Proceedings of the National Academy of Sciences}},
  title        = {{Structure–function study of a Ca2+-independent metacaspase involved in lateral root emergence}},
  url          = {{http://doi.org/10.1073/pnas.2303480120}},
  volume       = {{120}},
  year         = {{2023}},
}
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