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

被引：8

作者：

Stael, Simon ^{[1
,2
,3
,4
]}

Sabljic, Igor ^{[3
,4
]}

Audenaert, Dominique

Andersson, Thilde ^{[7
]}

Tsiatsiani, Liana ^{[1
,2
]}

Kumpf, Robert P.

Vidal-Albalat, Andreu

Lindgren, Cecilia

Vercammen, Dominique ^{[1
,2
]}

Jacques, Silke ^{[1
,2
]}

Nguyen, Long ^{[5
,6
]}

Njo, Maria ^{[1
,2
]}

Fernandez-Fernandez, Alvaro D.

Beunens, Tine ^{[1
,2
]}

Timmerman, Evy ^{[8
,9
]}

Gevaert, Kris ^{[8
,9
]}

Van Montagu, Marc ^{[1
,2
]}

Stahlberg, Jerry

V. Bozhkov, Peter ^{[3
,4
]}

Linusson, Anna ^{[7
]}

Beeckman, Tom ^{[1
,2
]}

Van Breusegem, Frank ^{[1
,2
]}

机构：

[1] Univ Ghent, Dept Plant Biotechnol & Bioinformat, B-9052 Ghent, Belgium

[2] Ctr Plant Syst Biol VIB, B-9052 Ghent, Belgium

[3] Swedish Univ Agr Sci, Dept Mol Sci, Uppsala Bioctr, S-75007 Uppsala, Sweden

[4] Linnean Ctr Plant Biol, S-75007 Uppsala, Sweden

[5] VIB Screening Core VIB, B-9052 Ghent, Belgium

[6] Univ Ghent, Ctr Bioassay Dev & Screening, B-9000 Ghent, Belgium

[7] Umea Univ, Dept Chem, S-90187 Umea, Sweden

[8] Univ Ghent, Dept Biomol Med, B-9052 Ghent, Belgium

[9] VIB, Ctr Med Biotechnol, B-9052 Ghent, Belgium

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2023年 / 120卷 / 22期

基金：

瑞典研究理事会;

关键词：

AtMCA-IIf crystal structure; cysteine protease; lateral root development; metacaspase; small chemical inhibitor; ARABIDOPSIS-THALIANA; CELL-DEATH; CRYSTAL-STRUCTURE; PROTEIN; RECEPTOR; CLASSIFICATION; PARACASPASES; MECHANISMS; RESPONSES; PEPTIDES;

D O I：

10.1073/pnas.2303480120

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：12

共 71 条

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