PXD040376

PXD040376 is an original dataset announced via ProteomeXchange.

Title	Structure-function analysis of a calcium-independent metacaspase reveals a novel proteolytic pathway for lateral root emergence
Description	Metacaspases are part of an evolutionarily broad family of multifunctional cysteine proteases, involved in disease and normal development. Despite the extensive study of metacaspases in the two decades since their discovery, the structure-function relationship of metacaspases remains poorly understood. Furthermore, previous studies on their function have been thwarted by the redundancy in gene copy number and potential phenotypic suppression of genetic mutations, especially in plants. Here, we have solved the X-ray crystal structure of an Arabidopsis thaliana type II metacaspase (AtMCA-IIf) that belongs to a particular sub-group that does not require calcium ions for activation. Compared to crystal structures of other metacaspases and caspases, the AtMCA-IIf active site is structurally similar and poses a conundrum for the catalytic mechanism of the cysteine-histidine dyad. To study metacaspase activity in plants, we developed an in vitro chemical screen to identify small molecule metacaspase inhibitors. Several hits with a minimal thioxodihydropyrimidine-dione (TDP) structure were identified, some being specific inhibitors of AtMCA-IIf. We provide a mechanistic basis for inhibition by the TDP-containing compounds through molecular docking onto the AtMCA-IIf crystal structure. Finally, a TDP-containing compound (TDP6) was effective at inhibiting lateral root emergence in vivo, likely through the inhibition of metacaspases that are specifically expressed in the endodermal cells overlaying developing lateral root primordia. In the future, the small compound inhibitors and crystal structure of AtMCA-IIf can be used to study metacaspases in various other species, such as important human pathogens including those causing neglected diseases.
HostingRepository	PRIDE
AnnounceDate	2023-03-06
AnnouncementXML	Submission_2023-03-06_05:09:59.322.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	PatrickWillems
SpeciesList	scientific name: Arabidopsis thaliana (Mouse-ear cress); NCBI TaxID: 3702;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	LTQ FT

Revision	Datetime	Status	ChangeLog Entry
0	2023-02-24 03:33:45	ID requested
⏵ 1	2023-03-06 05:09:59	announced

Dataset with its publication pending

submitter keyword: Arabidopsis thaliana, AtMCA-IIf, protease,Metacaspase, lateral root

SimonStael
contact affiliation	Swedish University of Agricultural Sciences
contact email	simon.stael@slu.se
lab head
PatrickWillems
contact affiliation	PSB-VIB
contact email	pawil@psb.ugent.be
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD040376
     1. Label: PRIDE project
     2. Name: Structure-function analysis of a calcium-independent metacaspase reveals a novel proteolytic pathway for lateral root emergence