Dataset Information

GNA13 – peptide interaction analysis (GST-tag co-purification)

ABSTRACT: Alpha-1-antitrypsin (AAT), a circulating serine protease inhibitor, is an acute inflammatory response protein with anti-inflammatory functions. The C-terminal peptides of AAT are found in various tissues and have been proposed as putative bioactive peptides with multiple functions, but its mechanism of action remains unclear. We previously reported that a mouse AAT C-terminal peptide of 35 amino acids (mAAT-C1-35) activates guanine nucleotide-binding protein subunit alpha 13 (Gα13). Here, we show that mAAT-C1-35 binds directly to the guanosine diphosphate (GDP)-bound form of Gα13 through the N-terminal region (mAAT-C1-17), thereby facilitating the association of Gα13・GDP with its downstream target proteins in the absence of GTP.

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

SUBMITTER: Fumiko Toyoshima

PROVIDER: PXD054789 | JPOST Repository | Wed Jan 01 00:00:00 GMT 2025

REPOSITORIES: jPOST

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Dataset's files

Source:

			Action	DRS
	210530ko02Control_GNA_UV.maxq.dat	Other
	210530ko02Control_GNA_UV.raw	Raw
	210530ko03Control_GNA_UV.maxq.dat	Other
	210530ko03Control_GNA_UV.raw	Raw
	210530ko04Control_GNA_UV.maxq.dat	Other

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Publications

Receptor-independent regulation of Gα13 by alpha-1-antitrypsin C-terminal peptides.

Park Yonghak Y Matsumoto Shigeyuki S Ogata Kosuke K Ma Biao B Kanada Ryo R Isaka Yuta Y Arichi Norihito N Liang Xiaowen X Maki Ritsuko R Kozasa Tohru T Okuno Yasushi Y Ohno Hiroaki H Ishihama Yasushi Y Toyoshima Fumiko F

The Journal of biological chemistry 20241225 2

Alpha-1-antitrypsin (AAT), a circulating serine protease inhibitor, is an acute inflammatory response protein with anti-inflammatory functions. The C-terminal peptides of AAT are found in various tissues and have been proposed as putative bioactive peptides with multiple functions, but its mechanism of action remains unclear. We previously reported that a mouse AAT C-terminal peptide of 35 amino acids (mAAT-C<sub>1-35</sub>) penetrates plasma membrane and associates guanine nucleotide-binding pr ...[more]

PMID: 39730062

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Project description:Background: Transient ischemic attack (TIA) induces ischemic tolerance that can reduce the subsequent ischemic damage and improve prognosis of stroke patients. However, the underlying mechanisms remain elusive. Recent advances in plasma metabolomics analysis have made it a powerful tool to investigate human pathophysiological phenotypes and mechanisms of diseases. In this study, we aimed to identify the bioactive metabolites from the plasma of TIA patients for determination of their prophylactic and therapeutic effects on protection against cerebral ischemic stroke, and the mechanism of TIA-induced ischemic tolerance against subsequent stroke. Methods: Metabolomic profiling using liquid chromatography-mass spectrometry was performed to identify the TIA-induced differential bioactive metabolites in the plasma samples of 20 patients at day 1 (time for basal metabolites) and day 7 (time for established chronic ischemic tolerance-associated metabolites) after onset of TIA. Mouse MCAO-induced stroke model was used to verify their prophylactic and therapeutic potentials. Transcriptomics changes in circulating neutrophils of TIA patients were determined by RNA-sequencing. Multivariate statistics and integrative analysis of metabolomics and transcriptomics were performed to elucidate the potential mechanism of TIA-induced ischemic tolerance. Findings: Plasma metabolomics analysis identified five differentially upregulated metabolites associated with TIA-induced ischemic tolerance, namely all-trans 13,14 dihydroretinol (atDR), 20-carboxyleukotriene B4, prostaglandin B2, cortisol and 9-KODE. They were associated with the metabolic pathways of retinol, arachidonic acid, and neuroactive ligand-receptor interaction. Prophylactic treatment of MCAO mice with these five metabolites significantly improved neurological functions. Additionally, post-stroke treatment with atDR or 9-KODE significantly reduced the cerebral infarct size and enhanced sensorimotor functions, demonstrating the therapeutic potential of these bioactive metabolites. Mechanistically, we found in TIA patients that these metabolites were positively correlated with circulating neutrophil counts. Integrative analysis of plasma metabolomics and neutrophil transcriptomics further revealed that TIA-induced metabolites are significantly correlated with specific gene expression in circulating neutrophils which showed prominent enrichment in FoxO signaling pathway and upregulation of the anti-inflammatory cytokine IL-10. Finally, we demonstrated that the protective effect of atDR-pretreatment on MCAO mice was abolished when circulating neutrophils were depleted. Interpretation: TIA-induced ischemic tolerance is associated with upregulation of plasma bioactive metabolites which can protect against cerebral ischemic damage and improve neurological functions through a positive role of circulating neutrophils.