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Preventing Site-specific Calpain Proteolysis of Junctophilin-2 Protects Against Stress-induced E-C Uncoupling and Heart Failure

ABSTRACT: Preventing Site-specific Calpain Proteolysis of Junctophilin-2 Protects Against Stress-induced E-C Uncoupling and Heart Failure

PROVIDER: PRJNA986537 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24999025_1.fastq.gz	Fastqsanger.gz
	SRR24999025_2.fastq.gz	Fastqsanger.gz
	SRR24999026_1.fastq.gz	Fastqsanger.gz
	SRR24999026_2.fastq.gz	Fastqsanger.gz
	SRR24999027_1.fastq.gz	Fastqsanger.gz

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Preventing Site-specific Calpain Proteolysis of Junctophilin-2 Protects Against Stress-induced E-C Uncoupling and Heart Failure

Project description:Junctophilin-2 (JP2) is an essential component of the excitation-contraction coupling apparatus in cardiomyocytes and becomes proteolytically cleaved in response to stress. We previously mapped the primary calpain cleavage site to JP2 residues 565-566 using in vitro assays. To determine whether this site is responsible for JP2 cleavage in vivo, we generated calpain resistant JP2 (JP2CR) knock-in mice lacking this site. We find JP2 is not cleaved in JP2CR mice during pressure overload stress resulting in better cardiac outcomes and an attenuated transcriptional response relative to wildtype mice.

2024-08-01 | GSE235601 | GEO

Fam20c regulates the calpain proteolysis system through phosphorylating Calpasatatin to maintain cell homeostasis

Project description:Background: The family with sequence similarity 20-member C (FAM20C) kinase, a Golgi casein kinase, which is responsible for phosphorylating the majority of the extracellular phosphoproteins within S-x-E/pS motifs, and is fundamentally associated with multiple biological processes to maintain cell proliferation, biomineralization, migration, adhesion, and phosphate homeostasis. In dissecting how FAM20C regulates downstream molecules and potential mechanisms, however, there are multiple target molecules of FAM20C, particularly many phenomena remain elusive, such as changes in cell-autonomous behaviors, incompatibility in genotypes and phenotypes, and others. Methods: Here, assay for transposase-accessible chromatin using sequencing (ATAC-seq), RNA sequencing (RNA-seq), proteomics, and phosphoproteomics were performed in Fam20c-dificient osteoblasts and to facilitate an integrated analysis and determine the impact of chromatin accessibility, genomic expression, protein alterations, signaling pathway, and post translational modifcations. Results: By combining ATAC-seq and RNA-seq, we identified TCF4 and Wnt signaling pathway as the key regulators in Fam20c-dificient cells. Further, we showed Calpastatin/Calpain proteolysis system as a novel target axis for FAM20C to regulate cell migration and F-actin cytoskeleton by integrated analysis of proteomics and phosphoproteomics. Furthermore, Calpastatin/Calpain proteolysis system could negatively regulate the Wnt signaling pathway. Conclusion: These observations implied that Fam20c knockout osteoblasts would cause cell homeostatic imbalance, involving changes in multiple signaling pathways in the conduction system.

2023-09-11 | GSE233445 | GEO

Fam20c regulates the calpain proteolysis system through phosphorylating Calpasatatin to maintain cell homeostasis

Project description:Fam20c regulates the calpain proteolysis system through phosphorylating Calpasatatin to maintain cell homeostasis

| PRJNA976281 | ENA

Proteomic QSAR analysis of calpain substrate specificity

Project description:Calpains are intracellular Ca2+-regulated cysteine proteases that are essential for various cellular functions. Mammalian conventional calpains (calpain-1 and calpain-2) modulate the structure and function of their substrates by limited proteolysis; however, their substrate specificity remains unclear because the amino acid (aa) sequences around their cleavage sites are very diverse. To clarify calpains’ substrate specificities, 84 20-mer oligopeptides, corresponding to P10-P10’ of reported cleavage site sequences, were proteolyzed by calpains, and the catalytic efficiencies (kcat/Km) were globally determined by LC/MS. This analysis revealed 483 cleavage site sequences, including 360 novel ones. The kcat/Kms for 119 sites ranged from 12.5~1,710 M-1s-1. Most sites were cleaved by both calpain-1 and -2 with a similar kcat/Km. The aa compositions of the novel sites were not significantly different from the 420 previously reported sites, suggesting calpains have a strict implicit rule for sequence specificity, and that the limited proteolysis of intact substrates is due to the substrates’ higher-order structures. Cleavage position frequencies indicated that longer sequences N-terminal to the cleavage site (P-sites) than C-terminal (P’-sites) were preferred for proteolysis. Quantitative structure-activity relationship (QSAR) analyses using partial least-squares regression and >1,300 aa descriptors achieved kcat/Km prediction with r=0.834, and binary-QSAR modeling attained 64.8% prediction accuracy for 132 reported calpain cleavage sites independent of our model construction. These results outperformed previous calpain cleavage predictors, and revealed the importance of the P2, P3’, P4’, and P1-P2 contexts. This study increases our understanding of calpain substrate specificities, and opens calpains to “next-generation,” i.e., activity-related quantitative and context-dependent analyses.

2016-07-19 | PXD002532 | Pride

Uncoupling from transcription protects polyadenylation site cleavage from inhibition by DNA damage

Project description:Uncoupling from transcription protects polyadenylation site cleavage from inhibition by DNA damage

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DEK1 calpain overexpression

Project description:Aim: To understand the role of DEK1 in Arabidopsis development. Background: DEK1 has an essential role during embryogenesis and is involved in the maintenance of the epidermis. Tissues: Comparison of wild-type and ADEK1 calpain-overexpressing line. 9 samples were used in this experiment.

2009-12-09 | E-GEOD-19268 | biostudies-arrayexpress

DEK1 calpain overexpression

2009-12-10 | GSE19268 | GEO

Mitochondrial dysfunction and consequences in calpain-3-deficient muscle

Project description:Microarray profiling to determine muscle cell-specific consequences of calpain-3 deficiency

2022-03-28 | GSE199621 | GEO

Mitochondrial dysfunction and consequences in calpain-3-deficient muscle myoblasts

Project description:Microarray profiling to determine muscle cell-specific consequences of calpain-3 deficiency

2022-03-28 | GSE199620 | GEO

Calpain activity is regulated by a KCTD7–cullin 3 complex via non-degradative ubiquitination

Project description:Calpains are a class of non-lysosomal cysteine proteases that exert their regulatory functions via limited proteolysis of their substrates. Similar to the lysosomal and proteasomal systems, calpain dysregulation is implicated in the pathogenesis of neurodegenerative disease and cancer. Despite intensive efforts placed on the identification of mechanisms that regulate calpains, however, global regulators of calpains activity have remained elusive. Here we show that calpains are regulated by KCTD7, a cytosolic protein of previously uncharacterized function whose pathogenic mutations result in epilepsy, progressive ataxia, and severe neurocognitive deterioration. We show that KCTD7 works in complex with Cullin-3 and Rbx1 to execute atypical, non-degradative ubiquitination of calpains at specific sites (K398 of calpain 1, and K280 and K674 of calpain 2). Experiments based on single-lysine mutants of ubiquitin determined that KCTD7 mediates ubiquitination of calpain 1 via K6-, K27-, K29-, and K63-linked chains, whereas it uses K6- mediated ubiquitination to modify calpain 2. Loss of KCTD7-mediated ubiquitination of calpains led to calpain hyperactivation, aberrant cleavage of downstream targets, and caspase-3 activation. CRISPR/Cas9-mediated knockout of Kctd7 in mice phenotypically recapitulated human KCTD7 deficiency and resulted in calpain hyperactivation, behavioral impairments, and neurodegeneration. These phenotypes were largely prevented by pharmacological inhibition of calpains, thus demonstrating a major role of calpain dysregulation in KCTD7-associated disease. Finally, we determined that Cullin-3–KCTD7 mediates ubiquitination of all ubiquitous calpains. These results unveil a global mechanism and potential target to restrain calpain activity in human disease and shed light on the molecular pathogenesis of KCTD7-associated disease.

2023-05-10 | PXD038842 | Pride

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