The Phosphorylation Status of Drp1-Ser637 by PKA in Mitochondrial Fission Modulates Mitophagy via PINK1/Parkin to Exert Multipolar Spindles Assembly during Mitosis.
Define the primary specificity of endogenous Parkin action on mitochondria the abundance of ubiquitin proteoforms the role of p97 in remodeling the mitochondrial proteome downstream of Parkin and the target specificity of USP30 during mitophagic signaling.
Mitochondrial E3 Ubiquitin Ligase Parkin: Relationships with Other Causal Proteins in Familial Parkinson's Disease and Its Substrate-Involved Mouse Experimental Models.
data show how autoinhibition in parkin is resolved and suggest a mechanism for how parkin ubiquitinates its substrates via an untethered RING2 domain; these findings open new avenues for the design of parkin activators for clinical use
The findings suggest that Parkin plays a novel role in innate immune signaling by targeting TRAF3 for degradation and maintaining the balance of innate antiviral immunity.
Define the kinetics and site specificity of PARKIN-dependent target ubiquitylation and mechanistically define the role of PARKIN UBL phosphorylation in pathway activation in induced neurons.
work provides a framework for the mechanisms of parkin's loss-of-function indicating an interplay between ARJP-associated substitutions and phosphorylation of its Ubl domain.
Parkin expression is inversely correlated with HIF-1alpha expression and metastasis in breast cancer. Results reveal an important mechanism for Parkin in tumor suppression and HIF-1alpha regulation.
The methylation of SNCA and PARK2 promoter regions were significantly lower in early-onset Parkinson's disease patients compared to control group. Methylation status of the SNCA might be associated with positive family history of Parkinson's disease.
These results demonstrate the feasibility of using UbFluor for quantitative studies of the biochemistry of RBR E3s and for high-throughput screening of small-molecule activators or inhibitors of PARKIN and other RBR E3 ligases.
Parkin hyper-activation by pUb(S57) demonstrates the first PINK1-independent route to active parkin revealing the roles of multiple ubiquitin phosphorylation sites in governing parkin stimulation and catalytic activity.
Show that the C-terminal GTPase of the Parkin primary substrates Miro1 and Miro2 are necessary and sufficient for efficient ubiquitination. We present several new X-ray crystal structures of both Miro1 and Miro2 that reveal substrate recognition and ubiquitin transfer to be specific to particular protein domains and lysine residues.
Results show that HERC5 mediates covalent ISG15 conjugation to parkin in mammalian cells and that ISG15 is conjugated to the Lys349 and Lys369 residues of parkin. This ISGylation increases the ubiquitin E3 ligase activity of parkin. Also some familial Parkinson's disease-associated missense mutations of parkin display defective ISGylation.
These results suggest that degradation of endogenous APE1 by Parkin occur when cells are stressed to activate Parkin and imply a role of Parkin in maintaining the quality of APE1 and loss of Parkin may contribute to elevated APE1 levels in glioblastoma.
findings underscore the importance of a mitophagy regulatory network of ATM and PINK1/Parkin and elucidate a novel mechanism by which ATM influences spermidine-induced mitophagy
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