ArticleThe Journal of biological chemistry2005
Unfolding-resistant translocase targeting: a novel mechanism for outer mitochondrial membrane localization exemplified by the Bbeta2 regulatory subunit of protein phosphatase 2A.
Article in The Journal of biological chemistry, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 38 citations in OpenAlex.
- A distinct PP2A subunit regulates local protein phosphorylation at the axon initial segment.Nature communications · 2025Article
- PPP2/PP2A-mediated dephosphorylation of LC3B links PINK1-PRKN/Parkin-mediated mitophagy to SCA12 pathogenesis.Autophagy · 2025Article
- De novo missense variants in the PP2A regulatory subunit PPP2R2B in a neurodevelopmental syndrome: potential links to mitochondrial dynamics and spinocerebellar ataxias.Human molecular genetics · 2025Article
- Deletion of a Neuronal Drp1 Activator Protects against Cerebral Ischemia.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2020Article
- A cell death assay for assessing the mitochondrial targeting of proteins.The Journal of nutritional biochemistry · 2018Article
- MitochondrialThe Journal of biological chemistry · 2017Article
- A new non-canonical pathway of Gα(q) protein regulating mitochondrial dynamics and bioenergetics.Cellular signalling · 2014Article
- PP2A-B55β antagonizes cyclin E1 proteolysis and promotes its dysregulation in cancer.Cancer research · 2014Article
- Cell signaling and mitochondrial dynamics: Implications for neuronal function and neurodegenerative disease.Neurobiology of disease · 2013Review
- N-terminal phosphorylation of protein phosphatase 2A/Bβ2 regulates translocation to mitochondria, dynamin-related protein 1 dephosphorylation, and neuronal survival.The FEBS journal · 2013Article
- Identification and functional analysis of variant haplotypes in the 5'-flanking region of protein phosphatase 2A-Bδ gene.PloS one · 2012Article
- Mitochondrially localized PKA reverses mitochondrial pathology and dysfunction in a cellular model of Parkinson's disease.Cell death and differentiation · 2011Article
- PKA/AKAP1 and PP2A/Bβ2 regulate neuronal morphogenesis via Drp1 phosphorylation and mitochondrial bioenergetics.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2011Article
- Mitochondrial dysfunction and oxidative stress contribute to the pathogenesis of spinocerebellar ataxia type 12 (SCA12).The Journal of biological chemistry · 2011Article
- Determinants for Substrate Specificity of Protein Phosphatase 2A.Enzyme research · 2011Article
- Structural determinants of PINK1 topology and dual subcellular distribution.BMC cell biology · 2010Article
- Article
- The protein phosphatase 2A regulatory subunits B'beta and B'delta mediate sustained TrkA neurotrophin receptor autophosphorylation and neuronal differentiation.Molecular and cellular biology · 2009Article
- The spinocerebellar ataxia 12 gene product and protein phosphatase 2A regulatory subunit Bbeta2 antagonizes neuronal survival by promoting mitochondrial fission.The Journal of biological chemistry · 2008Article
- PP2A as a master regulator of the cell cycle.Critical reviews in biochemistry and molecular biologyReview
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Heterotrimeric serine/threonine protein phosphatase 2A (PP2A) consists of scaffolding (A), catalytic (C), and variable (B, B', and B'') subunits. Variable subunits dictate subcellular localization and substrate specificity of the PP2A holoenzyme. The Bbeta regulatory subunit gene is mutated in spinocerebellar ataxia type 12, and one of its splice variants, Bbeta2, targets PP2A to mitochondria to promote apoptosis in PC12 cells (Dagda, R. K., Zaucha, J. A., Wadzinski, B. E., and Strack, S. (2003) J. Biol. Chem. 278, 24976-24985). Here, we report that Bbeta2 is localized to the outer mitochondrial membrane by a novel mechanism, combining a cryptic mitochondrial import signal with a structural arrest domain. Scanning mutagenesis demonstrates that basic and hydrophobic residues mediate mitochondrial association and the proapoptotic activity of Bbeta2. When fused to green fluorescent protein, the N terminus of Bbeta2 acts as a cleavable mitochondrial import signal. Surprisingly, full-length Bbeta2 is not detectably cleaved and is retained at the outer mitochondrial membrane, even though it interacts with the TOM22 import receptor, as shown by luciferase complementation in intact cells. Mutations that open the C-terminal beta-propeller of Bbeta2 facilitate mitochondrial import, indicating that this rigid fold acts as a stop-transfer domain by resisting the partial unfolding step prerequisite for matrix translocation. Because hybrids of prototypical import and beta-propeller domains recapitulate this behavior, we predict the existence of other similarly localized proteins and a selection against highly stable protein folds in the mitochondrial matrix. This unfolding-resistant targeting to the mitochondrial translocase is necessary but not sufficient for the proapoptotic activity of Bbeta2, which also requires association with the rest of the PP2A holoenzyme.
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