Probing the quality control mechanism of the Escherichia coli twin-arginine translocase with folding variants of a de novo–designed heme protein

Mutations in parkin (PARK2) and Pink1 (PARK6) are responsible for autosomal recessive forms of early onset Parkinson’s disease (PD). Attributed to the failure of neurons to clear dysfunctional mitochondria, loss of gene expression leads to loss of nigrostriatal neurons. The Pink1/parkin pathway plays a role in the quality control mechanism aimed at eliminating defective mitochondria, and the failure of this mechanism results in a reduced lifespan and impaired locomotor ability, among other phenotypes. Inhibition of parkin or Pink1 through the induction of stable RNAi transgene in the Ddc-Gal4-expressing neurons results in such phenotypes to model PD. To further evaluate the effects of the overexpression of the Bcl-2 homologue Buffy, we analysed lifespan and climbing ability in both parkin-RNAi- and Pink1-RNAi-expressing flies. In addition, the effect of Buffy overexpression upon parkin-induced developmental eye defects was examined through GMR-Gal4-dependent expression. Curiously, Buffy overexpression produced very different effects: the parkin-induced phenotypes were enhanced, whereas the Pink1-enhanced phenotypes were suppressed. Interestingly, the overexpression of Buffy along with the inhibition of parkin in the neuron-rich eye results in the suppression of the developmental eye defects.

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Where Parkin Parks

Science Signaling ◽

10.1126/scisignal.2004274 ◽

2013 ◽

Vol 6 (273) ◽

pp. ec96-ec96

Author(s):

L. Bryan Ray

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Quality Control ◽

Protein Kinase ◽

Full Text ◽

Control Mechanism ◽

Membrane Depolarization ◽

Mitofusin 2 ◽

Link Type ◽

Quality Control Mechanism

Damaged mitochondria are removed from cells in a process known as mitophagy. Failure of this quality-control mechanism contributes to Parkinson’s disease. When damaged mitochondria lose membrane depolarization, the protein kinase, PINK1, accumulates on the mitochondrial surface, recruits Parkin, and promotes mitophagy. Chen and Dorn describe another component of this process, mitofusin 2, which appears to function as the receptor for Parkin on the surface of damaged mitochondria.Y. Chen, G. W. Dorn II, PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science340, 471–475 (2013). [Abstract] [Full Text]

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Peters Plus Syndrome Mutations Disrupt a Noncanonical ER Quality-Control Mechanism

Current Biology ◽

10.1016/j.cub.2014.11.049 ◽

2015 ◽

Vol 25 (3) ◽

pp. 286-295 ◽

Cited By ~ 54

Author(s):

Deepika Vasudevan ◽

Hideyuki Takeuchi ◽

Sumreet Singh Johar ◽

Elaine Majerus ◽

Robert S. Haltiwanger

Keyword(s):

Quality Control ◽

Control Mechanism ◽

Er Quality Control ◽

Quality Control Mechanism

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Cytosolic chaperones mediate quality control of higher-order septin assembly in budding yeast

Molecular Biology of the Cell ◽

10.1091/mbc.e14-11-1531 ◽

2015 ◽

Vol 26 (7) ◽

pp. 1323-1344 ◽

Cited By ~ 18

Author(s):

Courtney R. Johnson ◽

Andrew D. Weems ◽

Jennifer M. Brewer ◽

Jeremy Thorner ◽

Michael A. McMurray

Keyword(s):

Quality Control ◽

De Novo ◽

Cell Types ◽

Binding Pocket ◽

Sole Source ◽

Eukaryotic Cell ◽

Higher Order ◽

Native Proteins ◽

Wild Type Counterpart ◽

Quality Control Mechanism

Septin hetero-oligomers polymerize into cytoskeletal filaments with essential functions in many eukaryotic cell types. Mutations within the oligomerization interface that encompasses the GTP-binding pocket of a septin (its “G interface”) cause thermoinstability of yeast septin hetero-oligomer assembly, and human disease. When coexpressed with its wild-type counterpart, a G interface mutant is excluded from septin filaments, even at moderate temperatures. We show that this quality control mechanism is specific to G interface mutants, operates during de novo septin hetero-oligomer assembly, and requires specific cytosolic chaperones. Chaperone overexpression lowers the temperature permissive for proliferation of cells expressing a G interface mutant as the sole source of a given septin. Mutations that perturb the septin G interface retard release from these chaperones, imposing a kinetic delay on the availability of nascent septin molecules for higher-order assembly. Unexpectedly, the disaggregase Hsp104 contributes to this delay in a manner that does not require its “unfoldase” activity, indicating a latent “holdase” activity toward mutant septins. These findings provide new roles for chaperone-mediated kinetic partitioning of non-native proteins and may help explain the etiology of septin-linked human diseases.

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