Regulation of synaptic Pumilio function by an aggregation-prone domain
Anna M Salazar1, Edward J Silverman, Kaushiki P Menon
1Division of Biology, California Institute of Technology, Pasadena, California 91125, USA.
Summary
Pumilio (Pum), a translational repressor, can form aggregates. A Pumilio domain (NQ1) and PUF-9 protein aggregate in yeast and cause heritable traits, suggesting a role for protein aggregation in regulating Pumilio function.
Area of Science:
- Molecular Biology
- Genetics
- Neuroscience
Background:
- Pumilio (Pum) is a Drosophila translational repressor.
- Proteins forming ordered aggregates can have regulated activities.
- Yeast prion proteins with Q/N-rich domains serve as a model for aggregation.
Purpose of the Study:
- To investigate the aggregation potential of Pumilio and its orthologs.
- To determine if Pumilio aggregation affects its function in vivo.
- To explore the mechanism of Pumilio regulation by aggregation-prone domains.
Main Methods:
- Computational search for aggregation-prone proteins.
- Expression of Pumilio and PUF-9 domains in yeast.
- In vitro amyloid fibril formation assays.
- In vivo studies in Drosophila neuromuscular junctions (NMJs).
Main Results:
- A Pumilio domain (NQ1) and PUF-9 protein aggregate in yeast and form amyloid fibrils in vitro.
- NQ1 expression in Drosophila muscles negatively regulates endogenous Pumilio.
- NQ1 induces gene dosage-dependent loss-of-function phenotypes at the NMJ.
- The Q/N-rich region of NQ1 is essential for its regulatory effects.
Conclusions:
- Pumilio proteins possess aggregation-prone domains that can influence their function.
- Aggregation or dominant-negative effects of Pumilio domains can modulate translational repression.
- This study reveals a novel mechanism for regulating protein activity through aggregation.
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