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Published on: October 17, 2015
The cellular modifier MOAG-4/SERF drives amyloid formation through charge complementation
Anita Pras1, Bert Houben2,3, Francesco A Aprile4
1European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
Abstract:
While aggregation-prone proteins are known to accelerate aging and cause age-related diseases, the cellular mechanisms that drive their cytotoxicity remain unresolved. The orthologous proteins MOAG-4, SERF1A, and SERF2 have recently been identified as cellular modifiers of such proteotoxicity. Using a peptide array screening approach on human amyloidogenic proteins, we found that SERF2 interacted with protein segments enriched in negatively charged and hydrophobic, aromatic amino acids. The absence of such segments, or the neutralization of the positive charge in SERF2, prevented these interactions and abolished the amyloid-promoting activity of SERF2. In protein aggregation models in the nematode worm Caenorhabditis elegans, protein aggregation and toxicity were suppressed by mutating the endogenous locus of MOAG-4 to neutralize charge. Our data indicate that MOAG-4 and SERF2 drive protein aggregation and toxicity by interactions with negatively charged segments in aggregation-prone proteins. Such charge interactions might accelerate primary nucleation of amyloid by initiating structural changes and by decreasing colloidal stability. Our study points at charge interactions between cellular modifiers and amyloidogenic proteins as potential targets for interventions to reduce age-related protein toxicity.
Insights
Cellular proteins MOAG-4 and SERF2 accelerate aging and disease by promoting protein aggregation. Neutralizing charge interactions with these proteins suppressed aggregation and toxicity, revealing a potential therapeutic target.
Area of Science:
- Molecular Biology
- Aging Research
- Biochemistry
Background:
- Protein aggregation is linked to aging and neurodegenerative diseases.
- Cellular modifiers like MOAG-4 and SERF2 influence protein aggregation and toxicity.
- The precise mechanisms of proteotoxicity remain incompletely understood.
Purpose of the Study:
- To elucidate the cellular mechanisms underlying proteotoxicity mediated by aggregation-prone proteins.
- To investigate the role of MOAG-4 and SERF2 in protein aggregation and age-related diseases.
- To identify potential therapeutic targets for reducing age-related protein toxicity.
Main Methods:
- Peptide array screening of human amyloidogenic proteins to identify interaction sites with SERF2.
- Biochemical assays to assess the impact of charge neutralization on SERF2's amyloid-promoting activity.
- Genetic manipulation in Caenorhabditis elegans models to study the in vivo effects of MOAG-4 charge neutralization on protein aggregation and toxicity.
Main Results:
- SERF2 specifically interacts with negatively charged and hydrophobic aromatic amino acid segments in aggregation-prone proteins.
- Eliminating these interaction sites or neutralizing positive charges on SERF2 abolished its amyloid-promoting activity.
- Mutating the MOAG-4 locus to neutralize charge significantly suppressed protein aggregation and toxicity in C. elegans models.
- These findings indicate that charge interactions between cellular modifiers and aggregation-prone proteins drive proteotoxicity.
Conclusions:
- MOAG-4 and SERF2 promote protein aggregation and toxicity through charge-based interactions with aggregation-prone proteins.
- These charge interactions may accelerate amyloid nucleation by altering protein structure and reducing colloidal stability.
- Targeting these charge interactions presents a promising strategy for therapeutic interventions against age-related protein toxicity.
