Title
The cellular modifier MOAG-4/SERF drives amyloid formation through charge complementation
Author
Anita Pras, Bert Houben, Francesco A Aprile, Renee Seinstra, Rodrigo Gallardo, Leen Janssen, Wytse Hogewerf, Christian Gallerein, Matthias De Vleeschouwer, Alejandro Mata-Cabana, Mandy Koopman, Esther Stroo, Mike de Vries, Samantha Louise Edwards, Janine Kristein, Michele Vendruscolo, Salvatore Fabio Faisone, Ellen A A Nollen
Year
2021
Journal
The EMBO Journal
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.
Instrument
FP-6500
Keywords
aggregation, interactions, protein, toxicity