The cellular modifier MOAG‐4/SERF drives amyloid formation through charge complementation

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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.


Funder: Ubbo Emmius fonds

Funder: Boehringer Ingelheim Fonds (BIF); Id:

Funder: Cornelis de Cock

Funder: FP7 People Marie‐Curie Actions (PEOPLE)

Funder: BCN Brain RUG

Funder: KU Leuven, Post‐doctoral Mandate PDM/20/150 and the Industrial Research Fund; Id:

EMBO27, EMBO32, Article, Articles, amyloid, MOAG‐4, protein aggregation, protein quality control, SERF
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The EMBO Journal
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FP7 Ideas European Research Council (FP7 Ideas) (281622)
NWO|Aard‐ en Levenswetenschappen, Nederlandse Organisatie voor Wetenschappelijk Onderzoek (ALW‐NWO) (83609001, 015014005)
Deutsche Forschungsgemeinschaft (DFG) (KI‐1988/5‐1)
European Union's Horizon 2020 Framework Programme ERC Grant agreement (647458)
Flanders Institute for Biotechnology (VIB) (C0401)
the Agency for Innovation by Science and Technology, IWT (60839, 141546)
Fonds Wetenschappelijk Onderzoek (FWO) (AKUL/15/34‐G0H1716N, G0C0320N)
IWT PHD fellowship (141546)
UK Research and Innovation (Future Leaders Fellowship) (MR/S033947/1)
Alzheimer’s Society, UK (511)