RRC ID 76035
Author Pras A, Houben B, Aprile FA, Seinstra R, Gallardo R, Janssen L, Hogewerf W, Gallrein C, De Vleeschouwer M, Mata-Cabana A, Koopman M, Stroo E, de Vries M, Louise Edwards S, Kirstein J, Vendruscolo M, Falsone SF, Rousseau F, Schymkowitz J, Nollen EAA.
Title The cellular modifier MOAG-4/SERF drives amyloid formation through charge complementation.
Journal EMBO J
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.
Volume 40(21)
Pages e107568
Published 2021-11-2
DOI 10.15252/embj.2020107568
PMID 34617299
PMC PMC8561633
MeSH Amino Acid Sequence Amyloid / chemistry* Amyloid / genetics Amyloid / metabolism Amyloidogenic Proteins / chemistry* Amyloidogenic Proteins / genetics Amyloidogenic Proteins / metabolism Animals Binding Sites Caenorhabditis elegans / genetics* Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins / chemistry* Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism Gene Expression Regulation HEK293 Cells Humans Hydrophobic and Hydrophilic Interactions Intracellular Signaling Peptides and Proteins / chemistry* Intracellular Signaling Peptides and Proteins / genetics Intracellular Signaling Peptides and Proteins / metabolism Nerve Tissue Proteins / chemistry* Nerve Tissue Proteins / genetics Nerve Tissue Proteins / metabolism Peptides / genetics Peptides / metabolism Protein Aggregates Protein Array Analysis Protein Binding Signal Transduction Static Electricity alpha-Synuclein / chemistry* alpha-Synuclein / genetics alpha-Synuclein / metabolism
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C.elegans tm4909