SERF Protein Is a Direct Modifier of Amyloid Fiber Assembly

SummaryThe inherent cytotoxicity of aberrantly folded protein aggregates contributes substantially to the pathogenesis of amyloid diseases. It was recently shown that a class of evolutionary conserved proteins, called MOAG-4/SERF, profoundly alter amyloid toxicity via an autonomous but yet unexplained mode. We show that the biological function of human SERF1a originates from its atypical ability to specifically distinguish between amyloid and nonamyloid aggregation. This inherently unstructured protein directly affected the aggregation kinetics of a broad range of amyloidogenic proteins in vitro, while being inactive against nonamyloid aggregation. A representative biophysical analysis of the SERF1a:α-synuclein (aSyn) complex revealed that the amyloid-promoting activity resulted from an early and transient interaction, which was sufficient to provoke a massive increase of soluble aSyn amyloid nucleation templates. Therefore, the autonomous amyloid-modifying activity of SERF1a observed in living organisms relies on a direct and dedicated manipulation of the early stages in the amyloid aggregation pathway.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► SERF1a drives the assembly of amyloidogenic proteins ► SERF1a discriminates between amyloid and nonamyloid aggregation ► SERF1a acts through an early interaction with α-synuclein amyloid precursors ► SERF1a catalyzes the formation of transient α-synuclein “on-pathway” aggregates