SERF Protein Is a Direct Modifier of Amyloid Fiber Assembly
S. Fabio Falsone,
N. Helge Meyer,
Evelyne Schrank,
Gerd Leitinger,
Chi L.L. Pham,
Michelle T. Fodero-Tavoletti,
Mats Holmberg,
Martin Dulle,
Benjamin Scicluna,
Bernd Gesslbauer,
Hanna-Marie Rückert,
Gabriel E. Wagner,
David A. Merle,
Ellen A. Nollen,
Andreas J. Kungl,
Andrew F. Hill,
Roberto Cappai,
Klaus Zangger
Affiliations
S. Fabio Falsone
Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, 8010 Graz, Austria
N. Helge Meyer
Institute of Chemistry, University of Graz, 8010 Graz, Austria
Evelyne Schrank
Institute of Chemistry, University of Graz, 8010 Graz, Austria
Gerd Leitinger
Institute of Cell Biology, Histology and Embryology, Center of Molecular Medicine, Medical University of Graz, 8010 Graz, Austria
Chi L.L. Pham
Department of Pathology, Bio21 Molecular Science & Biotechnology Institute, The University of Melbourne, Victoria 3010 Australia
Michelle T. Fodero-Tavoletti
Department of Pathology, Bio21 Molecular Science & Biotechnology Institute, The University of Melbourne, Victoria 3010 Australia
Mats Holmberg
Department of Genetics, University Medical Centre Groningen, University of Groningen, 9700 RB Groningen, The Netherlands
Martin Dulle
Institute of Chemistry, University of Graz, 8010 Graz, Austria
Benjamin Scicluna
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science & Biotechnology Institute, The University of Melbourne, Victoria 3010 Australia
Bernd Gesslbauer
Institute of Pharmaceutical Sciences, University of Graz, 8010 Graz, Austria
Hanna-Marie Rückert
Institute of Chemistry, University of Graz, 8010 Graz, Austria
Gabriel E. Wagner
Institute of Chemistry, University of Graz, 8010 Graz, Austria
David A. Merle
Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, 8010 Graz, Austria
Ellen A. Nollen
Department of Genetics, University Medical Centre Groningen, University of Groningen, 9700 RB Groningen, The Netherlands
Andreas J. Kungl
Institute of Pharmaceutical Sciences, University of Graz, 8010 Graz, Austria
Andrew F. Hill
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science & Biotechnology Institute, The University of Melbourne, Victoria 3010 Australia
Roberto Cappai
Department of Pathology, Bio21 Molecular Science & Biotechnology Institute, The University of Melbourne, Victoria 3010 Australia
Klaus Zangger
Institute of Chemistry, University of Graz, 8010 Graz, Austria
The 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.
