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Trinucleotide expansions leading to an extended poly-L-alanine segment in the poly (A) binding protein PABPN1 cause fibril formation

¹ Martin-Luther-Universität Halle-Wittenberg, Institut für Biotechnologie and
² Institut für Biochemie, 06120 Halle, Germany
³ Institut für Physikalische Chemie, 06108 Halle, Germany

Reprint requests to: Elisabeth Schwarz, Martin-Luther-Universität Halle-Wittenberg, Institut für Biotechnologie, Kurt-Mothes-Str. 3, 06120 Halle, Germany; e-mail: elisabeth.schwarz{at}biochemtech.uni-halle.de; fax: + 49-345-55-27-013.

The nuclear poly(A) binding protein (PABPN1) stimulates poly(A) polymerase and controls the lengths of poly(A) tails during pre-mRNA processing. The wild-type protein possesses 10 consecutive Ala residues immediately after the start methionine. Trinucleotide expansions in the coding sequence result in an extension of the Ala stretch to maximal 17 Ala residues in total. Individuals carrying the trinucleotide expansions suffer from oculopharyngeal muscular dystrophy (OPMD). Intranuclear inclusions consisting predominantly of PABPN1 have been recognized as a pathological hallmark of the genetic disorder. To elucidate the molecular events that lead to disease, recombinant PABPN1, and N-terminal fragments of the protein with varying poly-L-alanine stretches were analyzed. As the full-length protein displayed a strong tendency to aggregate into amorphous deposits, soluble N-terminal fragments were also studied. Expansion of the poly-L-alanine sequence to the maximal length observed in OPMD patients led to an increase of -helical structure. Upon prolonged incubation the protein was found in fibrils that showed all characteristics of amyloid-like fibers. The lag-phase of fibril formation could be reduced by seeding. Structural analysis of the fibrils indicated antiparallel ß-sheets.

Keywords: Amyloid-like fibrils; seeding; trinucleotide expansions; poly-L-alanine; oculopharyngeal muscular dystrophy

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