Conformational stability of the RNP domain controls fibril formation of PABPN1.

The disease oculopharyngeal muscular dystrophy is caused by alanine codon trinucleotide expansions in the N-terminal segment of the nuclear poly(A) binding protein PABPN1. As histochemical features of the disease, intranuclear inclusions of PABPN1 have been reported. Whereas the purified N-terminal domain of PABPN1 forms fibrils in an alanine-dependent way, fibril formation of the full-length protein occurs also in the absence of alanines.

The unresolved puzzle why alanine extensions cause disease.

The prospective increase in life expectancy will be accompanied by a rise in the number of elderly people who suffer from ill health caused by old age. Many diseases caused by aging are protein misfolding diseases. The molecular mechanisms underlying these disorders receive constant scientific interest.

Polyalanine-independent conformational conversion of nuclear poly(A)-binding protein 1 (PABPN1).

Oculopharyngeal muscular dystrophy is a late-onset disease caused by an elongation of a natural 10-alanine segment within the N-terminal domain of the nuclear poly(A)-binding protein 1 (PABPN1) to maximally 17 alanines. The disease is characterized by intranuclear deposits consisting primarily of PABPN1. In previous studies, we could show that the N-terminal domain of PABPN1 forms amyloid-like fibrils.

Influence of the stability of a fused protein and its distance to the amyloidogenic segment on fibril formation.

Conversion of native proteins into amyloid fibrils is irreversible and therefore it is difficult to study the interdependence of conformational stability and fibrillation by thermodynamic analyses. Here we approached this problem by fusing amyloidogenic poly-alanine segments derived from the N-terminal domain of the nuclear poly (A) binding protein PABPN1 with a well studied, reversibly unfolding protein, CspB from Bacillus subtilis. Earlier studies had indicated that CspB could maintain its folded structure in fibrils, when it was separated from the amyloidogenic segment by a long linker.