Conformational stability of the RNP domain controls fibril formation of PABPN1 |
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| Authors: | Jens Liebold Reno Winter Ralph Golbik Gerd Hause Christoph Parthier Elisabeth Schwarz |
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| Institution: | 1. Department of Protein Biochemistry, Institute of Biochemistry and Biotechnology, Martin Luther University, Halle Wittenberg, Halle, Germany;2. Department of Virology, Institute of Biochemistry and Biotechnology, Martin Luther University, Halle Wittenberg, Halle, Germany;3. Biocenter, Martin Luther University, Halle Wittenberg, Halle, Germany;4. Department of Physical Biotechnology, Institute of Biochemistry and Biotechnology, Martin Luther University, Halle Wittenberg, Halle, Germany |
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| Abstract: | 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. Here, we addressed the question whether the stability of the RNP domain or domain swapping within the RNP domain may add to fibril formation. A variant of full‐length PABPN1 with a stabilizing disulfide bond at position 185/201 in the RNP domain fibrillized in a redox‐sensitive manner suggesting that the integrity of the RNP domain may contribute to fibril formation. Thermodynamic analysis of the isolated wild‐type and the disulfide‐linked RNP domain showed two state unfolding/refolding characteristics without detectable intermediates. Quantification of the thermodynamic stability of the mutant RNP domain pointed to an inverse correlation between fibril formation of full‐length PABPN1 and the stability of the RNP domain. |
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| Keywords: | protein misfolding conformational stability domain swapping fibril formation thermodynamics PABPN1 |
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