Mechanisms of self-assembly and fibrillization of the prion-like domains

BioRxiv : the Preprint Server for Biology
Yimei LuJianxing Song

Abstract

The mechanism of the self-assembly and fibrillization of the prion-like domains lies at the heart of their physiology and pathology. Here with the same methods previously established, we aimed to further decipher the mechanism by characterizing two prion-like sequences with the electrostatic properties very different from that of the full-length TDP-43 prion-like domain with a very basic pI value: namely the C-half of the TDP-43 prion-like domain only abundant in Gly, Ser, Asn and Gln with a pI of ~6.3, and the FUS prion-like domain enriched with Gly, Ser, Gln and Tyr with a pI of ~3.5. Interestingly, the C-half with the TDP-43 unique hydrophobic region removed is no longer able to form insoluble aggregates/fibrils but still capable of self-assembling into the reversible hydrogel with cross-β structures, despite being much slower than the full-length. On the other hand, the FUS prion-like domain rapidly self-assembles into the reversible hydrogel with cross-β fibrillar structures in 1 mM phosphate buffer at pH 6.8 but its self-assembly becomes very slow in 50 mM MES buffer at pH 5.5. Our study reveals that despite having completely different electrostatic properties, the full-length and C-half of the TDP-43 prion-like domain, a...Continue Reading

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