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bioRxiv · 10.1101/2021.07.08.451535

Sequence determines the switch in the fibril forming regions in the low complexity FUS protein and its variants

Kumar, A.·Chakraborty, D.·Mugnai, M. L.·Straub, J. E.·Thirumalai, D.
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Abstract

Residues spanning distinct regions of the low-complexity domain of the RNA-binding protein, Fused in Sarcoma (FUS-LC), form fibril structures with different core morphologies. NMR experiments show that the 214 residue FUS-LC forms a fibril with an S-bend (core-1, residues 39-95), while the rest of the protein is disordered. In contrast, the fibrils of the C-terminal variant (FUS-LC-C; residues 111-214) has a U-bend topology (core-2, residues 112-150). Absence of the U-bend in FUS-LC implies that the two fibril cores do not coexist. Computer simulations show that these perplexing findings could be understood in terms of the population of sparsely-populated fibril-like excited states in the monomer. The propensity to form core-1 is higher compared to core-2. We predict that core-2 forms only in truncated variants that do not contain the core-1 sequence. At the monomer level, sequence-dependent enthalpic effects determine the relative stabilities of the core-1 and core-2 topologies. TOC graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=164 SRC="FIGDIR/small/451535v2_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@f81959org.highwire.dtl.DTLVardef@4859f3org.highwire.dtl.DTLVardef@96aecorg.highwire.dtl.DTLVardef@4ab94e_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Kumar, A., Chakraborty, D., Mugnai, M. L., Straub, J. E., Thirumalai, D.. 2021-07-09. Sequence determines the switch in the fibril forming regions in the low complexity FUS protein and its variants. https://doi.org/10.1101/2021.07.08.451535

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