Open AccessSequence Determines the Switch in the Fibril Forming Regions in the Low-Complexity FUS Protein and Its Variants
Author(s) -
Abhinaw Kumar,
Debayan Chakraborty,
Mauro L. Mugnai,
John E. Straub,
D. Thirumalai
Publication year - 2021
Publication title -
the journal of physical chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.563
H-Index - 203
ISSN - 1948-7185
DOI - 10.1021/acs.jpclett.1c02310
Subject(s) - fibril , monomer , sequence (biology) , chemistry , core (optical fiber) , crystallography , biophysics , population , protein structure , materials science , biochemistry , polymer , biology , demography , organic chemistry , sociology , composite material
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. Solid-state 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) have 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.