Abstract
The low complexity (LC) domain of the fused in sarcoma (FUS) RNA binding protein self-associates in a manner causing phase separation from an aqueous environment. Incubation of the FUS LC domain under physiologically normal conditions of salt and pH leads to rapid formation of liquid-like droplets that mature into a gel-like state. Both examples of phase separation have enabled reductionist biochemical assays allowing discovery of an N-terminal region of 56 residues that assembles into a labile, cross-β structure. Here we provide evidence of a non-overlapping, C-terminal region of the FUS LC domain that also forms specific cross-β interactions. We propose that biologic function of the FUS LC domain may operate via the mutually exclusive use of these N- and C-terminal cross-β cores. Neurodegenerative disease-causing mutations in the FUS LC domain are shown to imbalance the two cross-β cores, offering an unanticipated concept of LC domain function and dysfunction.
Significance Statement Single amino acid changes causative of neurologic disease often map to the cross-β forming regions of low complexity (LC) domains. All such mutations studied to date lead to enhanced avidity of cross-β interactions. The LC domain of the fused in sarcoma (FUS) RNA binding protein contains three different regions that are capable of forming labile cross-β interactions. Here we describe the perplexing effect of amyotrophic lateral sclerosis (ALS)-causing mutations localized to the LC domain of FUS to substantially weaken its ability to form one of its three cross-β interactions. An understanding of how these mutations abet uncontrolled polymerization of the FUS LC domain may represent an important clue as to how LC domains achieve their proper biological function.
Competing Interest Statement
The authors have declared no competing interest.
