FEM1C is a component of a cullin-RING E3 ligase complex, where it functions as the substrate receptor in the so-called “Arg/C-degron” pathway. The term “degron” refers to a short, specific sequence within a substrate protein that allows for its recognition and subsequent breakdown by the ubiquitin-proteasome system. In FEM1C’s case, these degrons typically feature an arginine residue at the extreme protein terminus (C-terminus).
Within FEM1C, the Asp126 residue helps form a negatively charged environment essential for binding the arginine in these C-terminal motifs. When Asp126 is replaced by histidine (Asp126His), there is a significant shift in charge properties. Unlike aspartate—which is negatively charged—histidine carries a partial positive charge at physiological pH. This charge swap disrupts the bonding network in the receptor pocket, weakening or preventing interaction with proteins that carry C-terminal arginine motifs. A similar disruption can occur with Asp126Val, where the negatively charged aspartate is replaced by the hydrophobic valine, likewise altering the pocket’s chemistry and compromising substrate recognition.
Loss of proper FEM1C binding in turn impairs the ubiquitination and degradation of certain proteins, likely allowing them to accumulate. This disruption may underlie the neurological manifestations observed in individuals harboring pathogenic FEM1C variants.
FEM1C