More than 100 genetic mutations causing
X-linked Emery-Dreifuss muscular dystrophy have been identified in the gene encoding the integral inner nuclear membrane
protein emerin. Most mutations are nonsense or frameshift mutations that lead to the absence of
emerin in cells. Only very few cases are due to missense or short in-frame deletions. Molecular mechanisms explaining the corresponding
emerin variants' loss of function are particularly difficult to identify because of the mostly intrinsically disordered state of the
emerin nucleoplasmic region. We now demonstrate that this EmN region can be produced as a disordered monomer, as revealed by nuclear magnetic resonance, but rapidly self-assembles in vitro. Increases in concentration and temperature favor the formation of long curvilinear filaments with diameters of approximately 10 nm, as observed by electron microscopy. Assembly of these filaments can be followed by fluorescence through
Thioflavin-T binding and by Fourier-transform Infrared spectrometry through formation of β-structures. Analysis of the assembly properties of five EmN variants reveals that del95-99 and Q133H impact filament assembly capacities. In cells, these variants are located at the nuclear envelope, but the corresponding quantities of
emerin-
emerin and
emerin-
lamin proximities are decreased compared to wild-type
protein. Furthermore, variant P183H favors EmN aggregation in vitro, and variant P183T provokes
emerin accumulation in cytoplasmic foci in cells. Substitution of residue Pro183 might systematically favor oligomerization, leading to
emerin aggregation and mislocalization in cells. Our results suggest that
emerin self-assembly is necessary for its proper function and that a loss of either the
protein itself or its ability to self-assemble causes
muscular dystrophy.