Modeling of a periodic instability in paired helical filaments reveals an axial repeat

Ultrastructural studies of paired helical filaments (PHF) have been facilitated by the ability to isolate enriched fractions of detergent-insoluble forms of PHF. These fractions are composed of a relatively homogeneous population of short (usually < 400 nm) highly fragmented PHF. A small proportion of isolated PHF have highly stereotyped angled profiles that represent deformations due to structural instability. These distorted PHF can be characterized quantitatively using a simple numerical procedure that reveals that the axial instabilities occur with predictable regularity over the length of the PHF. Using a structural model of PHF, it is shown that the periodicity of the axial instability can be correlated to an axially repeated subunit of uniform size. The upper limit for the axial extent of the repeated segment was calculated to be 80 nm, similar to the size of a single one-half twist in the PHF ribbon. It is proposed that this segment may represent one type of particle in the hierarchy of structural subunits in the PHF ribbon, or an oligomeric intermediate species in PHF assembly.