Formation of Intermediate Filaments

Two monomeric subunits interact laterally, or side-by-side, to form a coiled-coil dimer. This dimer can be homodimeric, made of identical monomers, or heterodimeric, made of two different monomer types. The dimer formation is the critical first step in the multistep self-assembly process of intermediate filaments.

A tetramer is the basic structural unit of intermediate filaments, formed when two oppositely oriented polar dimers associate in an antiparallel manner. This nonpolar tetramer is essential for subsequent polymerization steps. Eight tetramers then associate laterally to form larger structural units that continue building the filament.

Protofilaments form when tetramers bind end-to-end in a longitudinal arrangement. Protofibrils then form when multiple protofilaments associate laterally with each other, creating structures two to three nanometers wide. These protofibrils are intermediate building blocks that eventually coil together to form larger filament structures.

A unit-length filament (ULF) forms when four protofibrils coil laterally together. Each ULF is approximately 60 nanometers long and 10 nanometers wide. These unit-length filaments serve as the fundamental repeating units that polymerize further in a head-to-tail arrangement to form complete intermediate filaments.

Intermediate filament formation is multistep self-assembly that does not require enzymatic activity to hydrolyze nucleotides like ATP or GTP. In contrast, microtubule polymerization depends on nucleotide hydrolysis for energy. Additionally, no accessory proteins have been reported in intermediate filament formation, making it a purely self-directed assembly process.

Intermediate filament formation uses lateral association, or side-to-side binding, and longitudinal association, or head-to-tail binding. Lateral association occurs when monomers form dimers and when protofibrils coil together. Longitudinal association occurs when tetramers bind end-to-end and when unit-length filaments polymerize sequentially.

All intermediate filament monomers have a tripartite structure consisting of an α-helical rod domain flanked by two non-α-helical domains. This conserved core structure is similar across different types of intermediate filaments, enabling the consistent multistep assembly process. The structure of intermediate filaments reflects this fundamental monomeric organization.