Assembly of NFL and desmin intermediate filaments: Headed in the right direction

Abstract

Intermediate filaments (IFs), together with actin filaments and microtubules, form the cytoskeleton—a critical structural component of all cells. Humans express 73 unique IF proteins that associate as obligate homo- or heterodimers. IF dimers assemble into tetramers, which are the building blocks of the higher-order cytoskeletal and nucleoskeletal structures visualized in vitro and in cells (1). Cytoplasmic IFs are functionally suited to the needs of each cell and tissue type. For example, keratins provide mechanical resilience to the epidermis (2), whereas the light, medium, and heavy neurofilament proteins (NFL, NFM, and NFH) simultaneously provide axons with the stability and flexibility needed for proper neuronal function (3). In the past several decades, significant advancements have been made in the basic biology and disease involvement of IFs, but insights into the molecular structures are lacking for most IF proteins (4). In PNAS, Zhou et al. (5) address the hypothesis that interactions between N-terminal low complexity domains (LCDs) on IF proteins, shown previously to undergo phase separation (6), could provide structural insights into how mature filaments are formed. All IF proteins have three domains: N-terminal “head,” C-terminal “tail,” and central coiled-coil “rod” (Fig. 1) (1). The rod domains, which are highly conserved, form the dimer interface, while the head and tail are variable regions composed of few overrepresented amino acids (i.e., of low complexity) (5, 6). The present work builds upon previous observations that the aliphatic alcohol 1,6-hexanediol, which disrupts nonmembrane-bound structures and phase-separated liquid-like droplets, is able to rapidly disassemble vimentin and keratin IFs without affecting the organization of actin or microtubules in cells (6). This ultimately helped reveal that the head (but not the tail) domains of several human IFs, including vimentin, peripherin, α-internexin, and neurofilaments, form gel-like condensates composed of uniform polymers that are … [↵][1]1To whom correspondence may be addressed. Email: natasha_snider{at}med.unc.edu. [1]: #xref-corresp-1-1