Transiently Structured Head Domains Control Intermediate Filament Assembly
38 Pages Posted: 10 Apr 2020 Sneak Peek Status: Under ReviewMore...
Low complexity (LC) head domains 92 and 108 residues in length are, respectfully, required for assembly of neurofilament light (NFL) and desmin intermediate filaments (IFs). As studied in isolation, these IF head domains interconvert between states of conformational disorder and labile, β-strand-enriched polymers. Solid state nuclear magnetic resonance (ss-NMR) spectroscopic studies of NFL and desmin head domain polymers reveal spectral patterns consistent with structural order. A combination of intein chemistry and segmental isotope labeling allowed preparation of fully assembled NFL and desmin IFs that could also be studied by ss-NMR. Assembled IFs revealed spectra overlapping with those observed for β-strand-enriched polymers formed from the isolated NFL and desmin head domains. Phosphorylation and disease causing mutations reciprocally alter NFL and desmin head domain self-association, yet commonly impede IF assembly. These observations show how facultative structural assembly of LC domains via labile, β-strand-enriched self-interactions may broadly influence cell morphology.
Keywords: low complexity domains, intermediate filaments, intrinsically disordered proteins, phase separation, human genetic mutations, labile cross-β structures, dynamic cellular assemblies, solid state NMR, segmental isotope labeling, in situ structural analysis.
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