Abstract
Intracellular protein filaments are ubiquitous for cellular functions, but forming bona fide biomimetic intracellular filaments of small molecules in living cells remains elusive. Here, we report the in situ formation of self-limiting intracellular filaments of a small peptide via enzymatic morphological transition of a phosphorylated and trimethylated heterochiral tetrapeptide. Enzymatic dephosphorylation reduces repulsive intermolecular electrostatic interactions and converts the peptidic nanoparticles into filaments, which exhibit distinct types of cross-β structures with either C7 or C2 symmetries, with the hydrophilic C-terminal residues at the periphery of the helix. Macromolecular crowding promotes the peptide filaments to form bundles, which extend from the plasma membrane to nuclear membrane and hardly interact with endogenous components, including cytoskeletons. Stereochemistry and post-translational modification (PTM) of peptides are critical for generating the intracellular bundles. This work may offer a way to gain lost functions or to provide molecular insights for understanding normal and aberrant intracellular filaments.
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Enzymatic morphological transition constructs intracellular peptide filamentsPeptide assemblies form monodispersed filaments in the dynamic cellular environmentCryo-EM construction reveals the distinct types of cross-β structures of filamentsPhosphorylation of peptides controls the intermolecular interactions of filaments
Enzymatic morphological transition leads to the in situ formation of self-limiting intracellular peptide filaments in live cells. Illustrating that enzymatic reaction and post-translational modification (PTM) control the intermolecular interactions of molecular assemblies to generate artificial monodispersed filaments of small molecules in a highly dynamic and crowded intracellular environment, this work by Feng et al. highlights the critical role of multiple PTMs in the peptides and provides molecular insights for understanding normal and aberrant intracellular filaments.