Programming molecular self-assembly of intrinsically disordered proteins containing sequences of low complexity

By Joseph R. Simon, Nick J. Carroll, M. Rubinstein, A. Chilkoti, G. López. 2017

295 citations recorded by the source corpus.

Dynamic protein-rich intracellular structures that contain phase-separated intrinsically disordered proteins (IDPs) composed of sequences of low complexity (SLC) have been shown to serve a variety of important cellular functions, which include signalling, compartmentalization and stabilization. However, our understanding of these structures and our ability to synthesize models of them have been limited. We present design rules for IDPs possessing SLCs that phase separate into diverse assemblies within droplet microenvironments. Using theoretical analyses, we interpret the phase behaviour of archetypal IDP sequences and demonstrate the rational design of a vast library of multicomponent protein-rich structures that ranges from uniform nano-, meso- and microscale puncta (distinct protein droplets) to multilayered orthogonally phase-separated granular structures. The ability to predict and program IDP-rich assemblies in this fashion offers new insights into (1) genetic-to-molecular-to-macroscale relationships that encode hierarchical IDP assemblies, (2) design rules of such assemblies in cell biology and (3) molecular-level engineering of self-assembled recombinant IDP-rich materials.

Subfields: Genetics, Molecular Biology

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Citations in the corpus

Liquid phase condensation in cell physiology and disease (2017, background): “Although the molecular determinants of protein phase immiscibility are still poorly understood, systematic efforts are under way (78).”
A molecular grammar governing the driving forces for phase separation of prion-like RNA binding proteins (2018, unknown): “There are also examples in which self-assembly is mediated by hydrophobicity (Simon et al., 2017), multivalent folded domains connected by flexible linkers (Banani et al.”
Pi-Pi contacts are an overlooked protein feature relevant to phase separation (2018, methodology): “Phase separation critical concentration values for the N-terminus (1-236) of human Ddx4 and three mutants, 9FtoA and 14FtoA, as reported in (14), and RtoK, where all arginine residues have been mutated to lysine, as well as for the C-terminus (445-632) of human FMR1 and one mutant with all arginine ”