Organizing biochemistry in space and time using prion-like self-assembly

Abstract

Prion-like proteins have the capacity to adopt multiple stable conformations, at least one of which can recruit proteins from the native conformation into the alternative fold. Although classically associated with disease, prion-like assembly has recently been proposed to organize a range of normal biochemical processes in space and time. Organisms from bacteria to mammals use prion-like mechanisms to (re)organize their proteome in response to intracellular and extracellular stimuli. Prion-like behavior is an economical means to control biochemistry and gene regulation at the systems level, and prions can act as protein-based genes to facilitate quasi-Lamarckian inheritance of induced traits. These mechanisms allow individual cells to express distinct heritable traits using the same complement of polypeptides. Understanding and controlling prion-like behavior is therefore a promising strategy to combat diverse pathologies and organize engineered biological systems.

Figure 1

(A) Classical amyloid prion formation by nucleation of a prion-like seed followed by recruitment of monomers to the prion-like conformation to generate a cross-beta sheet amyloid oligomer [12]. The amyloid oligomer could be non-functional (top), as in the [PSI⁺] prion, or gain an emergent structural property (bottom), as in the HET-s prion [13] (B) Hypothetical mechanism of prion-like oligomerization leading to two distinct prion-like oligomers that maintain their molecular activity and are not amyloid in nature.

Figure 2

The [PRION⁺] state is a node that integrates diverse cell-intrinsic inputs (on short and long time scales) and cell-extrinsic stimuli, and actuates diverse phenotypic outputs. The naïve state is shown as a blue gene product; the prion-like [PRION⁺] state is shown as an orange gene product. Shown are selected examples of inputs and outputs of the [PRION⁺] state; this diagram is not exhaustive.