Fibril elongation mechanisms of HET-s prion-forming domain: Topological evidence for growth polarity

TL;DR

This study uses numerical simulations to reveal the topological basis of growth polarity in HET-s prion fibrils, showing a dock and lock elongation mechanism and asymmetric growth propensity.

Contribution

It provides the first detailed topological and thermodynamic analysis explaining the polarity of HET-s fibril growth based on its complex structure.

Findings

Fibril elongation occurs via a dock and lock mechanism.

One side of the fibril is more conducive to growth than the other.

Fibril growth polarity is driven by the topology of the fibrillar structure.

Abstract

The prion-forming C-terminal domain of the fungal prion HET-s forms infectious amyloid fibrils at physiological pH. The conformational switch from the non-prion soluble form to the prion fibrillar form is believed to have a functional role, since HET-s in its prion form participates in a recognition process of different fungal strains. Based on the knowledge of the high-resolution structure of HET-s(218-289) (the prion forming-domain) in its fibrillar form, we here present a numerical simulation of the fibril growth process which emphasizes the role of the topological properties of the fibrillar structure. An accurate thermodynamic analysis of the way an intervening HET-s chain is recruited to the tip of the growing fibril suggests that elongation proceeds through a dock and lock mechanism. First, the chain docks onto the fibril by forming the longest $\beta$-strands. Then, the re-arrangement in the fibrillar form of all the rest of molecule takes place. Interestingly, we predict also that one side of the HET-s fibril is more suitable for substaining its growth with respect to the other. The resulting strong polarity of fibril growth is a consequence of the complex topology of HET-s fibrillar structure, since the central loop of the intervening chain plays a crucially different role in favouring or not the attachment of the C-terminus tail to the fibril, depending on the growth side.