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

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

2012-03-19

arxiv.org/abs/1203.4082v1

Proteins 79, 3067-3081 (2011)

Physics

Condensed Matter

Soft Condensed Matter

16 pages, 10 figures

Scientific paper

10.1002/prot.23133

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.

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