4 research outputs found
Fibril elongation mechanisms of HET-s prion-forming domain: Topological evidence for growth polarity
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 -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.Comment: 16 pages, 10 figure
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