title: Fibril elongation mechanisms of HET-s prion-forming domain: topological evidence for growth polarity.
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 nonprion soluble form to the prion fibrillar form is believed to have a functional role, as HET-s in its prion form participates in a recognition process of different fungal strains. On the basis of the knowledge of the high-resolution structure of the prion forming domain HET-s(218-289) 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 β-strands. Then, the re-arrangement in the fibrillar form of all the rest of the molecule takes place. Interestingly, we also predict that one side of the HET-s fibril is more suitable for sustaining 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, as the central loop of the intervening chain plays a crucially different role in favoring or not the attachment of the C-terminus tail to the fibril, depending on the growth side.
authors: Department of Physics, Padua University, CNISM, Padova Unit, Padova I-35131, Italy.
authors: Marco
authors: M
authors: Baiesi
authors: Flavio
authors: F
authors: Seno
authors: Antonio
authors: A
authors: Trovato
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism; D005656:Fungal Proteins / Q000737:chemistry*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D009010:Monte Carlo Method; D048468:Podospora / Q000737:chemistry; D011328:Prions / Q000737:chemistry*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013816:Thermodynamics
chemical_list: D000682:Amyloid; D005656:Fungal Proteins; C083891:HET-S protein, Podospora anserina; D011328:Prions