title: Origins and evolution of the HET-s prion-forming protein: searching for other amyloid-forming solenoids.
abstract: The HET-s prion-forming domain from the filamentous fungus Podospora anserina is gaining considerable interest since it yielded the first well-defined atomic structure of a functional amyloid fibril. This structure has been identified as a left-handed beta solenoid with a triangular hydrophobic core. To delineate the origins of the HET-s prion-forming protein and to discover other amyloid-forming proteins, we searched for all homologs of the HET-s protein in a database of protein domains and fungal genomes, using a combined application of HMM, psi-blast and pGenThreader techniques, and performed a comparative evolutionary analysis of the N-terminal alpha-helical domain and the C-terminal prion-forming domain of HET-s. By assessing the tandem evolution of both domains, we observed that the prion-forming domain is restricted to Sordariomycetes, with a marginal additional sequence homolog in Arthroderma otae as a likely case of horizontal transfer. This suggests innovation and rapid evolution of the solenoid fold in the Sordariomycetes clade. In contrast, the N-terminal domain evolves at a slower rate (in Sordariomycetes) and spans many diverse clades of fungi. We performed a full three-dimensional protein threading analysis on all identified HET-s homologs against the HET-s solenoid fold, and present detailed structural annotations for identified structural homologs to the prion-forming domain. An analysis of the physicochemical characteristics in our set of structural models indicates that the HET-s solenoid shape can be readily adopted in these homologs, but that they are all less optimized for fibril formation than the P. anserina HET-s sequence itself, due chiefly to the presence of fewer asparagine ladders and salt bridges. Our combined structural and evolutionary analysis suggests that the HET-s shape has "limited scope" for amyloidosis across the wider protein universe, compared to the 'generic' left-handed beta helix. We discuss the implications of our findings on future identification of amyloid-forming proteins sharing the solenoid fold.
authors.affiliation: Department of Biology, McGill University, Montreal, Quebec, Canada.
authors.forename: Deena M A
authors.initials: DM
authors.lastname: Gendoo
authors.forename: Paul M
authors.initials: PM
authors.lastname: Harrison
mesh_terms: D000682:Amyloid; D019143:Evolution, Molecular; D005656:Fungal Proteins / Q000145:classification / Q000235:genetics*; D022761:Gene Transfer, Horizontal; D010802:Phylogeny; D048468:Podospora / Q000235:genetics / Q000378:metabolism*; D011328:Prions; D017434:Protein Structure, Tertiary
chemical_list: D000682:Amyloid; D005656:Fungal Proteins; C083891:HET-S protein, Podospora anserina; D011328:Prions
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