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Origins of amyloid-?.

ABSTRACT: Amyloid-? plaques are a defining characteristic of Alzheimer Disease. However, Amyloid-? deposition is also found in other forms of dementia and in non-pathological contexts. Amyloid-? deposition is variable among vertebrate species and the evolutionary emergence of the amyloidogenic property is currently unknown. Evolutionary persistence of a pathological peptide sequence may depend on the functions of the precursor gene, conservation or mutation of nucleotides or peptide domains within the precursor gene, or a species-specific physiological environment.In this study, we asked when amyloidogenic Amyloid-? first arose using phylogenetic trees constructed for the Amyloid-? Precursor Protein gene family and by modeling the potential for Amyloid-? aggregation across species in silico. We collected the most comprehensive set of sequences for the Amyloid-? Precursor Protein family using an automated, iterative meta-database search and constructed a highly resolved phylogeny. The analysis revealed that the ancestral gene for invertebrate and vertebrate Amyloid-? Precursor Protein gene families arose around metazoic speciation during the Ediacaran period. Synapomorphic frequencies found domain-specific conservation of sequence. Analyses of aggregation potential showed that potentially amyloidogenic sequences are a ubiquitous feature of vertebrate Amyloid-? Precursor Protein but are also found in echinoderm, nematode, and cephalochordate, and hymenoptera species homologues.The Amyloid-? Precursor Protein gene is ancient and highly conserved. The amyloid forming Amyloid-? domains may have been present in early deuterostomes, but more recent mutations appear to have resulted in potentially unrelated amyloid forming sequences. Our results further highlight that the species-specific physiological environment is as critical to Amyloid-? formation as the peptide sequence.

SUBMITTER: Tharp WG

PROVIDER: S-EPMC3660159 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Origins of amyloid-β.

Tharp William G WG Sarkar Indra Neil IN

BMC genomics 20130430

<h4>Background</h4>Amyloid-β plaques are a defining characteristic of Alzheimer Disease. However, Amyloid-β deposition is also found in other forms of dementia and in non-pathological contexts. Amyloid-β deposition is variable among vertebrate species and the evolutionary emergence of the amyloidogenic property is currently unknown. Evolutionary persistence of a pathological peptide sequence may depend on the functions of the precursor gene, conservation or mutation of nucleotides or peptide dom ...[more]

PMID: 23627794

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Project description: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.

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Origins of amyloid-?.

Publications

Origins of amyloid-β.

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