Disparate evolution of prion protein domains and the distinct origin of Doppel- and prion-related loci revealed by fish-to-mammal comparisons.
Prions result from the misfolding and selective accumulation of the host-encoded prion protein (PrP) in the brain. Despite intensive research on mammalian models, basic questions about the biological role of PrP and the evolutionary origin of prion disease remain unanswered. Following our previous identification of novel fish PrP homologues, here we generated new fish PrP sequences and performed genomic analysis to demonstrate the existence of two homologous PrP loci in bony fish, which display extensive molecular variation and are highly expressed in adult and developing fish brains. The fish PrP genomic regions contain PrP-related loci directly downstream of each PrP locus, suggesting an independent origin of prion-related proteins in fish and mammals. Our structural prediction analysis uncovers a conserved molecular "bauplan" for all vertebrate PrPs. The C- and N-terminal protein domains have evolved independently from one another, the former having retained its basic globular structure despite high sequence divergence and the latter having undergone differential expansion-degeneration cycles in its repetitive domains. Our evolutionary analysis redefines fundamental concepts on the functional significance of PrP domains and opens up new possibilities for the experimental analysis of prion misfolding and neurodegeneration in a non-mammalian model like the zebrafish.
Rivera-Milla
Eric
E
Department of Biology, University of Konstanz, Konstanz, Germany.
Oidtmann
Birgit
B
Panagiotidis
Cynthia H
CH
Baier
Michael
M
Sklaviadis
Theodoros
T
Hoffmann
Rudolf
R
Zhou
Yi
Y
Solis
Gonzalo P
GP
Stuermer
Claudia A O
CA
Málaga-Trillo
Edward
E
D000595:Amino Acid Sequence; D000818:Animals; D001001:Anura; D001717:Birds; D003001:Cloning, Molecular; D019143:Evolution, Molecular; D005399:Fishes / Q000196:embryology; D008322:Mammals; D008969:Molecular Sequence Data; D011328:Prions / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D012104:Reptiles; D017386:Sequence Homology, Amino Acid
D011328:Prions