Molecular evolution of the mammalian prion protein.
Prion protein (PrP) sequences are until now available for only six of the 18 orders of placental mammals. A broader comparison of mammalian prions might help to understand the enigmatic functional and pathogenic properties of this protein. We therefore determined PrP coding sequences in 26 mammalian species to include all placental orders and major subordinal groups. Glycosylation sites, cysteines forming a disulfide bridge, and a hydrophobic transmembrane region are perfectly conserved. Also, the sequences responsible for secondary structure elements, for N- and C-terminal processing of the precursor protein, and for attachment of the glycosyl-phosphatidylinositol membrane anchor are well conserved. The N-terminal region of PrP generally contains five or six repeats of the sequence P(Q/H)GGG(G/-)WGQ, but alleles with two, four, and seven repeats were observed in some species. This suggests, together with the pattern of amino acid replacements in these repeats, the regular occurrence of repeat expansion and contraction. Histidines implicated in copper ion binding and a proline involved in 4-hydroxylation are lacking in some species, which questions their importance for normal functioning of cellular PrP. The finding in certain species of two or seven repeats, and of amino acid substitutions that have been related to human prion diseases, challenges the relevance of such mutations for prion pathology. The gene tree deduced from the PrP sequences largely agrees with the species tree, indicating that no major deviations occurred in the evolution of the prion gene in different placental lineages. In one species, the anteater, a prion pseudogene was present in addition to the active gene.
van Rheede
Teun
T
Department of Biochemistry, NCMLS, University of Nijmegen, The Netherlands.
Smolenaars
Marcel M W
MM
Madsen
Ole
O
de Jong
Wilfried W
WW
D000595:Amino Acid Sequence; D000682:Amyloid / Q000145:classification / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D019143:Evolution, Molecular; D006801:Humans; D008969:Molecular Sequence Data; D010802:Phylogeny; D000072002:Prion Proteins; D011328:Prions; D011498:Protein Precursors / Q000145:classification / Q000235:genetics*; D016415:Sequence Alignment
D000682:Amyloid; C512656:PRNP protein, human; D000072002:Prion Proteins; D011328:Prions; D011498:Protein Precursors