Modeling by assembly and molecular dynamics simulations of the low Cu2+ occupancy form of the mammalian prion protein octarepeat region: gaining insight into Cu2+-mediated beta-cleavage.
The prion protein has garnered considerable interest because of its involvement in prion disease as well as its unresolved cellular function. The octarepeat region in the flexible N-domain is capable of binding copper through multiple coordination modes. Under conditions of low pH and low Cu(2+) concentration, the four octarepeats (ORs) cooperatively coordinate a single copper ion. Based on the average structure of the PHGG and GWGQ portions of a copper-free OR(2) model from molecular dynamics simulations, the starting structures of the OR(4) complex could be constructed by assembling the repeating structure of PHGG and GWGQ fragments. The resulting model contains a preformed site suitable for Cu(2+) coordination. Molecular dynamics simulations of Cu(2+) bound to the assembled OR(4) model (Cu:OR(4)) reveal a close association of specific Trp and Gly residues with the Cu(2+) center. This low Cu(2+)-occupancy form of prion protein is redox-active and can readily initiate cleavage of the OR region, mediated by reactive oxygen species generated by Cu(+). The OR region is known to be required for beta-cleavage, as are the Trp residues within the OR region. The beta-cleaved form of the prion protein accumulates in amyloid fibrils. Hence, the close approach of Trp and Gly residues to the Cu(2+) coordination site in the low Cu(2+)-occupancy form of the OR region may signal an important interaction for the initiation of prion disease.
Pushie
M Jake
MJ
Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada.
Vogel
Hans J
HJ
D000595:Amino Acid Sequence; D000818:Animals; D003300:Copper / Q000737:chemistry / Q000378:metabolism*; D005998:Glycine; D006639:Histidine / Q000737:chemistry; D006801:Humans; D007536:Isomerism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011328:Prions / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D020449:Repetitive Sequences, Amino Acid; D014364:Tryptophan
D011328:Prions; D006639:Histidine; D003300:Copper; D014364:Tryptophan; D005998:Glycine
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