Interaction between Prion Protein's Copper-Bound Octarepeat Domain and a Charged C-Terminal Pocket Suggests a Mechanism for N-Terminal Regulation.
Copper plays a critical role in prion protein (PrP) physiology. Cu(2+) binds with high affinity to the PrP N-terminal octarepeat (OR) domain, and intracellular copper promotes PrP expression. The molecular details of copper coordination within the OR are now well characterized. Here we examine how Cu(2+) influences the interaction between the PrP N-terminal domain and the C-terminal globular domain. Using nuclear magnetic resonance and copper-nitroxide pulsed double electron-electron resonance, with molecular dynamics refinement, we localize the position of Cu(2+) in its high-affinity OR-bound state. Our results reveal an interdomain cis interaction that is stabilized by a conserved, negatively charged pocket of the globular domain. Interestingly, this interaction surface overlaps an epitope recognized by the POM1 antibody, the binding of which drives rapid cerebellar degeneration mediated by the PrP N terminus. The resulting structure suggests that the globular domain regulates the N-terminal domain by binding the Cu(2+)-occupied OR within a complementary pocket.
Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
Eric G B
EG
Evans
Department of Geological Sciences, University of Saskatchewan, Saskatoon, SK S7N 5E2, Canada.
M Jake
MJ
Pushie
Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
Kate A
KA
Markham
Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
Hsiau-Wei
HW
Lee
Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA 95064, USA. Electronic address: glennm@ucsc.edu.
Glenn L
GL
Millhauser
D000818:Animals; D001665:Binding Sites; D003300:Copper / Q000378:metabolism*; D051379:Mice; D062105:Molecular Docking Simulation; D000072002:Prion Proteins / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding
D000072002:Prion Proteins; D003300:Copper