PrP overdrive: does inhibition of α-cleavage contribute to PrP(C) toxicity and prion disease?
Knockout of the cellular prion protein (PrP(C)) in mice is tolerated, as is complete elimination of the protein's N-terminal domain. However, deletion of select short segments between the N- and C-terminal domains is lethal. How can one reconcile this apparent paradox? Research over the last few years demonstrates that PrP(C) undergoes α-cleavage in the vicinity of residue 109 (mouse sequence) to release the bioactive N1 and C1 fragments. In biophysical studies, we recently characterized the action of relevant members of the ADAM (A Disintegrin And Metalloproteinase) enzyme family (ADAM8, 10, and 17) and found that they all produce α-cleavage, but at 3 distinct cleavage sites, with proteolytic efficiency modulated by the physiologic metals copper and zinc. Remarkably, the shortest lethal deletion segment in PrP(C) fully encompasses the 3 α-cleavage sites. Analysis of all reported PrP(C) deletion mutants suggests that elimination of α-cleavage, coupled with retention of the protein's N-terminal residues, segments 23-31 and longer, confers the lethal phenotype. Interestingly, these N-terminal residues are implicated in the activation of several membrane proteins, including synaptic glutamate receptors. We propose that α-cleavage is a general mechanism essential for downregulating PrP(C)'s intrinsic activity, and that blockage of proteolysis leads to constitutively active PrP(C) and consequent dyshomeostasis.
Department of Biochemistry; Boston University School of Medicine; Boston, MA USA.
Alex J
AJ
McDonald
Department of Chemistry and Biochemistry; University of California; Santa Cruz, CA USA.
Glenn L
GL
Millhauser
D000818:Animals; D051379:Mice; D018345:Mice, Knockout; D018621:PrPC Proteins / Q000235:genetics / Q000502:physiology* / Q000633:toxicity; D017096:Prion Diseases / Q000378:metabolism*; D059748:Proteolysis; D015032:Zinc / Q000378:metabolism
D018621:PrPC Proteins; D015032:Zinc
ADAM enzyme; AMPA receptor; Alzheimer disease; copper; prion protein; zinc; α-cleavage