ABSTRACT
The octarepeat (OR) domain of the prion protein (PrP) is deceptively simple in sequence and structure, yet appears to carry out a remarkable copper regulatory role (see reviews in Millhauser 2004, 2007). The domain is composed of a repeating eight-amino acid sequence, with glycine representing 50% of its amino acid content, and is devoid of secondary or tertiary structure in the absence of copper. Despite its lack of fold or sequence complexity, it takes up multiple divalent copper ions (Cu2+) with remarkable selectivity over other metal ions (Whittal et al. 2000), binds with profound negative cooperativity (Walter, Chattopadhyay, and Millhauser 2006), exhibits Cu2+ affinity well matched to micromolar copper levels in extracellular fluids (Kramer et al. 2001), and alters copper’s intrinsic redox properties (Bonomo et al. 2000). Moreover, insert expansions increasing the OR domain length by one to nine repeats, but without alterations of the canonical repeat sequence, are linked to inherited prion disease (Croes et al. 2004; Kong et al. 2004).
