Several NMR structures have been obtained for the recombinant mammalian prion proteins in solution [11-15], and a solid state structure has also been reported . The structure is dimeric and results from domain swapping between monomeric structures. Each monomer comprises two distinct domains: (i) a C-terminal globular domain encompassing residues 125-228 in human PrP; and (ii) an N-terminal flexible disordered 'tail' (Figure 1) [11-15]. The crystal structure of the globular domain of the sheep prion protein is in very good agreement with the data obtained from NMR studies .
The 3D structures of the C-terminal domain of human (hPrP), murine (mPrP), bovine (bPrP), and Syrian hamster (shPrP) PrP are closely similar to each other, with hPrP(121-230) especially matching bPrP(121-230).
As first reported by Hornshaw et al. [18,19], the prion protein tightly binds copper and this ability is physiologically relevant in affecting the brain copper content . Since then, many reports have delineated that PrP accommodates several binding sites for copper and, incidentally, for other metal ions, such as zinc and manganese. As shown in Chapter 4 of this volume, the basic role in copper ion binding, which is biologically relevant, is played by residues 60-91 made of four octapeptide (OP) repeats (PHGGGWGQ) placed within the N-terminal unstructured domain. Residues 51-59 are homologous (PQGGGTWGQ), but lack the His residue. This region, rich in glycines, is the most conserved sequence among mammalian prion proteins . Other metal binding sites are found in the 90-126 region encompassing a neurotoxic fragment and in the C-terminal region (see Sections 2.5 and 2.6).
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