Abstract
Insertional mutations leading to expansion of the octarepeat domain of the prion protein (PrP) are directly linked to prion disease. While normal PrP has four PHGGGWGQ octapeptide segments in its flexible N-terminal domain, expanded forms may have up to nine additional octapeptide inserts. The type of prion disease segregates with the degree of expansion. With up to four extra octarepeats, the average onset age is above 60 years, whereas five to nine extra octarepeats results in an average onset age between 30 and 40 years, a difference of almost three decades. In wild-type PrP, the octarepeat domain takes up copper (Cu2+) and is considered essential for in vivo function. Work from our lab demonstrates that the copper coordination mode depends on the precise ratio of Cu2+ to protein. At low Cu2+ levels, coordination involves histidine side chains from adjacent octarepeats, whereas at high levels each repeat takes up a single copper ion through interactions with the histidine side chain and neighboring backbone amides. Here we use both octarepeat constructs and recombinant PrP to examine how copper coordination modes are influenced by octarepeat expansion. We find that there is little change in affinity or coordination mode populations for octarepeat domains with up to seven segments (three inserts). However, domains with eight or nine total repeats (four or five inserts) become energetically arrested in the multi-histidine coordination mode, as dictated by higher copper uptake capacity and also by increased binding affinity. We next pooled all published cases of human prion disease resulting from octarepeat expansion and find remarkable agreement between the sudden length-dependent change in copper coordination and onset age. Together, these findings suggest that either loss of PrP copper-dependent function or loss of copper-mediated protection against PrP polymerization makes a significant contribution to early onset prion disease.
Highlights
Prion diseases are infectious neurodegenerative disorders that arise from accumulation of PrPSc, a misfolded form of the normal cellular prion protein (PrPC) that is found ubiquitously throughout the central nervous system [1,2,3]
We find that elongation beyond a specific threshold, which confers profound early onset disease, gives rise to concomitant changes in copper uptake
We find a remarkable agreement between alteration in copper coordination properties and octarepeat inserts associated with early onset disease
Summary
Prion diseases are infectious neurodegenerative disorders that arise from accumulation of PrPSc (scrapie conformer), a misfolded form of the normal cellular prion protein (PrPC) that is found ubiquitously throughout the central nervous system [1,2,3]. PrPC is a GPI anchored glycoprotein possessing a largely a-helical Cterminal domain and a flexible N-terminal domain (Figure 1). Within the N-terminal domain are four tandem copies of the octapeptide repeat (octarepeat) sequence PHGGGWGQ. 15% of human prion diseases are inherited [4]. The known disease-causing mutations are either point mutations, located primarily in the C-terminal domain, or insertions of one to nine extra octarepeats resulting in expansion of the N-terminal domain [5]. With octarepeat expansion disease, progression is determined by the number of repeat inserts. With one to four extra octarepeats, the average onset age is 64 years, whereas five to nine extra octarepeats results in an average onset age of 38 years, a difference of almost three decades [5]
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