**4. Conclusions**

Recent advances in computational biophysics [31,32,52] have led, for the first time, to a description of the conformational ensemble on the full-length N-term MoPrPC, a fully disordered domain of 125 amino acids, with high similarity to the human domain. This has made it possible to probe the impact of disease-related mutations on the structural properties of this flexible region of the protein.

N-term\_HuPrPC binds copper ions in vivo [24]. It yields a diverse range of Cu coordination modes, each with distinct redox properties and binding affinity features. The Cu-binding properties of the N-term region provide HuPrP<sup>C</sup> with the ability to respond to the wide range of Cu concentrations that the protein is exposed to at the synapse, adopting different metal-induced conformations, which in turn may have distinct functional implications. On the other hand, Cu2+-PrPC interactions and their perturbation by disease-related mutations may play a role in protein aggregation and prion disease progression.

While the interplay between metal ion binding and conformational flexibility in the entire N-term remains to be understood, it is well established that copper displays site-specific effects on its folding, either by promoting stabilizing interactions or inducing conversion to beta-sheet folds. Conversely, molecular simulations suggest that some disease-related mutations may affect the local conformation around the Cu anchoring sites, thus affecting the Cu-binding properties of the N-term\_HuPrPC and the stability of the protein.

Combined computational and experimental studies on the structural impact of Cu2+ binding and disease-related mutations at the N-term\_HuPrPC, such as those on copper(II)-alpha-synuclein—an intrinsically disordered protein undergoing fibril formation in Parkinson's disease [118]—could advance dramatically our understanding of the functional role of Cu2+-PrPC interactions in health and disease.

**Author Contributions:** Conceptualization, all the authors; Writing-Review & Editing, all the authors.

**Funding:** This research received no external funding.

**Acknowledgments:** C.S.L. acknowledges SECITI CDMX, Mexico for the postdoctoral fellowship.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


© 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
