Copper(II) Ion Binding to Cellular Prion Protein

AbstractRecent computational advancements in the simulation of biochemical processes allow investigating the mechanisms involved in protein regulation with realistic physics-based models, at an atomistic level of resolution. These techniques allowed us to design a drug discovery approach, named Pharmacological Protein Inactivation by Folding Intermediate Targeting (PPI-FIT), based on the rationale of negatively regulating protein levels by targeting folding intermediates. Here, PPI-FIT was tested for the first time on the cellular prion protein (PrP), a cell surface glycoprotein playing a key role in fatal and transmissible neurodegenerative pathologies known as prion diseases. We predicted the all-atom structure of an intermediate appearing along the folding pathway of PrP and identified four different small molecule ligands for this conformer, all capable of selectively lowering the load of the protein by promoting its degradation. Our data support the notion that the level of target proteins could be modulated by acting on their folding pathways, implying a previously unappreciated role for folding intermediates in the biological regulation of protein expression.

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Functions of the cellular prion protein, the end of Moore's law, and Ockham's razor theory

Prion ◽

10.1080/19336896.2015.1126038 ◽

2016 ◽

Vol 10 (1) ◽

pp. 25-40 ◽

Cited By ~ 13

Author(s):

José A. del Río ◽

Rosalina Gavín

Keyword(s):

Prion Protein ◽

Cellular Prion Protein ◽

Moore’S Law ◽

Moore's Law ◽

Ockham’S Razor ◽

Ockham's Razor

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Peptide NMHRYPNQ of the Cellular Prion Protein (PrPC) Inhibits Aggregation and Is a Potential Key for Understanding Prion–Prion Interactions

Journal of Molecular Biology ◽

10.1016/j.jmb.2009.07.014 ◽

2009 ◽

Vol 392 (1) ◽

pp. 198-207 ◽

Cited By ~ 5

Author(s):

Dirk Rehders ◽

Birgit Claasen ◽

Lars Redecke ◽

Alexander Buschke ◽

Caroline Reibe ◽

...

Keyword(s):

Prion Protein ◽

Cellular Prion Protein

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Mouse Brain Synaptosomes Accumulate Copper-67 Efficiently by Two Distinct Processes Independent of Cellular Prion Protein

Journal of Molecular Neuroscience ◽

10.1385/jmn:27:3:347 ◽

2005 ◽

Vol 27 (3) ◽

pp. 347-354 ◽

Cited By ~ 21

Author(s):

Armin Giese ◽

Malte Buchholz ◽

Jochen Herms ◽

Hans A. Kretzschmar

Keyword(s):

Prion Protein ◽

Mouse Brain ◽

Cellular Prion Protein ◽

Brain Synaptosomes

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The Cellular Prion Protein Prevents Copper-Induced Inhibition of P2X4Receptors

International Journal of Alzheimer s Disease ◽

10.4061/2011/706576 ◽

2011 ◽

Vol 2011 ◽

pp. 1-6

Author(s):

Ramón A. Lorca ◽

Lorena Varela-Nallar ◽

Nibaldo C. Inestrosa ◽

J. Pablo Huidobro-Toro

Keyword(s):

Amino Acids ◽

Synaptic Transmission ◽

Prion Protein ◽

Adenosine Triphosphate ◽

Response Curve ◽

Physiological Function ◽

Cellular Prion Protein ◽

Synaptic Activity ◽

Receptor Subtype ◽

Concentration Response Curve

Although the physiological function of the cellular prion protein (PrPC) remains unknown, several evidences support the notion of its role in copper homeostasis. PrPCbinds Cu2+through a domain composed by four to five repeats of eight amino acids. Previously, we have shown that the perfusion of this domain prevents and reverses the inhibition by Cu2+of the adenosine triphosphate (ATP)-evoked currents in the P2X4receptor subtype, highlighting a modulatory role for PrPCin synaptic transmission through regulation of Cu2+levels. Here, we study the effect of full-length PrPCin Cu2+inhibition of P2X4receptor when both are coexpressed. PrPCexpression does not significantly change the ATP concentration-response curve in oocytes expressing P2X4receptors. However, the presence of PrPCreduces the inhibition by Cu2+of the ATP-elicited currents in these oocytes, confirming our previous observations with the Cu2+binding domain. Thus, our observations suggest a role for PrPCin modulating synaptic activity through binding of extracellular Cu2+.

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