Structural Determinants of the Prion Protein N-Terminus and Its Adducts with Copper Ions

Carolina Sánchez-López; Giulia Rossetti; Liliana Quintanar; Paolo Carloni

doi:10.3390/ijms20010018

Structural Determinants of the Prion Protein N-Terminus and Its Adducts with Copper Ions

International Journal of Molecular Sciences ◽

10.3390/ijms20010018 ◽

2018 ◽

Vol 20 (1) ◽

pp. 18 ◽

Cited By ~ 5

Author(s):

Carolina Sánchez-López ◽

Giulia Rossetti ◽

Liliana Quintanar ◽

Paolo Carloni

Keyword(s):

Prion Protein ◽

Copper Ions ◽

Proteolytic Processing ◽

Copper Binding ◽

Structural Determinants ◽

Intrinsically Disordered ◽

Structural And Functional Properties ◽

N Terminus ◽

Functional Implications ◽

Health And Disease

The N-terminus of the prion protein is a large intrinsically disordered region encompassing approximately 125 amino acids. In this paper, we review its structural and functional properties, with a particular emphasis on its binding to copper ions. The latter is exploited by the region’s conformational flexibility to yield a variety of biological functions. Disease-linked mutations and proteolytic processing of the protein can impact its copper-binding properties, with important structural and functional implications, both in health and disease progression.

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Trace elements and prion diseases: a review of the interactions of copper, manganese and zinc with the prion protein

Animal Health Research Reviews ◽

10.1017/s1466252307001181 ◽

2006 ◽

Vol 7 (1-2) ◽

pp. 97-105 ◽

Cited By ~ 42

Author(s):

Scott P. Leach ◽

M. D. Salman ◽

Dwayne Hamar

Keyword(s):

Trace Elements ◽

Prion Protein ◽

Copper Ions ◽

Prion Diseases ◽

Normal Function ◽

Transmissible Spongiform Encephalopathies ◽

Copper Binding ◽

Spongiform Encephalopathies ◽

Copper Manganese ◽

The Brain

Transmissible spongiform encephalopathies (TSEs) are a family of neurodegenerative diseases characterized by their long incubation periods, progressive neurological changes, and spongiform appearance in the brain. There is much evidence to show that TSEs are caused by an isoform of the normal cellular surface prion protein PrPC. The normal function of PrPC is still unknown, but it exhibits properties of a cupro-protein, capable of binding up to six copper ions. There are two differing views on copper's role in prion diseases. While one view looks at the PrPC copper-binding as the trigger for conversion to PrPSc, the opposing viewpoint sees a lack of PrPC copper-binding resulting in the conformational change into the disease causing isoform. Manganese and zinc have been shown to interact with PrPC as well and have been found in abnormal levels in prion diseases. This review addresses the interaction between select trace elements and the PrPC.

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Clustering of human prion protein and α-synuclein oligomers requires the prion protein N-terminus

Communications Biology ◽

10.1038/s42003-020-1085-z ◽

2020 ◽

Vol 3 (1) ◽

Cited By ~ 1

Author(s):

Nadine S. Rösener ◽

Lothar Gremer ◽

Michael M. Wördehoff ◽

Tatsiana Kupreichyk ◽

Manuel Etzkorn ◽

...

Keyword(s):

Prion Protein ◽

Amyloid Β ◽

Intrinsically Disordered Protein ◽

Molar Ratio ◽

Intrinsically Disordered ◽

Disordered Protein ◽

N Terminus ◽

Human Prion Protein ◽

Intrinsically Disordered Protein Region ◽

Slow Dissociation

AbstractThe interaction of prion protein (PrP) and α-synuclein (αSyn) oligomers causes synaptic impairment that might trigger Parkinson’s disease and other synucleinopathies. Here, we report that αSyn oligomers (αSynO) cluster with human PrP (huPrP) into micron-sized condensates. Multivalency of αSyn within oligomers is required for condensation, since clustering with huPrP is not observed for monomeric αSyn. The stoichiometry of the heteroassemblies is well defined with an αSyn:huPrP molar ratio of about 1:1. The αSynO−huPrP interaction is of high affinity, signified by slow dissociation. The huPrP region responsible for condensation of αSynO, residues 95−111 in the intrinsically disordered N-terminus, corresponds to the region required for αSynO-mediated cognitive impairment. HuPrP, moreover, achieves co-clustering of αSynO and Alzheimer’s disease-associated amyloid-β oligomers, providing a case of a cross-interaction of two amyloidogenic proteins through an interlinking intrinsically disordered protein region. The results suggest that αSynO-mediated condensation of huPrP is involved in the pathogenesis of synucleinopathies.

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Structural Consequences of Copper Binding to the Prion Protein

Cells ◽

10.3390/cells8080770 ◽

2019 ◽

Vol 8 (8) ◽

pp. 770 ◽

Cited By ~ 4

Author(s):

Giulia Salzano ◽

Gabriele Giachin ◽

Giuseppe Legname

Keyword(s):

Prion Protein ◽

Animal Species ◽

State Of The Art ◽

Copper Ions ◽

Cellular Prion Protein ◽

Transmissible Spongiform Encephalopathies ◽

Copper Binding ◽

Spongiform Encephalopathies ◽

And Function

Prion, or PrPSc, is the pathological isoform of the cellular prion protein (PrPC) and it is the etiological agent of transmissible spongiform encephalopathies (TSE) affecting humans and animal species. The most relevant function of PrPC is its ability to bind copper ions through its flexible N-terminal moiety. This review includes an overview of the structure and function of PrPC with a focus on its ability to bind copper ions. The state-of-the-art of the role of copper in both PrPC physiology and in prion pathogenesis is also discussed. Finally, we describe the structural consequences of copper binding to the PrPC structure.

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Abnormal Proteolytic Processing of von Willebrand Factor Arg611 Cys and Arg 611 His

Thrombosis and Haemostasis ◽

10.1055/s-0038-1655927 ◽

1997 ◽

Vol 77 (01) ◽

pp. 174-182 ◽

Cited By ~ 3

Author(s):

Toshiya Nishikubo ◽

Olivier Christophe ◽

Jean-Maurice Lavergne ◽

Bernadette Obert ◽

Kyoko Nonami ◽

...

Keyword(s):

Functional Analysis ◽

Platelet Count ◽

Proteolytic Processing ◽

Terminal Part ◽

Structural And Functional Properties ◽

N Terminus ◽

Abnormal Pattern ◽

Von Willebrand ◽

Willebrand Factor ◽

Count Change

SummaryThe structural and functional properties of plasma and platelet vWF were studied in 8 patients (5 unrelated families) with vWD demonstrating a mutation at position 611 (R611C or R611H). Following reduction, electrophoresis and immunoblotting with a polyclonal anti-reduced vWF antibody, abnormal proteolysis of vWF was demonstrated in plasma and to a lesser extent in platelets from all patients, leading to the formation of a unique 209 kDa fragment undetectable in control as well as in type 2A, 2B or 2N vWF. Immunoblotting with MoAbs to reduced vWF showed that the C-terminal end of the 209 kDa fragment was located beyond residue 1744 of the subunit and that its N-terminus was between residues 523 and 1114. Multimeric analysis of patients vWF showed an abnormal pattern in both plasma and platelets, with a moderate decrease of the HMW multimers together with a significant increase of the lowest MW forms. The specific sensitivity of vWF R611C and vWF R611H to proteolysis was further evidenced using V-8 protease. In all patient’s samples the enzyme produced a unique monomeric 80 kDa fragment, absent in V-8 digested normal vWF, which overlapped the N-terminal part of the subunit. The functional analysis of vWF showed a markedly decreased affinity of mutated plasma vWF for platelet GPIb in the presence of ristocetin. Infusion of DDAVP in two of these patients did not lead to significant platelet count change. It induced a limited increase of the HMW multimers in plasma together with a poor correction of the vWF binding to platelet GPIb. In conclusion, our data demonstrate that in addition to a normal proteolysis, vWF mutated at position 611 undergoes a specific cleavage in plasma and platelets. In contrast to the increased proteolysis observed in type 2A and 2B patients’ plasma, this additional cleavage produced a unique 209 kDa species but maintained a HMW multimer-like structure of vWF R611C and R611H.

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Functional implications of multistage copper binding to the prion protein

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0903807106 ◽

2009 ◽

Vol 106 (28) ◽

pp. 11576-11581 ◽

Cited By ~ 26

Author(s):

Miroslav Hodak ◽

Robin Chisnell ◽

Wenchang Lu ◽

J. Bernholc

Keyword(s):

Prion Protein ◽

Copper Binding ◽

Functional Implications

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Multiple forms of copper (II) co-ordination occur throughout the disordered N-terminal region of the prion protein at pH 7.4

Biochemical Journal ◽

10.1042/bj20060721 ◽

2006 ◽

Vol 400 (3) ◽

pp. 501-510 ◽

Cited By ~ 59

Author(s):

Mark A. Wells ◽

Clare Jelinska ◽

Laszlo L. P. Hosszu ◽

C. Jeremy Craven ◽

Anthony R. Clarke ◽

...

Keyword(s):

Prion Protein ◽

Tandem Repeats ◽

Copper Ions ◽

Equilibrium Dialysis ◽

Terminal Region ◽

Copper Binding ◽

Binding Modes ◽

Self Association

Although the physiological function of the prion protein remains unknown, in vitro experiments suggest that the protein may bind copper (II) ions and play a role in copper transport or homoeostasis in vivo. The unstructured N-terminal region of the prion protein has been shown to bind up to six copper (II) ions, with each of these ions co-ordinated by a single histidine imidazole and nearby backbone amide nitrogen atoms. Individually, these sites have micromolar affinities, which is weaker than would be expected of a true cuproprotein. In the present study, we show that with subsaturating levels of copper, different forms of co-ordination will occur, which have higher affinity. We have investigated the copper-binding properties of two peptides representing the known copper-binding regions of the prion protein: residues 57–91, which contains four tandem repeats of the octapeptide GGGWGQPH, and residues 91–115. Using equilibrium dialysis and spectroscopic methods, we unambiguously demonstrate that the mode of copper co-ordination in both of these peptides depends on the number of copper ions bound and that, at low copper occupancy, copper ions are co-ordinated with sub-micromolar affinity by multiple histidine imidazole groups. At pH 7.4, three different modes of copper co-ordination are accessible within the octapeptide repeats and two within the peptide comprising residues 91–115. The highest affinity copper (II)-binding modes cause self-association of both peptides, suggesting a role for copper (II) in controlling prion protein self-association in vivo.

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Metallic prions

Biochemical Society Symposium ◽

10.1042/bss0710193 ◽

2004 ◽

Vol 71 ◽

pp. 193-202 ◽

Cited By ~ 9

Author(s):

David R Brown

Keyword(s):

Prion Protein ◽

Binding Capacity ◽

Normal Function ◽

Transmissible Spongiform Encephalopathies ◽

Published Data ◽

Normal Brain ◽

Copper Binding ◽

Loss Of Function ◽

Spongiform Encephalopathies ◽

The Brain

Prion diseases, also referred to as transmissible spongiform encephalopathies, are characterized by the deposition of an abnormal isoform of the prion protein in the brain. However, this aggregated, fibrillar, amyloid protein, termed PrPSc, is an altered conformer of a normal brain glycoprotein, PrPc. Understanding the nature of the normal cellular isoform of the prion protein is considered essential to understanding the conversion process that generates PrPSc. To this end much work has focused on elucidation of the normal function and activity of PrPc. Substantial evidence supports the notion that PrPc is a copper-binding protein. In conversion to the abnormal isoform, this Cu-binding activity is lost. Instead, there are some suggestions that the protein might bind other metals such as Mn or Zn. PrPc functions currently under investigation include the possibility that the protein is involved in signal transduction, cell adhesion, Cu transport and resistance to oxidative stress. Of these possibilities, only a role in Cu transport and its action as an antioxidant take into consideration PrPc's Cu-binding capacity. There are also more published data supporting these two functions. There is strong evidence that during the course of prion disease, there is a loss of function of the prion protein. This manifests as a change in metal balance in the brain and other organs and substantial oxidative damage throughout the brain. Thus prions and metals have become tightly linked in the quest to understand the nature of transmissible spongiform encephalopathies.

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SUMO's Intrinsically Disordered N-Terminus is an Intramolecular Inhibitor of SUMO - SIM Interactions

SSRN Electronic Journal ◽

10.2139/ssrn.3554087 ◽

2020 ◽

Author(s):

Sebastian M. Richter ◽

Fan Jin ◽

Eric Maurer ◽

Annette Flotho ◽

Frauke Gräter ◽

...

Keyword(s):

Intrinsically Disordered ◽

N Terminus

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Hyaluronate/black phosphorus complexes as a copper chelating agent for Wilson disease treatment

Biomaterials Research ◽

10.1186/s40824-021-00221-x ◽

2021 ◽

Vol 25 (1) ◽

Author(s):

Seong-Jong Kim ◽

Hye Hyeon Han ◽

Sei Kwang Hahn

Keyword(s):

Targeted Delivery ◽

Wilson Disease ◽

Copper Ions ◽

Binding Capacity ◽

Genetic Disorder ◽

Chelating Agent ◽

Black Phosphorus ◽

The Body ◽

Copper Binding

Abstract Background Wilson disease (WD) is a genetic disorder of copper storage, resulting in pathological accumulation of copper in the body. Because symptoms are generally related to the liver, chelating agents capable of capturing excess copper ions after targeted delivery to the liver are highly required for the treatment of WD. Methods We developed hyaluronate-diaminohexane/black phosphorus (HA-DAH/BP) complexes for capturing copper ions accumulated in the liver for the treatment of WD. Results HA-DAH/BP complexes showed high hepatocyte-specific targeting efficiency, selective copper capturing capacity, excellent biocompatibility, and biodegradability. HA enhanced the stability of BP nanosheets and increased copper binding capacity. In vitro cellular uptake and competitive binding tests verified targeted delivery of HA-DAH/BP complexes to liver cells via HA receptor mediated endocytosis. The cell viability test confirmed the high biocompatibility of HA-DAH/BP complexes. Conclusion HA-DAH/BP complexes would be an efficient copper chelating agent to remove accumulated copper in the liver for the WD treatment.

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