Structural Consequences of Copper Binding to the Prion Protein

Salzano, Giulia; Giachin, Gabriele; Legname, Giuseppe

doi:10.3390/cells8080770

Cited by 49 publications

(49 citation statements)

References 157 publications

(207 reference statements)

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“…Indeed, from numerous metal ions tested (including Cu 2+ ), Zn 2+ alone could induce Tau protein condensates, another prime causative agent of neurodegenerative disease deposits [ 14 ]. The cellular prion protein also binds to both Zn 2+ and Cu 2+ , with both metals inducing structural changes and decreased solubility [ 140 ] and differentially affecting its fold variants [ 141 , 142 ], where Cu 2+ -binding induces protease resistant variants [ 143 , 144 ]. Relevant to viruses existing in cells and tissues, in plasma and in external environments, studies comparing competitive binding of Cu ions to peptides containing both cysteines (e.g., ZnFs) and arginines (e.g., RRMs), Cu ions were found to preferentially bind to arginine, lysine, and histidine in the gas phase [ 145 ].…”

Section: Resultsmentioning

confidence: 99%

Zinc and Copper Ions Differentially Regulate Prion-Like Phase Separation Dynamics of Pan-Virus Nucleocapsid Biomolecular Condensates

Monette

Mouland

2020

Viruses

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Liquid-liquid phase separation (LLPS) is a rapidly growing research focus due to numerous demonstrations that many cellular proteins phase-separate to form biomolecular condensates (BMCs) that nucleate membraneless organelles (MLOs). A growing repertoire of mechanisms supporting BMC formation, composition, dynamics, and functions are becoming elucidated. BMCs are now appreciated as required for several steps of gene regulation, while their deregulation promotes pathological aggregates, such as stress granules (SGs) and insoluble irreversible plaques that are hallmarks of neurodegenerative diseases. Treatment of BMC-related diseases will greatly benefit from identification of therapeutics preventing pathological aggregates while sparing BMCs required for cellular functions. Numerous viruses that block SG assembly also utilize or engineer BMCs for their replication. While BMC formation first depends on prion-like disordered protein domains (PrLDs), metal ion-controlled RNA-binding domains (RBDs) also orchestrate their formation. Virus replication and viral genomic RNA (vRNA) packaging dynamics involving nucleocapsid (NC) proteins and their orthologs rely on Zinc (Zn) availability, while virus morphology and infectivity are negatively influenced by excess Copper (Cu). While virus infections modify physiological metal homeostasis towards an increased copper to zinc ratio (Cu/Zn), how and why they do this remains elusive. Following our recent finding that pan-retroviruses employ Zn for NC-mediated LLPS for virus assembly, we present a pan-virus bioinformatics and literature meta-analysis study identifying metal-based mechanisms linking virus-induced BMCs to neurodegenerative disease processes. We discover that conserved degree and placement of PrLDs juxtaposing metal-regulated RBDs are associated with disease-causing prion-like proteins and are common features of viral proteins responsible for virus capsid assembly and structure. Virus infections both modulate gene expression of metalloproteins and interfere with metal homeostasis, representing an additional virus strategy impeding physiological and cellular antiviral responses. Our analyses reveal that metal-coordinated virus NC protein PrLDs initiate LLPS that nucleate pan-virus assembly and contribute to their persistence as cell-free infectious aerosol droplets. Virus aerosol droplets and insoluble neurological disease aggregates should be eliminated by physiological or environmental metals that outcompete PrLD-bound metals. While environmental metals can control virus spreading via aerosol droplets, therapeutic interference with metals or metalloproteins represent additional attractive avenues against pan-virus infection and virus-exacerbated neurological diseases.

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Section: Resultsmentioning

confidence: 99%

Zinc and Copper Ions Differentially Regulate Prion-Like Phase Separation Dynamics of Pan-Virus Nucleocapsid Biomolecular Condensates

Monette

Mouland

2020

Viruses

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“…There is increasing evidence suggesting that Cu may be involved in the conformational conversion of PrP C and the transmission of prion diseases. When Cu binds to the octarepeat region of a flexible N-terminal domain, Cu interacts and crosslinks with the α-helix-rich C-terminal domain and changes it to a β-sheet rich PrP Sc [ 27 ]. Giachin et al suggested that the non-octarepeat Cu binding site is also a key regulator of the conversion of PrP C [ 28 ].…”

Section: Functions Of Normal Cellular Prion Protein and Neurometalmentioning

confidence: 99%

Neurometals in the Pathogenesis of Prion Diseases

Kawahara

Kato-Negishi

Tanaka

2021

IJMS

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Prion diseases are progressive and transmissive neurodegenerative diseases. The conformational conversion of normal cellular prion protein (PrPC) into abnormal pathogenic prion protein (PrPSc) is critical for its infection and pathogenesis. PrPC possesses the ability to bind to various neurometals, including copper, zinc, iron, and manganese. Moreover, increasing evidence suggests that PrPC plays essential roles in the maintenance of homeostasis of these neurometals in the synapse. In addition, trace metals are critical determinants of the conformational change and toxicity of PrPC. Here, we review our studies and other new findings that inform the current understanding of the links between trace elements and physiological functions of PrPC and the neurotoxicity of PrPSc.

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“…PrP C has the ability to bind copper ions through its flexible N-terminal domain. This specific binding seems to mediate structural changes in PrP C moiety, stabilizing interactions between the N- and C-terminal regions, which may play a role as transporter and sensor of metal ions [ 71 ]. Interestingly, the aforementioned LRP1 also participates in PrP C Cu 2+ -mediated endocytosis from lipid rafts in neuronal cells, when its octapeptide repeats domain is fully loaded with copper ions [ 61 ].…”

Section: Prp C In Intracellular Traffickingmentioning

confidence: 99%

A New Take on Prion Protein Dynamics in Cellular Trafficking

Alves

Iglesia

Prado

et al. 2020

IJMS

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The mobility of cellular prion protein (PrPC) in specific cell membrane domains and among distinct cell compartments dictates its molecular interactions and directs its cell function. PrPC works in concert with several partners to organize signaling platforms implicated in various cellular processes. The scaffold property of PrPC is able to gather a molecular repertoire to create heterogeneous membrane domains that favor endocytic events. Dynamic trafficking of PrPC through multiple pathways, in a well-orchestrated mechanism of intra and extracellular vesicular transport, defines its functional plasticity, and also assists the conversion and spreading of its infectious isoform associated with neurodegenerative diseases. In this review, we highlight how PrPC traffics across intra- and extracellular compartments and the consequences of this dynamic transport in governing cell functions and contributing to prion disease pathogenesis.

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Structural Consequences of Copper Binding to the Prion Protein

Cited by 49 publications

References 157 publications

Zinc and Copper Ions Differentially Regulate Prion-Like Phase Separation Dynamics of Pan-Virus Nucleocapsid Biomolecular Condensates

Zinc and Copper Ions Differentially Regulate Prion-Like Phase Separation Dynamics of Pan-Virus Nucleocapsid Biomolecular Condensates

Neurometals in the Pathogenesis of Prion Diseases

A New Take on Prion Protein Dynamics in Cellular Trafficking

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