A novel copper(II) coordination at His186 in full-length murine prion protein

Watanabe, Yasuko; Hiraoka, Wakako; Igarashi, Manabu; Ito, Kimihito; Shimoyama, Yuhei; Horiuchi, Motohiro; Yamamori, Tohru; Yasui, Hirofumi; Kuwabara, Mikinori; Inagaki, Fuyuhiko; Inanami, Osamu

doi:10.1016/j.bbrc.2010.03.003

Cited by 7 publications

(5 citation statements)

References 32 publications

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“…The advantages offered by paramagnetic restraints are more and more exploited thanks to the development of paramagnetic tags that can be attached to diamagnetic proteins, so that PCSs and RDCs can be easily measured also for molecules without a natural metal binding site (Wöhnert et al 2003;Rodriguez-Castañeda et al 2006;Su et al 2006;Su et al 2008a;Keizers et al 2008;Su et al 2008b;Zhuang et al 2008;Häussinger et al 2009;Su and Otting 2010;Hass et al 2010;Man et al 2010;Das Gupta et al 2011;Liu et al 2012;Cerofolini et al 2013;Yagi et al 2013a;Gempf et al 2013;Kobashigawa et al 2012;Saio et al 2011;Watanabe et al 2010;Loh et al 2013;Swarbrick et al 2011aSwarbrick et al , 2011b.…”

Section: Introductionmentioning

confidence: 98%

FANTEN: a new web-based interface for the analysis of magnetic anisotropy-induced NMR data

et al. 2014

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Pseudocontact shifts (PCSs) and residual dipolar couplings (RDCs) arising from the presence of paramagnetic metal ions in proteins as well as RDCs due to partial orientation induced by external orienting media are nowadays routinely measured as a part of the NMR characterization of biologically relevant systems. PCSs and RDCs are becoming more and more popular as restraints (1) to determine and/or refine protein structures in solution, (2) to monitor the extent of conformational heterogeneity in systems composed of rigid domains which can reorient with respect to one another, and (3) to obtain structural information in protein-protein complexes. The use of both PCSs and RDCs proceeds through the determination of the anisotropy tensors which are at the origin of these NMR observables. A new user-friendly web tool, called FANTEN (Finding ANisotropy TENsors), has been developed for the determination of the anisotropy tensors related to PCSs and RDCs and has been made freely available through the WeNMR ( http://fanten-enmr.cerm.unifi.it:8080 ) gateway. The program has many new features not available in other existing programs, among which the possibility of a joint analysis of several sets of PCS and RDC data and the possibility to perform rigid body minimizations.

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Section: Introductionmentioning

confidence: 98%

FANTEN: a new web-based interface for the analysis of magnetic anisotropy-induced NMR data

et al. 2014

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“…Recently, two C-terminal histidines, H140 and H177, were shown to co-bind Cu 2+ , thereby tethering PrP N- and C-terminal domains and promoting their interaction 17 . Additionally, H187 was also shown to coordinate Cu 2+ 18 . The Cu 2+ coordinating octarepeat region of PrP was predicted to contain a distinctive uniform distribution of aromatic residues 19 and to form low-complexity amyloid-like kinked segments (LARKS) 20 , which establish transient β-sheet interactions and seem to be involved in driving liquid-liquid phase separation (LLPS) of low complexity domains (LCDs) in proteins forming biomolecular condensates, e.g.…”

Section: Introductionmentioning

confidence: 99%

Copper drives prion protein phase separation and modulates aggregation

Amaral

Passos

Mohapatra

et al. 2023

Preprint

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Prion diseases are characterized by prion protein (PrP) transmissible aggregation and toxicity in the brain. The physiological function of PrP seems related to sequestering and internalization of redox-active Cu2+. It is unclear whether Cu2+contributes to PrP aggregation, recently shown to be mediated by PrP condensation. We investigated the role of Cu2+and oxidation in PrP condensation and aggregation using multiple biophysical and biochemical methods. We find that Cu2+promotes PrP condensation at the cell surface andin vitrothrough co-partitioning. Molecularly, Cu2+inhibited PrP β-structure and hydrophobic residues exposure. Oxidation, induced by H2O2, triggered liquid-to-solid transition of PrP:Cu2+condensates and promoted amyloid-like PrP aggregation. In cells, overexpression of PrPCinitially protected against Cu2+cytotoxicity but led to PrPCaggregation upon extended copper exposure. Our data suggest that PrP condensates function as a buffer for copper that prevent copper toxicity but can transition into PrP aggregation at prolonged oxidative stress.

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“…Although both metals bound to the amino-terminal region, copper binding did not reveal the structural changes affiliated with low solubility under these conditions. Copper binds to histidine residues via the octarepeats and to single sites outside this region with high efficiency with a K d of 6.7 to 14 µM [ 16 – 18 ; 24 ; 32 – 33 ]. Zinc interacts with a lower affinity than copper, and the K d was determined as approximately 200 µM [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Copper and Zinc Interactions with Cellular Prion Proteins Change Solubility of Full-Length Glycosylated Isoforms and Induce the Occurrence of Heterogeneous Phenotypes

2016

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Prion diseases are characterized biochemically by protein aggregation of infectious prion isoforms (PrPSc), which result from the conformational conversion of physiological prion proteins (PrPC). PrPC are variable post-translationally modified glycoproteins, which exist as full length and as aminoterminally truncated glycosylated proteins and which exhibit differential detergent solubility. This implicates the presence of heterogeneous phenotypes, which overlap as protein complexes at the same molecular masses. Although the biological function of PrPC is still enigmatic, evidence reveals that PrPC exhibits metal-binding properties, which result in structural changes and decreased solubility. In this study, we analyzed the yield of PrPC metal binding affiliated with low solubility and changes in protein banding patterns. By implementing a high-speed centrifugation step, the interaction of zinc ions with PrPC was shown to generate large quantities of proteins with low solubility, consisting mainly of full-length glycosylated PrPC; whereas unglycosylated PrPC remained in the supernatants as well as truncated glycosylated proteins which lack of octarepeat sequence necessary for metal binding. This effect was considerably lower when PrPC interacted with copper ions; the presence of other metals tested exhibited no effect under these conditions. The binding of zinc and copper to PrPC demonstrated differentially soluble protein yields within distinct PrPC subtypes. PrPC–Zn2+-interaction may provide a means to differentiate glycosylated and unglycosylated subtypes and offers detailed analysis of metal-bound and metal-free protein conversion assays.

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A novel copper(II) coordination at His186 in full-length murine prion protein

Abstract: To explore Cu(II) ion coordination by His 186 in the C-terminal domain of full-length prion protein (moPrP), we utilized the magnetic dipolar interaction between a paramagnetic metal,

Cited by 7 publications

References 32 publications

FANTEN: a new web-based interface for the analysis of magnetic anisotropy-induced NMR data

FANTEN: a new web-based interface for the analysis of magnetic anisotropy-induced NMR data

Copper drives prion protein phase separation and modulates aggregation

Copper and Zinc Interactions with Cellular Prion Proteins Change Solubility of Full-Length Glycosylated Isoforms and Induce the Occurrence of Heterogeneous Phenotypes

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