Copper coordination to the prion protein: Insights from theoretical studies

Quintanar, Liliana; Rivillas‐Acevedo, Lina; Grande‐Aztatzi, Rafael; Gómez-Castro, Carlos Z.; Arcos-López, Trinidad; Vela, Alberto

doi:10.1016/j.ccr.2012.06.026

Cited by 35 publications

(37 citation statements)

References 155 publications

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“…The Hamilton operator includes the kinetic and potential energy contributions of all the electrons and nuclei within a molecule as described in eqn (2) and (3). 19 Here, h is Planck's constant divided by 2p, m e is the electron mass, e is the elementary charge, e 0 represents the permittivity in vacuum, and r Ij are the distances between nuclei and electrons, whereas the distances between two electrons and two nuclei are described by r ij and R IJ , respectively.…”

Section: H C = E Cmentioning

confidence: 99%

“…Often the enzymes contain a transition metal active site, where the catalysis takes place. As iron is abundant relative to other metals on planet Earth, many enzymes utilize iron in their active site, 1,2 but there are also numerous examples of copper-, 3 vanadium-, 4 molybdenum-, 5 and other transition metal-containing enzymes as well as non-transition metal containing enzymes. In addition, enzymes sometimes use clusters of two or more transition metal atoms as catalytic centres, as is, for instance, the case in the diiron enzyme ribonucleotide reductase 6 or the multi-metal cluster in photosystem II.…”

Section: Introductionmentioning

confidence: 99%

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Computational modelling of oxygenation processes in enzymes and biomimetic model complexes

et al. 2014

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With computational resources becoming more efficient and more powerful and at the same time cheaper, computational methods have become more and more popular for studies on biochemical and biomimetic systems. Although large efforts from the scientific community have gone into exploring the possibilities of computational methods for studies on large biochemical systems, such studies are not without pitfalls and often cannot be routinely done but require expert execution. In this review we summarize and highlight advances in computational methodology and its application to enzymatic and biomimetic model complexes. In particular, we emphasize on topical and state-of-the-art methodologies that are able to either reproduce experimental findings, e.g., spectroscopic parameters and rate constants, accurately or make predictions of short-lived intermediates and fast reaction processes in nature. Moreover, we give examples of processes where certain computational methods dramatically fail.

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Section: H C = E Cmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Computational modelling of oxygenation processes in enzymes and biomimetic model complexes

et al. 2014

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“…It is well established that PrP C is a copper-binding protein, with up to six copper ions binding to histidine residues in the N-terminal region both within (mouse PrP C residues 60, 68, 76, and 84) and outside of (mouse PrP C residues 95 and 110) the octarepeat region (Figure 1 ; Klewpatinond et al, 2008 ; Quintanar et al, 2013 ). In addition, copper may bind to histidine residues 176 and 186 (mouse sequence) in the C-terminus of PrP C (Quintanar et al, 2013 ), and recent evidence shows that copper can bind to the N-terminal amino group of PrP C (Stanyon et al, 2014 ). Occupancy of these copper sites is known to alter PrP C structure (Qin et al, 2000 ; Thakur et al, 2011 ; Younan et al, 2011 ; Quintanar et al, 2013 ), and thus likely its interactions with other protein partners.…”

Section: Prp C As a Regulator Of Nmda Receptorsmentioning

confidence: 99%

“…In addition, copper may bind to histidine residues 176 and 186 (mouse sequence) in the C-terminus of PrP C (Quintanar et al, 2013 ), and recent evidence shows that copper can bind to the N-terminal amino group of PrP C (Stanyon et al, 2014 ). Occupancy of these copper sites is known to alter PrP C structure (Qin et al, 2000 ; Thakur et al, 2011 ; Younan et al, 2011 ; Quintanar et al, 2013 ), and thus likely its interactions with other protein partners. The ability to examine NMDA receptor activity as an indirect readout of the interaction of the receptors with PrP C has provided interesting insights into the roles of the copper binding sites for PrP C function.…”

Section: Prp C As a Regulator Of Nmda Receptorsmentioning

confidence: 99%

Cellular prion protein and NMDA receptor modulation: protecting against excitotoxicity

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Zamponi

et al. 2014

Front. Cell Dev. Biol.

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Although it is well established that misfolding of the cellular prion protein (PrPC) into the β-sheet-rich, aggregated scrapie conformation (PrPSc) causes a variety of transmissible spongiform encephalopathies (TSEs), the physiological roles of PrPC are still incompletely understood. There is accumulating evidence describing the roles of PrPC in neurodegeneration and neuroinflammation. Recently, we identified a functional regulation of NMDA receptors by PrPC that involves formation of a physical protein complex between these proteins. Excessive NMDA receptor activity during conditions such as ischemia mediates enhanced Ca2+ entry into cells and contributes to excitotoxic neuronal death. In addition, NMDA receptors and/or PrPC play critical roles in neuroinflammation and glial cell toxicity. Inhibition of NMDA receptor activity protects against PrPSc-induced neuronal death. Moreover, in mice lacking PrPC, infarct size is increased after focal cerebral ischemia, and absence of PrPC increases susceptibility of neurons to NMDA receptor-dependent death. Recently, PrPC was found to be a receptor for oligomeric beta-amyloid (Aβ) peptides, suggesting a role for PrPC in Alzheimer's disease (AD). Our recent findings suggest that Aβ peptides enhance NMDA receptor current by perturbing the normal copper- and PrPC-dependent regulation of these receptors. Here, we review evidence highlighting a role for PrPC in preventing NMDA receptor-mediated excitotoxicity and inflammation. There is a need for more detailed molecular characterization of PrPC-mediated regulation of NMDA receptors, such as determining which NMDA receptor subunits mediate pathogenic effects upon loss of PrPC-mediated regulation and identifying PrPC binding site(s) on the receptor. This knowledge will allow development of novel therapeutic interventions for not only TSEs, but also for AD and other neurodegenerative disorders involving dysfunction of PrPC.

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“… 24 , 25 Cu II coordination to the N-terminal region of PrP C as well as related synthetic peptides have been extensively studied. 26 Because these copper binding sites are unstructured, the study of peptide fragments has been a successful approach to studying copper binding to PrP. In the octarepeat region (OR), a domain comprised of four tandem repeats of eight amino acids with the sequence PHGGGWGQ, Cu II sites are populated in response to the pH and Cu II concentration.…”

Section: Introductionmentioning

confidence: 99%

Spectroscopic and Theoretical Study of Cu^I Binding to His111 in the Human Prion Protein Fragment 106–115

et al. 2016

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The ability of the cellular prion protein (PrPC) to bind copper in vivo points to a physiological role for PrPC in copper transport. Six copper binding sites have been identified in the nonstructured N-terminal region of human PrPC. Among these sites, the His111 site is unique in that it contains a MKHM motif that would confer interesting CuI and CuII binding properties. We have evaluated CuI coordination to the PrP(106–115) fragment of the human PrP protein, using NMR and X-ray absorption spectroscopies and electronic structure calculations. We find that Met109 and Met112 play an important role in anchoring this metal ion. CuI coordination to His111 is pH-dependent: at pH >8, 2N1O1S species are formed with one Met ligand; in the range of pH 5–8, both methionine (Met) residues bind to CuI, forming a 1N1O2S species, where N is from His111 and O is from a backbone carbonyl or a water molecule; at pH <5, only the two Met residues remain coordinated. Thus, even upon drastic changes in the chemical environment, such as those occurring during endocytosis of PrPC (decreased pH and a reducing potential), the two Met residues in the MKHM motif enable PrPC to maintain the bound CuI ions, consistent with a copper transport function for this protein. We also find that the physiologically relevant CuI-1N1O2S species activates dioxygen via an inner-sphere mechanism, likely involving the formation of a copper(II) superoxide complex. In this process, the Met residues are partially oxidized to sulfoxide; this ability to scavenge superoxide may play a role in the proposed antioxidant properties of PrPC. This study provides further insight into the CuI coordination properties of His111 in human PrPC and the molecular mechanism of oxygen activation by this site.

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Copper coordination to the prion protein: Insights from theoretical studies

Cited by 35 publications

References 155 publications

Computational modelling of oxygenation processes in enzymes and biomimetic model complexes

Computational modelling of oxygenation processes in enzymes and biomimetic model complexes

Cellular prion protein and NMDA receptor modulation: protecting against excitotoxicity

Spectroscopic and Theoretical Study of Cu^I Binding to His111 in the Human Prion Protein Fragment 106–115

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Copper coordination to the prion protein: Insights from theoretical studies

Cited by 35 publications

References 155 publications

Computational modelling of oxygenation processes in enzymes and biomimetic model complexes

Computational modelling of oxygenation processes in enzymes and biomimetic model complexes

Cellular prion protein and NMDA receptor modulation: protecting against excitotoxicity

Spectroscopic and Theoretical Study of CuI Binding to His111 in the Human Prion Protein Fragment 106–115

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Spectroscopic and Theoretical Study of Cu^I Binding to His111 in the Human Prion Protein Fragment 106–115