Coordination chemistry of copper proteins: How nature handles a toxic cargo for essential function

Rubino, Jeffrey T.; Franz, Katherine J.

doi:10.1016/j.jinorgbio.2011.11.024

Cited by 308 publications

(305 citation statements)

References 204 publications

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“…Our findings are consistent with previous work indicating that the affinity of Met-rich sites for Cu(I) depends not only of the number of Met residues but also the number of amino acids separating them [27][28][29][30]. Indeed, in model peptides containing two Met residues the affinity N HSQC spectra of AS in the absence and presence of increasing Cu(I) concentrations, from red to green (darker to lighter gray in the print version): 0 to 5 equivalents of Cu(I).…”

supporting

confidence: 93%

Bioinorganic chemistry of synucleinopathies: Deciphering the binding features of Met motifs and His-50 in AS–Cu(I) interactions

Miotto

Binolfi

Zweckstetter

et al. 2014

Journal of Inorganic Biochemistry

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The aggregation of alpha-synuclein (AS) is a critical step in the etiology of Parkinson's disease (PD) and other neurodegenerative synucleinopathies. This process is selectively enhanced by copper in vitro and the interaction is proposed to play a potential role in vivo. Presently, the identity of the Cu(I) binding sites in AS and their relative affinities are under debate. In this work we have addressed unresolved details related to the structural binding specificity and affinity of Cu(I) to full-length AS. We demonstrated conclusively that: (i) the binding preferences of Cu(I) for the Met-binding sites at the N-(K d = 20 μM) and C-terminus (K d = 270 μM) of AS are widely different: (ii) the imidazole ring of His-50 acts as an effective anchoring residue (K d = 50 μM) for Cu(I) binding to AS; and (iii) no major structural rearrangements occur in the protein upon Cu(I) binding. Overall, our work shows that Cu(I) binding to the N-and C-terminal regions of AS are two independent events, with substantial differences in their affinities, and suggest that protein oxidative damage derived from a misbalance in cellular copper homeostasis would target preferentially the N-terminal region of AS. This knowledge is key to understanding the structural-aggregation basis of the copper catalyzed oxidation of AS.

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supporting

confidence: 93%

Bioinorganic chemistry of synucleinopathies: Deciphering the binding features of Met motifs and His-50 in AS–Cu(I) interactions

Miotto

Binolfi

Zweckstetter

et al. 2014

Journal of Inorganic Biochemistry

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“…A modest response is observed with free copper salts, as is similarly observed for the related fluorescence probe FIP-1 (15). However, as a typical eukaryotic cell exhibits a ∼10-fold higher level of iron over copper coupled with the high buffering capacity of copper with glutathione and metallochaperones (picomolar to femtomolar K d values) (55)(56)(57)(58)(59)(60), the modest response to free copper salts suggests that ICL-1 should have sufficient selectivity to detect alterations in biological ferrous iron levels. ICL-1 is also selective for labile Fe 2+ over other biologically relevant forms of iron that are tightly bound to proteins and cofactors, such as transferrin, ferritin, hemin, and hemoglobin, as well as Fe 3+ , along with reductants glutathione, N-acetyl cysteine, β-mercaptoethanol, and ascorbic acid (Fig.…”

Section: Resultsmentioning

confidence: 71%

In vivo bioluminescence imaging of labile iron accumulation in a murine model of Acinetobacter baumannii infection

Aron

Heffern

Lonergan

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

118

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Iron is an essential metal for all organisms, yet disruption of its homeostasis, particularly in labile forms that can contribute to oxidative stress, is connected to diseases ranging from infection to cancer to neurodegeneration. Iron deficiency is also among the most common nutritional deficiencies worldwide. To advance studies of iron in healthy and disease states, we now report the synthesis and characterization of iron-caged luciferin-1 (ICL-1), a bioluminescent probe that enables longitudinal monitoring of labile iron pools (LIPs) in living animals. ICL-1 utilizes a bioinspired endoperoxide trigger to release D-aminoluciferin for selective reactivity-based detection of Fe 2+ with metal and oxidation state specificity. The probe can detect physiological changes in labile Fe 2+ levels in live cells and mice experiencing iron deficiency or overload. Application of ICL-1 in a model of systemic bacterial infection reveals increased iron accumulation in infected tissues that accompany transcriptional changes consistent with elevations in both iron acquisition and retention. The ability to assess iron status in living animals provides a powerful technology for studying the contributions of iron metabolism to physiology and pathology.labile iron | molecular imaging | luciferin | metal homeostasis | infectious disease I ron is an essential mineral for nearly every form of life, owing in large part to its ability to cycle between different oxidation states for processes such as nucleotide synthesis, oxygen transport, and respiration (1, 2). At the same time, the potent redox activity of iron is potentially toxic, particularly in unregulated labile forms that can trigger aberrant production of reactive oxygen species via Fenton chemistry (3). Indeed, iron deficiency remains one of the most common nutritional deficiencies in the world (4), and aberrant iron levels have been linked to various ailments, including cancer (5-7), cardiovascular (8), and neurodegenerative (9) disorders, as well as aging (10). The situation is especially complex in infectious diseases, where the requirement for iron by both host organism and invading pathogen leads to an intricate chemical tug-of-war for this metal nutrient during various stages of the immune response (11,12).The foregoing examples provide motivation for developing technologies to monitor biological iron status, with particular interest in methods to achieve in vivo iron imaging in live animal models that go beyond current state-of-the-art assays that are limited primarily to cell culture specimens. In this regard, detection of iron with both metal and oxidation state specificity is of central importance, because while iron is stored primarily in the ferric oxidation state, a ferrous iron pool loosely bound to cellular ligands, defined as the labile iron pool (LIP), exists at the center of highly regulated networks that control iron acquisition, trafficking, and excretion. Indeed, as a weak binder on the Irving-Williams stability series (13), Fe 2+ provides a challenge for d...

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“…Copper is an essential trace element required as a cofactor for cellular enzymes (Rubino & Franz, 2012). Nevertheless, micromolar copper concentrations are toxic to cells (Macomber & Imlay, 2009), which is why intracellular copper levels are tightly controlled by homeostatic mechanisms (Osman & Cavet, 2008).…”

Section: Introductionmentioning

confidence: 99%

Periplasmic proteins encoded by VCA0261–0260 and VC2216 genes together with copA and cueR products are required for copper tolerance but not for virulence in Vibrio cholerae

Marrero¹,

Sánchez

González

et al. 2012

Microbiology

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Coordination chemistry of copper proteins: How nature handles a toxic cargo for essential function

Cited by 308 publications

References 204 publications

Bioinorganic chemistry of synucleinopathies: Deciphering the binding features of Met motifs and His-50 in AS–Cu(I) interactions

Bioinorganic chemistry of synucleinopathies: Deciphering the binding features of Met motifs and His-50 in AS–Cu(I) interactions

In vivo bioluminescence imaging of labile iron accumulation in a murine model of Acinetobacter baumannii infection

Periplasmic proteins encoded by VCA0261–0260 and VC2216 genes together with copA and cueR products are required for copper tolerance but not for virulence in Vibrio cholerae

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