9 results on '"Marco C. Miotto"'
Search Results
2. Structural analyses of human ryanodine receptor type 2 channels reveal the mechanisms for sudden cardiac death and treatment
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Marco C. Miotto, Gunnar Weninger, Haikel Dridi, Qi Yuan, Yang Liu, Anetta Wronska, Zephan Melville, Leah Sittenfeld, Steven Reiken, and Andrew R. Marks
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Multidisciplinary - Abstract
Ryanodine receptor type 2 (RyR2) mutations have been linked to an inherited form of exercise-induced sudden cardiac death called catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT results from stress-induced sarcoplasmic reticular Ca 2+ leak via the mutant RyR2 channels during diastole. We present atomic models of human wild-type (WT) RyR2 and the CPVT mutant RyR2-R2474S determined by cryo–electron microscopy with overall resolutions in the range of 2.6 to 3.6 Å, and reaching local resolutions of 2.25 Å, unprecedented for RyR2 channels. Under nonactivating conditions, the RyR2-R2474S channel is in a “primed” state between the closed and open states of WT RyR2, rendering it more sensitive to activation that results in stress-induced Ca 2+ leak. The Rycal drug ARM210 binds to RyR2-R2474S, reverting the primed state toward the closed state. Together, these studies provide a mechanism for CPVT and for the therapeutic actions of ARM210.
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- 2022
3. Catching the next wave of recombinant RyR2 cryo-EM structures. Commentary on 'Molecular basis for gating of cardiac ryanodine receptor explains the mechanisms for gain- and loss-of function mutations'
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Marco C. Miotto and Andrew R. Marks
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Physiology ,Cryoelectron Microscopy ,Mutation ,Calcium ,Ryanodine Receptor Calcium Release Channel ,Cell Biology ,Molecular Biology - Published
- 2022
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4. A moderate metal-binding hydrazone meets the criteria for a bioinorganic approach towards Parkinson's disease: Therapeutic potential, blood-brain barrier crossing evaluation and preliminary toxicological studies
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Daphne S. Cukierman, Anastácia Sá P. da Silva, Ricardo Q. Aucélio, Sergio L.P. Castiñeiras-Filho, Thales de P. Ribeiro, Marco C. Miotto, Rachel Ann Hauser-Davis, Nicolás A. Rey, Alessandra L. M. C. da Cunha, Tiago F. Outeiro, Anna De Falco, Marcos D. Pereira, Jesus Landeira-Fernandez, Ana Beatriz Pinheiro, Claudio O. Fernández, and Silvia Maisonette
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Male ,0301 basic medicine ,Wistar Rats ,CIENCIAS MÉDICAS Y DE LA SALUD ,Parkinson's disease ,Stereochemistry ,Drug Evaluation, Preclinical ,Hydrazone ,Química Inorgánica y Nuclear ,010402 general chemistry ,Blood–brain barrier ,01 natural sciences ,Biochemistry ,Ciencias Biológicas ,Inorganic Chemistry ,03 medical and health sciences ,Toxicología ,medicine ,Animals ,Mpac ,Parkinson Disease, Secondary ,Rats, Wistar ,Chelating Agents ,chemistry.chemical_classification ,Metal binding ,Chemistry ,Hydrazones ,Ciencias Químicas ,Bioinorganic chemistry ,Bioquímica y Biología Molecular ,medicine.disease ,Rats ,3. Good health ,0104 chemical sciences ,Parkinson'S Disease ,Medicina Básica ,030104 developmental biology ,medicine.anatomical_structure ,Blood-Brain Barrier ,Α-Synuclein ,Metal Hypothesis ,α synuclein ,Copper ,CIENCIAS NATURALES Y EXACTAS - Abstract
Alzheimer's and Parkinson's diseases share similar amyloidogenic mechanisms, in which metal ions might play an important role. In this last neuropathy, misfolding and aggregation of α-synuclein (α-Syn) are crucial pathological events. A moderate metal-binding compound, namely, 8-hydroxyquinoline-2-carboxaldehyde isonicotinoyl hydrazone (INHHQ), which was previously reported as a potential ‘Metal-Protein Attenuating Compound’ for Alzheimer's treatment, is well-tolerated by healthy Wistar rats and does not alter their major organ weights, as well as the tissues' reduced glutathione and biometal levels, at a concentration of 200 mg kg− 1. INHHQ definitively crosses the blood-brain barrier and can be detected in the brain of rats so late as 24 h after intraperitoneal administration. After 48 h, brain clearance is complete. INHHQ is able to disrupt, in vitro, anomalous copper-α-Syn interactions, through a mechanism probably involving metal ions sequestering. This compound is non-toxic to H4 (human neuroglioma) cells and partially inhibits intracellular α-Syn oligomerization. INHHQ, thus, shows definite potential as a therapeutic agent against Parkinson's as well. Fil: Cukierman, Daphne Schneider. Pontifícia Universidade Católica do Rio de Janeiro; Brasil Fil: Pinheiro, Ana Beatriz. Pontifícia Universidade Católica do Rio de Janeiro; Brasil Fil: Castiñeiras-Filho, Sergio L.P.. Pontifícia Universidade Católica do Rio de Janeiro; Brasil Fil: da Silva, Anastácia Sá P.. Pontifícia Universidade Católica do Rio de Janeiro; Brasil Fil: Miotto, Marco César. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario. Universidad Nacional de Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario; Argentina Fil: De Falco, Anna. Pontifícia Universidade Católica do Rio de Janeiro; Brasil Fil: de P. Ribeiro, Thales. Universidade Federal do Rio de Janeiro; Brasil Fil: Maisonette, Silvia. Pontifícia Universidade Católica do Rio de Janeiro; Brasil Fil: da Cunha, Alessandra L.M.C.. Pontifícia Universidade Católica do Rio de Janeiro; Brasil Fil: Hauser-Davis, Rachel A.. Pontifícia Universidade Católica do Rio de Janeiro; Brasil Fil: Fernandez, Claudio Oscar. Pontifícia Universidade Católica do Rio de Janeiro; Brasil Fil: Aucélio, Ricardo Q.. Pontifícia Universidade Católica do Rio de Janeiro; Brasil Fil: Outeiro, Tiago F.. Universität Göttingen; Alemania Fil: Pereira, Marcos D.. Universidade Federal do Rio de Janeiro; Brasil Fil: Fernandez, Claudio Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario. Universidad Nacional de Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario; Argentina Fil: Rey, Nicolás A.. Pontifícia Universidade Católica do Rio de Janeiro; Brasil
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- 2017
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5. Spectroscopic and Theoretical Study of CuI Binding to His111 in the Human Prion Protein Fragment 106–115
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Alberto Vela, Claudio O. Fernández, Edward I. Solomon, Lina Rivillas-Acevedo, Trinidad Arcos-López, Marco C. Miotto, Liliana Quintanar, Keith O. Hodgson, Britt Hedman, Rafael Grande-Aztatzi, and Munzarin F. Qayyum
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0301 basic medicine ,Stereochemistry ,Biophysics ,chemistry.chemical_element ,Plasma protein binding ,Prion Protein ,010402 general chemistry ,Endocytosis ,01 natural sciences ,Article ,Prion Proteins ,Inorganic Chemistry ,Metal ,03 medical and health sciences ,chemistry.chemical_compound ,Humans ,Molecule ,Physical and Theoretical Chemistry ,Nuclear Magnetic Resonance, Biomolecular ,Methionine ,Superoxide ,Otras Ciencias Químicas ,Ciencias Químicas ,Sulfoxide ,Hydrogen-Ion Concentration ,Models, Theoretical ,Copper ,Peptide Fragments ,nervous system diseases ,0104 chemical sciences ,3. Good health ,Kinetics ,Crystallography ,X-Ray Absorption Spectroscopy ,030104 developmental biology ,chemistry ,visual_art ,visual_art.visual_art_medium ,Cu(I) ,Oxidation-Reduction ,CIENCIAS NATURALES Y EXACTAS ,Protein Binding - Abstract
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, CuI coordination to the His111 site in the HuPrP protein is highly dependent on the pH: at pH 8, 2N1O1S species are formed with only a Met ligand. The CuI-1N1O2S species activates dioxygen, and in this process, the Met residues are partially oxidized to sulfoxide.
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- 2016
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6. Aroylhydrazones constitute a promising class of 'metal-protein attenuating compounds' for the treatment of Alzheimer's disease: a proof-of-concept based on the study of the interactions between zinc(II) and pyridine-2-carboxaldehyde isonicotinoyl hydrazone
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Elio Accardo, Claudio O. Fernández, Nicolás A. Rey, Rosana Garrido Gomes, Daphne S. Cukierman, Maria Clara R. Freitas, Anna De Falco, Mauricio Lanznaster, and Marco C. Miotto
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AROYLHYDRAZONES ,Pyridines ,Population ,Hydrazone ,Disease ,Química Inorgánica y Nuclear ,010402 general chemistry ,Ligands ,01 natural sciences ,Biochemistry ,Proof of Concept Study ,Inorganic Chemistry ,ZINC(II) ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,ALZHEIMER’S DISEASE ,Alzheimer Disease ,Coordination Complexes ,Pyridine ,Lack of efficacy ,Moiety ,education ,Nootropic Agents ,chemistry.chemical_classification ,Aundefined PEPTIDE ,education.field_of_study ,Amyloid beta-Peptides ,Molecular Structure ,Chemistry ,Ligand ,Aβ peptide ,Ciencias Químicas ,Hydrazones ,Combinatorial chemistry ,Peptide Fragments ,0104 chemical sciences ,Zinc ,MPAC ,CIENCIAS NATURALES Y EXACTAS ,030217 neurology & neurosurgery ,Protein Binding - Abstract
With the increasing life expectancy of the world’s population, neurodegenerative diseases, such as Alzheimer’s disease (AD), will become a much more relevant public health issue. This fact, coupled with the lack of efficacy of the available treatments, has been driving research directed to the development of new drugs for this pathology. Metal-protein attenuating compounds (MPACs) constitute a promising class of agents with potential application on the treatment of neurodegenerative diseases, such as AD. Currently, most MPACs are based on 8-hydroxyquinoline. Recently, our research group has described the hybrid aroylhydrazone containing the 8-hydroxyquinoline group INHHQ as a promising MPAC. By studying the known structure-related ligand HPCIH, which does not contain the phenol moiety, as a simplified chemical model for INHHQ, we aimed to clarify the real impact of the aroylhydrazone group for the MPAC activity of a compound with potential anti-Alzheimer’s activity. The present work describes a detailed solution and solid-state study of the coordination of HPCIH with Zn2+ ions, as well as its in vitro binding-ability towards this metal in the presence of the Aβ(1–40) peptide. Similar to INHHQ, HPCIH is able to efficiently compete with Aβ(1–40) for Zn2+ ions, performing as expected for an MPAC. The similarity between the behaviors of both ligands is remarkable. Taken together, the data presented herein point to aroylhydrazones, such as the compounds HPCIH and the previously published INHHQ, as encouraging MPACs for the treatment of AD. Fil: Cukierman, Daphne S.. Pontifícia Universidade Católica do Rio de Janeiro; Brasil Fil: Accardo, Elio. Pontifícia Universidade Católica do Rio de Janeiro; Brasil Fil: Gomes, Rosana Garrido. Pontifícia Universidade Católica do Rio de Janeiro; Brasil Fil: De Falco, Anna. Pontifícia Universidade Católica do Rio de Janeiro; Brasil Fil: Miotto, Marco César. Universidad Nacional de Rosario; Argentina Fil: Freitas, Maria Clara Ramalho. Universidade Federal do Rio de Janeiro; Brasil Fil: Lanznaster, Mauricio. Universidade Federal Fluminense; Brasil Fil: Fernández, Claudio O.. Universidad Nacional de Rosario; Argentina Fil: Rey, Nicolás A.. Pontifícia Universidade Católica do Rio de Janeiro; Brasil
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- 2018
7. Phthalocyanines as Molecular Scaffolds to Block Disease-Associated Protein Aggregation
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Marco C. Miotto, Ariel A. Valiente-Gabioud, Maria Eugenia Chesta, Verónica A. Lombardo, Andres Binolfi, and Claudio O. Fernández
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0301 basic medicine ,Indoles ,Amyloid beta ,Otras Ciencias Biológicas ,Phthalocyanines ,Tau protein ,Peptide ,Brain damage ,Disease ,Plasma protein binding ,Neurodegenerative ,Protein aggregation ,Isoindoles ,Ciencias Biológicas ,purl.org/becyt/ford/1 [https] ,Aggregation ,03 medical and health sciences ,Structure-Activity Relationship ,mental disorders ,medicine ,Structure–activity relationship ,Humans ,Parkinson ,purl.org/becyt/ford/1.6 [https] ,chemistry.chemical_classification ,biology ,Proteins ,Neurodegenerative Diseases ,General Medicine ,General Chemistry ,nervous system diseases ,030104 developmental biology ,Biochemistry ,chemistry ,Cancer research ,biology.protein ,medicine.symptom ,CIENCIAS NATURALES Y EXACTAS ,Protein Binding - Abstract
ConspectusThe aggregation of proteins into toxic conformations plays a critical role in the development of different neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Creutzfled-Jakob's disease (CJD). These disorders share a common pathological mechanism that involves the formation of aggregated protein species including toxic oligomers and amyloid fibrils. The aggregation of alpha-synuclein (αS) in PD and the amyloid beta peptide (Aβ) and tau protein in AD results in neuronal death and disease onset. In the case of CJD, the misfolding of the physiological prion protein (PrP) induces a chain reaction that results in accumulation of particles that elicit brain damage. Currently, there is no preventive therapy for these diseases and the available therapeutic approaches are based on the treatment of the symptoms rather than the underlying causes of the disease. Accordingly, the aggregation pathway of these proteins represents a useful target for therapeutic intervention. Therefore, understanding the mechanism of amyloid formation and its inhibition is of high clinical importance. The design of small molecules that efficiently inhibit the aggregation process and/or neutralize its associated toxicity constitutes a promising tool for the development of therapeutic strategies against these disorders. In this accounts, we discuss current knowledge on the anti-amyloid activity of phthalocyanines and their potential use as drug candidates in neurodegeneration. These tetrapyrrolic compounds modulate the amyloid assembly of αS, tau, Aβ, and the PrP in vitro, and protect cells from the toxic effects of amyloid aggregates. In addition, in scrapie-infected mice, these compounds showed important prophylactic antiscrapie properties. The structural basis for the inhibitory effect of phthalocyanines on amyloid filament assembly relies on specific π-π interactions between the aromatic ring system of these molecules and aromatic residues in the amyloidogenic proteins. Analysis of the structure-activity relationship in phthalocyanines revealed that their anti-amyloid activity is highly dependent on the type of metal ion coordinated to the tetrapyrrolic system but is not sensitive to the number of peripheral charged substituents. The tendency of phthalocyanines to oligomerize (self-association) via aromatic-aromatic stacking interactions correlates precisely with their binding capabilities to target proteins and, more importantly, determines their efficiency as anti-amyloid agents. The ability to block different types of disease-associated protein aggregation raises the possibility that these cyclic tetrapyrrole compounds have a common mechanism of action to impair the formation of a variety of pathological aggregates. Because the structural and molecular basis for the anti-amyloid effects of these molecules is starting to emerge, combined efforts from the fields of structural, cellular, and animal biology will result critical for the rational design and discovery of new drugs for the treatment of amyloid related neurological disorders. Fil: Valiente Gabioud, Ariel Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario. Universidad Nacional de Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario; Argentina Fil: Miotto, Marco César. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario. Universidad Nacional de Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario; Argentina Fil: Chesta, María Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario. Universidad Nacional de Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario; Argentina Fil: Lombardo, Veronica Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario. Universidad Nacional de Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario; Argentina Fil: Binolfi, Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario. Universidad Nacional de Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario; Argentina Fil: Fernandez, Claudio Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario. Universidad Nacional de Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario; Argentina
- Published
- 2016
8. Disruption of zinc and copper interactions with Aβ(1-40) by a non-toxic, isoniazid-derived, hydrazone: a novel biometal homeostasis restoring agent in Alzheimer's disease therapy?
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Jesus Landeira-Fernandez, Daphne S. Cukierman, Nicolás A. Rey, Rachel Ann Hauser-Davis, L. V. de Freitas, Ariel A. Valiente-Gabioud, Claudio O. Fernández, Marco C. Miotto, and W. S. Cruz
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Drug ,Male ,media_common.quotation_subject ,In silico ,Biophysics ,Hydrazone ,Pharmacology ,Biochemistry ,Biomaterials ,In vivo ,Alzheimer Disease ,medicine ,Isoniazid ,Animals ,Homeostasis ,Humans ,Rats, Wistar ,media_common ,chemistry.chemical_classification ,Amyloid beta-Peptides ,Chemistry ,Metals and Alloys ,Hydrazones ,In vitro ,Acute toxicity ,Peptide Fragments ,Zinc ,Chemistry (miscellaneous) ,Blood-Brain Barrier ,Copper ,medicine.drug - Abstract
Disruptions of biometal-Aβ(1-40) interactions by an isoniazid-derived hydrazone, INHHQ, were demonstrated via in vitro NMR titrations. The compound has adequate theoretical BBB absorption properties, assessed by in silico studies. In vivo acute toxicity assays indicate that INHHQ is innocuous up to 300 mg kg(-1), showing potential as an anti-Alzheimer's drug.
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- 2015
9. Bioinorganic chemistry of synucleinopathies: deciphering the binding features of Met motifs and His-50 in AS-Cu(I) interactions
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Marco C. Miotto, Markus Zweckstetter, Claudio O. Fernández, Christian Griesinger, and Andres Binolfi
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ALPHA-SYNUCLEIN ,Stereochemistry ,chemistry [Recombinant Proteins] ,Molecular Sequence Data ,CU(I) ,Biochemistry ,Protein Structure, Secondary ,Inorganic Chemistry ,Residue (chemistry) ,chemistry.chemical_compound ,chemistry [Histidine] ,Imidazole ,Humans ,Histidine ,Protein Interaction Domains and Motifs ,Amino Acid Sequence ,Binding site ,Binding selectivity ,Alpha-synuclein ,Synucleinopathies ,Binding Sites ,Otras Ciencias Químicas ,Ciencias Químicas ,Bioinorganic chemistry ,Cations, Monovalent ,chemistry [Copper] ,Affinities ,Recombinant Proteins ,genetics [Recombinant Proteins] ,Solutions ,Kinetics ,chemistry [alpha-Synuclein] ,chemistry ,ddc:540 ,genetics [alpha-Synuclein] ,alpha-Synuclein ,Thermodynamics ,MET-RICH SITES ,PARKINSON ,Oxidation-Reduction ,CIENCIAS NATURALES Y EXACTAS ,Copper ,Protein Binding - Abstract
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- (Kd = 20 μM) and C-terminus (Kd = 270 μM) of AS are widely different: (ii) the imidazole ring of His-50 acts as an effective anchoring residue (Kd = 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. Fil: Miotto, Marco César. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina Fil: Binolfi, Andrés. Leibniz-institut Für Molekulare Pharmakologie; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina Fil: Zweckstetter, Markus. Universität Göttingen; Alemania Fil: Griesinger, Christian. Max Planck Institute For Biophysical Chemistry; Alemania Fil: Fernandez, Claudio Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
- Published
- 2014
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