Copper Coordination Features of Human Islet Amyloid Polypeptide: The Type 2 Diabetes Peptide
| Autor: | Carolina Sánchez-López, Andres Binolfi, Jorge M. del Campo, Rodrigo Cortés-Mejía, Claudio O. Fernández, Liliana Quintanar, Marco C. Miotto |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Circular dichroism
Amyloid Stereochemistry BIOINORGANIC COPPER Peptide 010402 general chemistry 01 natural sciences law.invention BIOPHYSICS Inorganic Chemistry purl.org/becyt/ford/1 [https] Molecular dynamics chemistry.chemical_compound law purl.org/becyt/ford/1.4 [https] Imidazole DIABETES Physical and Theoretical Chemistry Electron paramagnetic resonance chemistry.chemical_classification geography geography.geographical_feature_category 010405 organic chemistry Chemistry Otras Ciencias Químicas Ciencias Químicas Islet Ligand (biochemistry) 0104 chemical sciences Biochemistry CIENCIAS NATURALES Y EXACTAS |
| Zdroj: | CONICET Digital (CONICET) Consejo Nacional de Investigaciones Científicas y Técnicas instacron:CONICET |
| Popis: | Human islet amyloid polypeptide (hIAPP) is the major component of amyloid deposits found in pancreatic β-cells of patients with type 2 diabetes (T2D). Copper ions have an inhibitory effect on the amyloid aggregation of hIAPP, and they may play a role in the etiology of T2D. However, deeper knowledge of the structural details of the copper-hIAPP interaction is required to understand the molecular mechanisms involved. Here, we performed a spectroscopic study of Cu(II) binding to hIAPP and several variants, using electron paramagnetic resonance (EPR), nuclear magnetic resonance (NMR), electronic absorption, and circular dichroism (CD) in the UV-vis region in combination with Born-Oppenheimer molecular dynamics (BOMD) and density functional theory geometry optimizations. We find that Cu(II) binds to the imidazole N1 of His18, the deprotonated amides of Ser19 and Ser20, and an oxygen-based ligand provided by Ser20, either via its hydroxyl group or its backbone carbonyl, while Asn22 might also play a role as an axial ligand. Ser20 plays a crucial role in stabilizing Cu(II) coordination toward the C-terminal, providing a potential link between the S20G mutation associated with early onset of T2D, its impact in Cu binding properties, and hIAPP amyloid aggregation. Our study defines the nature of the coordination environment in the Cu(II)-hIAPP complex, revealing that the amino acid residues involved in metal ion binding are also key residues for the formation of β-sheet structures and amyloid fibrils. Cu(II) binding to hIAPP may lead to the coexistence of more than one coordination mode, which in turn could favor different sets of Cu-induced conformational ensembles. Cu-induced hIAPP conformers would display a higher energetic barrier to form amyloid fibrils, hence explaining the inhibitory effect of Cu ions in hIAPP aggregation. Overall, this study provides further structural insights into the bioinorganic chemistry of T2D. Fil: Sánchez López, Carolina. Centro de Investigación y de Estudios Avanzados. Departamento de Química; México Fil: Cortés Mejía, Rodrigo. Universidad Nacional Autónoma de México; México 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. Max Planck Laboratory for Structural Biology; 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. Max Planck Laboratory for Structural Biology; 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. Max Planck Laboratory for Structural Biology; Argentina Fil: Del Campo, Jorge M.. Universidad Nacional Autónoma de México; México Fil: Quintanar, Liliana. Centro de Investigación y de Estudios Avanzados. Departamento de Química; México |
| Databáze: | OpenAIRE |
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