The Palladium(II) Complex of A<i>β</i><sub>4−16</sub> as Suitable Model for Structural Studies of Biorelevant Copper(II) Complexes of N-Truncated Beta-Amyloids
The A<inline-formula><math display="inline"><semantics><msub><mi>β</mi><mrow><mn>4</mn><mo>−</mo><mn>42</mn></mrow></msub></semantics></math></inline-formula> peptide is a major beta...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-12-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/21/23/9200 |
| Summary: | The A<inline-formula><math display="inline"><semantics><msub><mi>β</mi><mrow><mn>4</mn><mo>−</mo><mn>42</mn></mrow></msub></semantics></math></inline-formula> peptide is a major beta-amyloid species in the human brain, forming toxic aggregates related to Alzheimer’s Disease. It also strongly chelates Cu(II) at the N-terminal Phe-Arg-His ATCUN motif, as demonstrated in A<inline-formula><math display="inline"><semantics><msub><mi>β</mi><mrow><mn>4</mn><mo>−</mo><mn>16</mn></mrow></msub></semantics></math></inline-formula> and A<inline-formula><math display="inline"><semantics><msub><mi>β</mi><mrow><mn>4</mn><mo>−</mo><mn>9</mn></mrow></msub></semantics></math></inline-formula> model peptides. The resulting complex resists ROS generation and exchange processes and may help protect synapses from copper-related oxidative damage. Structural characterization of Cu(II)A<inline-formula><math display="inline"><semantics><msub><mi>β</mi><mrow><mn>4</mn><mo>−</mo><mi>x</mi></mrow></msub></semantics></math></inline-formula> complexes by NMR would help elucidate their biological function, but is precluded by Cu(II) paramagneticism. Instead we used an isostructural diamagnetic Pd(II)-A<inline-formula><math display="inline"><semantics><msub><mi>β</mi><mrow><mn>4</mn><mo>−</mo><mn>16</mn></mrow></msub></semantics></math></inline-formula> complex as a model. To avoid a kinetic trapping of Pd(II) in an inappropriate transient structure, we designed an appropriate pH-dependent synthetic procedure for ATCUN Pd(II)A<inline-formula><math display="inline"><semantics><msub><mi>β</mi><mrow><mn>4</mn><mo>−</mo><mn>16</mn></mrow></msub></semantics></math></inline-formula>, controlled by CD, fluorescence and ESI-MS. Its assignments and structure at pH 6.5 were obtained by TOCSY, NOESY, ROESY, <inline-formula><math display="inline"><semantics><msup><mrow></mrow><mn>1</mn></msup></semantics></math></inline-formula>H-<inline-formula><math display="inline"><semantics><msup><mrow></mrow><mn>13</mn></msup></semantics></math></inline-formula>C HSQC and <inline-formula><math display="inline"><semantics><msup><mrow></mrow><mn>1</mn></msup></semantics></math></inline-formula>H-<inline-formula><math display="inline"><semantics><msup><mrow></mrow><mn>15</mn></msup></semantics></math></inline-formula>N HSQC NMR experiments, for natural abundance <inline-formula><math display="inline"><semantics><msup><mrow></mrow><mn>13</mn></msup></semantics></math></inline-formula>C and <inline-formula><math display="inline"><semantics><msup><mrow></mrow><mn>15</mn></msup></semantics></math></inline-formula>N isotopes, aided by corresponding experiments for Pd(II)-Phe-Arg-His. The square-planar Pd(II)-ATCUN coordination was confirmed, with the rest of the peptide mostly unstructured. The diffusion rates of A<inline-formula><math display="inline"><semantics><msub><mi>β</mi><mrow><mn>4</mn><mo>−</mo><mn>16</mn></mrow></msub></semantics></math></inline-formula>, Pd(II)-A<inline-formula><math display="inline"><semantics><msub><mi>β</mi><mrow><mn>4</mn><mo>−</mo><mn>16</mn></mrow></msub></semantics></math></inline-formula> and their mixture determined using PGSE-NMR experiment suggested that the Pd(II) complex forms a supramolecular assembly with the apopeptide. These results confirm that Pd(II) substitution enables NMR studies of structural aspects of Cu(II)-A<inline-formula><math display="inline"><semantics><mi>β</mi></semantics></math></inline-formula> complexes. |
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| ISSN: | 1661-6596 1422-0067 |