Copper ions involve in many cellular function such as enzymatic activities and neurotransmission in the central nervous system. The copper ion homeostasis are controlled by a complex cell mechanism, however, distortion in the homeostatic mechanisms lead to abnormal level of copper ions and may cause neurodegenerative diseases such as Alzheimer’s disease (AD). Investigating the structural interactions of copper ions with tau protein, as one of the hallmark for AD, is essential for understanding the molecular mechanism of AD pathogenesis in order to develop an effective therapies. We previously reported the direct interaction of copper ions with full length human tau protein. In this contribution, we focus on the impact of Cu2+ in microtubule binding domain of tau protein, which is the critical sequence of tau that involve in microtubule assembly. The complexation of copper with R4, fourth repeat microtubule-binding domain (residues 337-368 of the full length human tau441: VEVKSEKLDFKDRVQSKIGSLDNITHVPGGGN) were investigated. The ESI-MS results confirmed the complexation of Cu-R4; the impact of Cu2+ on R4 structural changes and dimerization were studied by IMS-MS and MS-MS. The NMR studies revealed that His362 is the binding site of copper. This study provides a new insight into the possible role of Cu2+ in tau dimerization and aggregation, which may involve in AD pathogenesis.

Investigation of Cu(II) complexation with fourth microtubule-binding repeat of tau protein by ESI-MS, IMS-MS and NMR

253rd National Meeting (2017)

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