The Acetyl Mimicking Mutation, K274Q in Tau, Enhances the Metal Binding Affinity of Tau and Reduces the Ability of Tau to Protect DNA.

Abstract

The aggregation of tau, a microtubule-associated protein, is known to play an important role in several neurological disorders including Alzheimer's disease. Alzheimer's disease is considered to be associated with the dyshomeostasis of metal ions such as aluminum, zinc, copper, and ferric ions. Tau is predominately acetylated at the K274 residue in Alzheimer's disease, and the acetylation of the K274 residue is thought to be linked with dementia. Using acetyl mimicking K274Q mutation in tau, we have examined the effects of the acetylation at K274 residue of tau on the interactions of tau with metal ions and also on the ability of tau to protect DNA from the heat and other stressors. We found that Zn2+ and Al3+ increased the liquid-liquid phase separation of tau, an initial stage of tau aggregation. Further, Zn2+ and Al3+ considerably reduced the critical concentration for the phase separation of K274Q tau. Using far-UV circular dichroism and fluorescence spectroscopy, we provide evidence suggesting that the binding of Zn2+ and Al3+ induces conformational changes in tau. The K274Q mutation enhanced the binding affinity of tau for Zn2+, Al3+, Cu2+, and Fe3+ ions. In addition, Zn2+, Al3+, Cu2+, and Fe3+ significantly enhanced the aggregation propensity of K274Q tau in comparison to tau. Interestingly, tau binds to DNA with a higher affinity than K274Q tau. Tau protects DNA from the DNase treatment in vitro as well as from the heat stress in neuroblastoma cells more efficiently than K274Q tau. The results indicated that the acetylation of K274 residue of tau may increase metal ion-induced toxicity and diminish the ability of tau to protect DNA.

• Authors: Jitendra Subhash Rane, Anuradha Kumari, Dulal Panda
• Journal: ACS chemical neuroscience (ACS Chem Neurosci) Vol. 11 Issue 3 Pg. 291-303 (02 05 2020) ISSN: 1948-7193 [Electronic] United States
• PMID: 31886644 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ions
• Metals
• tau Proteins
• Copper
• DNA
• Zinc

Topics

• Acetylation (drug effects)
• Alzheimer Disease (metabolism)
• Circular Dichroism (methods)
• Copper (metabolism)
• DNA (drug effects)
• Humans
• Ions (metabolism)
• Metals (metabolism)
• Mutation (genetics)
• Protein Binding
• Zinc (metabolism)
• tau Proteins (genetics, metabolism)