Alzheimer's disease: a dangerous mistake
Chaperone Binds Protein Responsible for Alzheimer's Disease
LifeSciencesToday based on the materials of Technische Universitaet Muenchen:
Dangerous mistaken identity: Chaperone binds protein responsible for Alzheimer’s diseaseTau protein, directly associated with the development of Alzheimer's disease, interacts with the folding protein chaperone Hsp90.
A research team led by scientists from the Technical University of Munich and the Helmholtz Center of Munich has published an article in the journal Cell (Karagoz et al., Hsp90-Tau Complex Reveals Molecular Basis for Specificity in Chaperone Action), in which it explains which molecular recognition mechanisms play a role in this interaction, and suggests a new pharmacological target for treatment this deadly disease.
Proteins, such as heat shock protein Hsp90, play an important role in almost all processes occurring in human cells. They help other proteins to fold into three-dimensional structures or restore the correct configuration of damaged protein molecules.
Recently, scientists have been getting more and more evidence that the heat shock protein Hsp90 is involved in tau protein folding. Accumulations of tau protein in brain cells are characteristic of Alzheimer's disease and are responsible for the degeneration of nerve cells.
Although Hsp90 usually prefers already folded proteins, it nevertheless binds to the tau protein responsible for the development of Alzheimer's disease. An international team of scientists has deciphered the molecular mechanisms of recognition by the chaperone Hsp90 tau protein. The picture shows the protein complex Hsp90-tau (Hsp90 light blue, tau protein orange). (Photo: Tobias Madl/Technische Universitat Munchen/Helmholz Zentrum Munchen)Chaperone Hsp90 binds mainly to proteins that have already passed the early stage of folding.
The tau protein molecules in the solution are more like long elongated chains. Dr. Tobias Madl, head of the BioSysNet working group, Junior researcher at the Technische Universitat Munchen, Head of the Emmy Noether Signal Transduction Structural Biology Group at the Institute of Structural Biology (Institut fgr Strukturbiologie) of the Helmholtz Center of Munich (Helmholz Zentrum), found out why Hsp90, nevertheless, interacts with tau Mgpshep). The co-author of the study is Professor Stefan Rudiger from the University of Utrecht, the Netherlands.
Using magnetic resonance spectroscopy, small-angle X-ray scattering and computer modeling, scientists have determined the structure and dynamics of the interaction between two biomolecules. Based on this information, they established how Hsp90 recognizes and binds tau: for Hsp90, the tau protein looks like a folded protein of large size. In addition, the researchers were able to shed light on how Hsp90 affects the aggregation of tau molecules.
Protein folding in the cell is based on the coordinated action of conservative families of chaperones – the Hsp70 and Hsp90 systems. Hsp70 acts at an early stage, and Hsp90 at the end of folding, but the molecular basis of such timing is a mystery, which is mainly due to insufficient knowledge of the substrate specificity of Hsp90. German and Dutch scientists have obtained a structural model of Hsp90 in combination with its natural substrate associated with Alzheimer's disease – an internally disordered tau protein. Hsp90 binds to a wide area of tau, including repeats predisposed to aggregation, interacting with microtubules. In addition, the 106 angstrom-long substrate-binding interface of Hsp90 makes possible many contacts with low affinity and recognition of scattered hydrophobic residues in late coagulation intermediates remaining after early binding of Hsp70 chaperone sites. This model resolves the paradox of how Hsp90 simultaneously specifically selects late folding intermediates and some internally disordered proteins: from the point of view of Hsp90, they look the same. (Fig. Cell)"Deposits of tau protein can lead to the development of Alzheimer's disease.
We have identified the region of the protein in which the interaction between its molecules takes place. This is a new and important starting point for influencing the formation of this structure and for the development of future therapeutic drugs for the treatment of Alzheimer's disease," comments Dr. Madl.
Protein aggregation is the cause not only of Alzheimer's disease, but also of other neurodegenerative diseases, and chaperones play a significant role in the development of cancer and fibrotic cysts. Thus, these discoveries can form the basis for a deeper understanding of the mechanisms of development of all these diseases.
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