The disorderly conduct of Hsc70 and its interaction with the Alzheimer's-related Tau protein

The Journal of Biological Chemistry
Isabelle R TaylorErik R P Zuiderweg

Abstract

Hsp70 chaperones bind to various protein substrates for folding, trafficking, and degradation. Considerable structural information is available about how prokaryotic Hsp70 (DnaK) binds substrates, but less is known about mammalian Hsp70s, of which there are 13 isoforms encoded in the human genome. Here, we report the interaction between the human Hsp70 isoform heat shock cognate 71-kDa protein (Hsc70 or HSPA8) and peptides derived from the microtubule-associated protein Tau, which is linked to Alzheimer's disease. For structural studies, we used an Hsc70 construct (called BETA) comprising the substrate-binding domain but lacking the lid. Importantly, we found that truncating the lid does not significantly impair Hsc70's chaperone activity or allostery in vitro Using NMR, we show that BETA is partially dynamically disordered in the absence of substrate and that binding of the Tau sequence GKVQIINKKG (with a KD = 500 nm) causes dramatic rigidification of BETA. NOE distance measurements revealed that Tau binds to the canonical substrate-binding cleft, similar to the binding observed with DnaK. To further develop BETA as a tool for studying Hsc70 interactions, we also measured BETA binding in NMR and fluorescent competition assays ...Continue Reading

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Citations

Jul 21, 2020·PLoS Biology·Seung W RyuTanya T Paull
Mar 8, 2020·Scientific Reports·Imad BaakliniJason C Young
Jun 13, 2020·Cellular and Molecular Neurobiology·Nalini Vijay Gorantla, Subashchandrabose Chinnathambi
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Oct 20, 2018·F1000Research·María Rosario Fernández-Fernández, José María Valpuesta
Oct 18, 2019·Frontiers in Aging Neuroscience·Nataliya I TrushinaRoland Brandt
Sep 30, 2018·Journal of Molecular Neuroscience : MN·Nalini Vijay Gorantla, Subashchandrabose Chinnathambi
May 20, 2021·Journal of Medicinal Chemistry·Andrew J Ambrose, Eli Chapman

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