The Hsp90 Cochaperone, FKBP51, Increases Tau Stability and Polymerizes Microtubules

Abstract

Imbalanced protein load within cells is a critical aspect for most diseases of aging. In particular, the accumulation of proteins into neurotoxic aggregates is a common thread for a host of neurodegenerative diseases. Our previous work demonstrated that age-related changes to the cellular chaperone repertoire contributes to abnormal buildup of the microtubule-associated protein tau that accumulates in a group of diseases termed tauopathies, the most common being Alzheimer's disease. Here, we show that the Hsp90 cochaperone, FK506-binding protein 51 (FKBP51), which possesses both an Hsp90-interacting tetratricopeptide domain and a peptidyl-prolyl cis-trans isomerase (PPIase) domain, prevents tau clearance and regulates its phosphorylation status. Regulation of the latter is dependent on the PPIase activity of FKBP51. FKB51 enhances the association of tau with Hsp90, but the FKBP51/tau interaction is not dependent on Hsp90. In vitro FKBP51 stabilizes microtubules with tau in a reaction depending on the PPIase activity of FKBP51. Based on these new findings, we propose that FKBP51 can use the Hsp90 complex to isomerize tau, altering its phosphorylation pattern and stabilizing microtubules.

Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

“…However, it is noteworthy that the repeat domain possesses two motifs of the consensus type KVERQ, which interact with hsc70 for chaperonemediated autophagy (Wang et al 2009). Other interactors of Tau are linked to chaperone components, for example the prolyl isomerase Pin-1 (Liou et al 2003), FKBP51, FKBP52 (Chambraud et al 2010;Jinwal et al 2010). Pin-1 isomerizes the motifs pT212-P and pS231-P in the proline-rich domain from cis to trans and thus allows the dephosphorylation by PP-2a and recovery of microtubule binding (Smet et al 2004).…”

Endoplasmic reticulum stress or mutation of an EF-hand Ca2+-binding domain directs the FKBP65 rotamase to an ERAD-based proteolysis

“…The FKBP52/HSP90 complex binds to cytoplasmic glucocorticoid receptors, enhancing receptor affinity for steroid ligand and facilitating interaction between the bound receptor and dynein during receptor translocation to the nucleus (Davies and Sanchez 2005). In neurodegenerative diseases displaying a toxic accumulation of Tau protein, FKBP51/HSP90 complexes bind microtubuleassociated Tau protein, elevating the association of Tau proteins with microtubules and enhancing the formation of toxic Tau aggregates (Jinwal et al 2010).…”

Functional Protein Interactions in Steroid Receptor-Chaperone Complexes

“…The aim of targeting and pharmacological manipulation of the Hsp90 chaperoning system has led to the ongoing development and clinical evaluation of novel Hsp90 and chaperone inhibitors for potential application in therapies against selected malignancies (Donnelly et al, 2010;Kim et al, 2009), syndromes arising from dysfunctional protein folding and neurodegenerative diseases (Jinwal et al, 2010). With growing understanding of the novel mechanisms through which Hsp90 cochaperones modulate the function of specific clients, strategies are now evolving for the targeting of chaperone-client interactions in a wide range of human diseases (De Leon et al, 2011;Gray et al, 2008).…”