Bending Tau into Shape: The Emerging Role of Peptidyl-Prolyl Isomerases in Tauopathies

Koren, John; Jinwal, Umesh K.; Davey, Zachary; Kiray, Janine; Arulselvam, Karthik; Dickey, Chad A.

doi:10.1007/s12035-011-8182-4

Cited by 30 publications

(21 citation statements)

References 70 publications

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“…In vitro studies demonstrated that PPIase activity of FKBP51 regulates and balances the phosphorylation state of tau for microtubule stabilization (Jinwal et al 2010;Koren et al 2011). Interestingly, knockdown of FKBP51 dramatically reduced tau levels while inhibiting its PPIase activity led to increased stability and accumulation of phosphorylated tau (Jinwal et al 2010).…”

Section: Fkbp51mentioning

confidence: 99%

Functions of the Hsp90-Binding FKBP Immunophilins

Guy

Garcia

Sivils

et al. 2014

Subcellular Biochemistry

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Hsp90 functionally interacts with a broad array of client proteins, but in every case examined Hsp90 is accompanied by one or more co-chaperones. One class of co-chaperone contains a tetratricopeptide repeat domain that targets the co-chaperone to the C-terminal region of Hsp90. Within this class are Hsp90-binding peptidylprolyl isomerases, most of which belong to the FK506-binding protein (FKBP) family. Despite the common association of FKBP co-chaperones with Hsp90, it is now clear that the client protein influences, and is influenced by, the particular FKBP bound to Hsp90. Examples include Xap2 in aryl hydrocarbon receptor complexes and FKBP52 in steroid receptor complexes. In this chapter, we discuss the known functional roles played by FKBP co-chaperones and, where possible, relate distinctive functions to structural differences between FKBP members.

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Section: Fkbp51mentioning

confidence: 99%

Functions of the Hsp90-Binding FKBP Immunophilins

Guy

Garcia

Sivils

et al. 2014

Subcellular Biochemistry

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“…Indeed, genetic studies have shown that PPIases are essential to the function/folding of proteins important in cancer, neurodegenerative disorders, viral infection, and psychiatric disorders. 4–7 …”

Section: Introductionmentioning

confidence: 99%

Peptidyl-Proline Isomerases (PPIases): Targets for Natural Products and Natural Product-Inspired Compounds

2016

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Peptidyl-proline isomerases (PPIases) are a chaperone superfamily comprising the FK506-binding proteins (FKBPs), cyclophilins, and parvulins. PPIases catalyze the cis/trans isomerization of proline, acting as a regulatory switch during folding, activation, and/or degradation of many proteins. These “clients” include proteins with key roles in cancer, neurodegeneration, and psychiatric disorders, suggesting that PPIase inhibitors could be important therapeutics. However, the active site of PPIases is shallow, solvent-exposed, and well conserved between family members, making selective inhibitor design challenging. Despite these hurdles, macrocyclic natural products, including FK506, rapamycin, and cyclosporin, bind PPIases with nanomolar or better affinity. De novo attempts to derive new classes of inhibitors have been somewhat less successful, often showcasing the “undruggable” features of PPIases. Interestingly, the most potent of these next-generation molecules tend to integrate features of the natural products, including macrocyclization or proline mimicry strategies. Here, we review recent developments and ongoing challenges in the inhibition of PPIases, with a focus on how natural products might inform the creation of potent and selective inhibitors.

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“…PTMs are also involved in the effect of FKBP51 on microtubule dynamics. It is assumed that phosphorylation of tau leads to its dissociation from microtubules and adoption of the trans configuration of specific peptidylprolyl bonds, while the association of phosphorylated tau with FKBP51 promotes its dephosphorylation and cis configuration that is required for microtubule association [71][72][73].…”

Section: On or Off? Fkbp51 Associates With Both Kinases And Phosphatasesmentioning

confidence: 99%

Post-translational modifications and stress adaptation: the paradigm of FKBP51

Rein

2020

Biochemical Society Transactions

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Adaptation to stress is a fundamental requirement to cope with changing environmental conditions that pose a threat to the homeostasis of cells and organisms. Post-translational modifications (PTMs) of proteins represent a possibility to quickly produce proteins with new features demanding relatively little cellular resources. FK506 binding protein (FKBP) 51 is a pivotal stress protein that is involved in the regulation of several executers of PTMs. This mini-review discusses the role of FKBP51 in the function of proteins responsible for setting the phosphorylation, ubiquitination and lipidation of other proteins. Examples include the kinases Akt1, CDK5 and GSK3β, the phosphatases calcineurin, PP2A and PHLPP, and the ubiquitin E3-ligase SKP2. The impact of FKBP51 on PTMs of signal transduction proteins significantly extends the functional versatility of this protein.As a stress-induced protein, FKBP51 uses re-setting of PTMs to relay the effect of stress on various signaling pathways.

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Bending Tau into Shape: The Emerging Role of Peptidyl-Prolyl Isomerases in Tauopathies

Cited by 30 publications

References 70 publications

Functions of the Hsp90-Binding FKBP Immunophilins

Functions of the Hsp90-Binding FKBP Immunophilins

Peptidyl-Proline Isomerases (PPIases): Targets for Natural Products and Natural Product-Inspired Compounds

Post-translational modifications and stress adaptation: the paradigm of FKBP51

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