Inhibition of the FKBP family of peptidyl prolyl isomerases induces abortive translocation and degradation of the cellular prion protein

Stocki, Paweł; Sawicki, Maxime; Mays, Charles E.; Hong, Seo Jung; Chapman, Daniel C.; Westaway, David; Williams, David B.

doi:10.1091/mbc.e15-10-0729

Cited by 21 publications

(24 citation statements)

References 47 publications

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“…49 FKBP38 (gene FKBP8 ) has a single PPIase domain, which is normally inactive. However, this family member also has a TPR domain and a putative calmodulin-binding motif.…”

Section: Superfamily Of Ppiasesmentioning

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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“…49 FKBP38 (gene FKBP8 ) has a single PPIase domain, which is normally inactive. However, this family member also has a TPR domain and a putative calmodulin-binding motif.…”

Section: Superfamily Of Ppiasesmentioning

confidence: 99%

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

2016

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“…9). These findings have been interpreted to mean that FKBP family proteins have distinct roles in different subtypes of physiological or pathological context [15,37,38]. Our data provide a possible strategy for regulating the function of FKBP25, developing specific inhibitors of nitrosative stress.…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 76%

Elucidation of the FKBP25-60S Ribosomal Protein L7a Stress Response Signaling During Ischemic Injury

Jiang

Yang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Peptidyl-prolyl cis-trans isomerase FKBP25 is a member of the FK506-binding proteins family which has peptidyl-prolyl cis/trans isomerase domain. The biological function and pathophysiologic role of FKBP25 remain elusive. Methods: The spatio-temporal changes in expression of endothelial FKBP25 upon oxygen-glucose deprivation (OGD) treatment were examined by Western blot and immunofluorescence. The immunoprecipitation and fluorescence resonance energy transfer (FRET) were used to address the interacting proteins with FKBP25. Results: In the present study, nuclear translocation of FKBP25 was observed following OGD in cultured endothelial cells. Intriguingly, FKBP25 nuclear translocation was further validated in peroxynitrite (ONOO^-)-treated endothelial cells. Coimmunoprecipitation and FRET data indicated that FKBP25 translocated into the nucleus, in which it interacted with 60S ribosomal protein L7a, while overexpression FKBP25 protect endothelial cells against OGD injury. Conclusion: Our findings reveal that the nuclear import of FKBP25 and binding with 60S ribosomal protein L7a are protective stress responses to ischemia/nitrosaive stress injury.

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“…One difficulty to this strategy is that prion diseases are hard to diagnose early on, and therefore, use of the drug in this manner must be preceded by better detection methods. The study by Stocki, et al also implicated FK binding protein 10 as a target for blocking prion disease, as results from knocking down this molecule mirrored those from FK506 treatment [79].…”

Section: Targeting Autophagymentioning

confidence: 98%

“…Treatment of prion infected mice with calcineurin inhibitor FK506 diminishes clinical disease [77]. Furthermore, treatment of mouse neuroblastoma cells with FK506 results in loss of PrP TSE , and treatment of cells with FK506 blocks cellular PrP translocation to the ER and promotes degradation in a Ca +2 independent manner [75,79]. This is of importance because PrP TSE cannot be produced in the absence of PrP c [79], and FK506 could be used to block progression early in disease.…”

Section: Targeting Autophagymentioning

confidence: 99%

“…Furthermore, treatment of mouse neuroblastoma cells with FK506 results in loss of PrP TSE , and treatment of cells with FK506 blocks cellular PrP translocation to the ER and promotes degradation in a Ca +2 independent manner [75,79]. This is of importance because PrP TSE cannot be produced in the absence of PrP c [79], and FK506 could be used to block progression early in disease. One difficulty to this strategy is that prion diseases are hard to diagnose early on, and therefore, use of the drug in this manner must be preceded by better detection methods.…”

Section: Targeting Autophagymentioning

confidence: 99%

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Prion disease and endoplasmic reticulum stress pathway correlations and treatment pursuits

Satterfield

Pritchett

Cruz

et al. 2017

Endoplasmic Reticulum Stress in Diseases

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Background: Transmissible spongiform encephalopathies are a collection of rare neurodegenerative disorders characterized by loss of neuronal cells, astrocytosis, and plaque formation. The causative agent of these diseases is thought to be abnormally folded prions and is characterized by a conformational change from normal, cellular prion protein (PrPc) to the abnormal form (PrPTSE). Although, there is evidence that normal prion protein can contribute to these disorders. The unfolded protein response, a conserved series of pathways involved in resolving stress associated with unfolded protein accumulation in the Endoplasmic Reticulum (ER), has been shown to play a role in regulating the development of prion diseases. Methods: This review chose papers based on their relevance to current studies involved in prion protein synthesis and transformation, identifies various links between prion diseases and ER stress, and reports on current and potential treatments as they relate to ER stress and prion diseases. Conclusion: For the advancement of prion disease treatment, it is important to understand the mechanisms involved in prion formation, and ER stress is implicated in prion disease progression. Therefore, targeting the ER or pathways involved in response to stress in the ER may help us treat prion diseases.

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Inhibition of the FKBP family of peptidyl prolyl isomerases induces abortive translocation and degradation of the cellular prion protein

Cited by 21 publications

References 47 publications

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

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

Elucidation of the FKBP25-60S Ribosomal Protein L7a Stress Response Signaling During Ischemic Injury

Prion disease and endoplasmic reticulum stress pathway correlations and treatment pursuits

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