Browse
Submit Data
Databases
API
Help

Dataset Information

24 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

FKBP65-dependent peptidyl-prolyl isomerase activity potentiates the lysyl hydroxylase 2-driven collagen cross-link switch.

ABSTRACT: Bruck Syndrome is a connective tissue disease associated with inactivating mutations in lysyl hydroxylase 2 (LH2/PLOD2) or FK506 binding protein 65 (FKBP65/FKBP10). However, the functional relationship between LH2 and FKBP65 remains unclear. Here, we postulated that peptidyl prolyl isomerase (PPIase) activity of FKBP65 positively modulates LH2 enzymatic activity and is critical for the formation of hydroxylysine-aldehyde derived intermolecular collagen cross-links (HLCCs). To test this hypothesis, we analyzed collagen cross-links in Fkbp10-null and -wild-type murine embryonic fibroblasts. Although LH2 protein levels did not change, FKBP65 deficiency significantly diminished HLCCs and increased the non-hydroxylated lysine-aldehyde-derived collagen cross-links (LCCs), a pattern consistent with loss of LH2 enzymatic activity. The HLCC-to-LCC ratio was rescued in FKBP65-deficient murine embryonic fibroblasts by reconstitution with wild-type but not mutant FKBP65 that lacks intact PPIase domains. Findings from co-immunoprecipitation, protein-fragment complementation, and co-immunofluorescence assays showed that LH2 and FKBP65 are part of a common protein complex. We conclude that FKBP65 regulates LH2-mediated collagen cross-linking. Because LH2 promotes fibrosis and cancer metastasis, our findings suggest that pharmacologic strategies to target FKBP65 and LH2 may have complementary therapeutic activities.

SUBMITTER: Chen Y

PROVIDER: S-EPMC5380960 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma.

Project description:Epithelial tumor metastasis is preceded by an accumulation of collagen cross-links that heighten stromal stiffness and stimulate the invasive properties of tumor cells. However, the biochemical nature of collagen cross-links in cancer is still unclear. Here, we postulated that epithelial tumorigenesis is accompanied by changes in the biochemical type of collagen cross-links. Utilizing resected human lung cancer tissues and a p21CIP1/WAF1-deficient, K-rasG12D-expressing murine metastatic lung cancer model, we showed that, relative to normal lung tissues, tumor stroma contains higher levels of hydroxylysine aldehyde-derived collagen cross-links (HLCCs) and lower levels of lysine aldehyde-derived cross-links (LCCs), which are the predominant types of collagen cross-links in skeletal tissues and soft tissues, respectively. Gain- and loss-of-function studies in tumor cells showed that lysyl hydroxylase 2 (LH2), which hydroxylates telopeptidyl lysine residues on collagen, shifted the tumor stroma toward a high-HLCC, low-LCC state, increased tumor stiffness, and enhanced tumor cell invasion and metastasis. Together, our data indicate that LH2 enhances the metastatic properties of tumor cells and functions as a regulatory switch that controls the relative abundance of biochemically distinct types of collagen cross-links in the tumor stroma.

| S-EPMC4362236 | biostudies-literature

The peptidyl prolyl cis/trans isomerase FKBP38 determines hypoxia-inducible transcription factor prolyl-4-hydroxylase PHD2 protein stability.

Project description:The heterodimeric hypoxia-inducible transcription factors (HIFs) are central regulators of the response to low oxygenation. HIF-alpha subunits are constitutively expressed but rapidly degraded under normoxic conditions. Oxygen-dependent hydroxylation of two conserved prolyl residues by prolyl-4-hydroxylase domain-containing enzymes (PHDs) targets HIF-alpha for proteasomal destruction. We identified the peptidyl prolyl cis/trans isomerase FK506-binding protein 38 (FKBP38) as a novel interactor of PHD2. Yeast two-hybrid, glutathione S-transferase pull-down, coimmunoprecipitation, colocalization, and mammalian two-hybrid studies confirmed specific FKBP38 interaction with PHD2, but not with PHD1 or PHD3. PHD2 and FKBP38 associated with their N-terminal regions, which contain no known interaction motifs. Neither FKBP38 mRNA nor protein levels were regulated under hypoxic conditions or after PHD inhibition, suggesting that FKBP38 is not a HIF/PHD target. Stable RNA interference-mediated depletion of FKBP38 resulted in increased PHD hydroxylation activity and decreased HIF protein levels and transcriptional activity. Reconstitution of FKBP38 expression abolished these effects, which were independent of the peptidyl prolyl cis/trans isomerase activity. Downregulation of FKBP38 did not affect PHD2 mRNA levels but prolonged PHD2 protein stability, suggesting that FKBP38 is involved in PHD2 protein regulation.

| S-EPMC1899990 | biostudies-literature

Disentangling mechanisms involved in collagen pyridinoline cross-linking: The immunophilin FKBP65 is critical for dimerization of lysyl hydroxylase 2.

Project description:Collagens are subjected to extensive posttranslational modifications, such as lysine hydroxylation. Bruck syndrome (BS) is a connective tissue disorder characterized at the molecular level by a loss of telopeptide lysine hydroxylation, resulting in reduced collagen pyridinoline cross-linking. BS results from mutations in the genes coding for lysyl hydroxylase (LH) 2 or peptidyl-prolyl cis-trans isomerase (PPIase) FKBP65. Given that the immunophilin FKBP65 does not exhibit LH activity, it is likely that LH2 activity is somehow dependent on FKPB65. In this report, we provide insights regarding the interplay between LH2 and FKBP65. We found that FKBP65 forms complexes with LH2 splice variants LH2A and LH2B but not with LH1 and LH3. Ablating the catalytic activity of FKBP65 or LH2 did not affect complex formation. Both depletion of FKBP65 and inhibition of FKBP65 PPIase activity reduced the dimeric (active) form of LH2 but did not affect the binding of monomeric (inactive) LH2 to procollagen Iα1. Furthermore, we show that LH2A and LH2B cannot form heterodimers with each other but are able to form heterodimers with LH1 and LH3. Collectively, our results indicate that FKBP65 is linked to pyridinoline cross-linking by specifically mediating the dimerization of LH2. Moreover, FKBP65 does not interact with LH1 and LH3, explaining why in BS triple-helical hydroxylysines are not affected. Our results provide a mechanistic link between FKBP65 and the loss of pyridinolines and may hold the key to future treatments for diseases related to collagen cross-linking anomalies, such as fibrosis and cancer.

| S-EPMC4932945 | biostudies-literature

Post-translational Modifications of the Peptidyl-Prolyl Isomerase Pin1.

Project description:The peptidyl-prolyl cis/trans isomerase (PPIase) Pin1 is a unique enzyme that only binds to Ser/Thr-Pro peptide motifs after phosphorylation and regulates the conformational changes of the bond. The Pin1-catalyzed isomerization upon phosphorylation can have profound effects on substrate biological functions, including their activity, stability, assembly, and subcellular localization, affecting its role in intracellular signaling, transcription, and cell cycle progression. The functions of Pin1 are regulated by post-translational modifications (PTMs) in many biological processes, which include phosphorylation, ubiquitination, SUMOylation and oxidation. Phosphorylation of different Pin1 sites regulates Pin1 enzymatic activity, binding ability, localization, and ubiquitination by different kinases under various cellular contexts. Moreover, SUMOylation and oxidation have been shown to downregulate Pin1 activity. Although Pin1 is tightly regulated under physiological conditions, deregulation of Pin1 PTMs contributes to the development of human diseases including cancer and Alzheimer's disease (AD). Therefore, manipulating the PTMs of Pin1 may be a promising therapeutic option for treating various human diseases. In this review, we focus on the molecular mechanisms of Pin1 regulation by PTMs and the major impact of Pin1 PTMs on the progression of cancer and AD.

| S-EPMC7064559 | biostudies-literature

Peptidyl-Prolyl Cis/Trans Isomerase Pin1 and Alzheimer's Disease.

Project description:Alzheimer's disease (AD) is the most common cause of dementia with cognitive decline. The neuropathology of AD is characterized by intracellular aggregation of neurofibrillary tangles consisting of hyperphosphorylated tau and extracellular deposition of senile plaques composed of beta-amyloid peptides derived from amyloid precursor protein (APP). The peptidyl-prolyl cis/trans isomerase Pin1 binds to phosphorylated serine or threonine residues preceding proline and regulates the biological functions of its substrates. Although Pin1 is tightly regulated under physiological conditions, Pin1 deregulation in the brain contributes to the development of neurodegenerative diseases, including AD. In this review, we discuss the expression and regulatory mechanisms of Pin1 in AD. We also focus on the molecular mechanisms by which Pin1 controls two major proteins, tau and APP, after phosphorylation and their signaling cascades. Moreover, the major impact of Pin1 deregulation on the progression of AD in animal models is discussed. This information will lead to a better understanding of Pin1 signaling pathways in the brain and may provide therapeutic options for the treatment of AD.

| S-EPMC7243138 | biostudies-literature

Distribution of Peptidyl-Prolyl Isomerase (PPIase) in the Archaea.

Project description:Cis-trans isomerization of the peptide bond prior to proline is an intrinsically slow process but plays an essential role in protein folding. In vivo cis-trans isomerization reaction is catalyzed by Peptidyl-prolyl isomerase (PPIases), a category of proteins widely distributed among all the three domains of life. The present study is majorly focused on the distribution of different types of PPIases in the archaeal domain. All the three hitherto known families of PPIases (namely FKBP, Cyclophilin and parvulin) were studied to identify the evolutionary conservation across the phylum archaea. The basic function of cyclophilin, FKBP and parvulin has been conserved whereas the sequence alignment suggested variations in each clade. The conserved residues within the predicted motif of each family are unique. The available protein structures of different PPIase across various domains were aligned to ascertain the structural variation in the catalytic site. The structural alignment of native PPIase proteins among various groups suggested that the apo-protein may have variable conformations but when bound to their specific inhibitors, they attain similar active site configuration. This is the first study of its kind which explores the distribution of archaeal PPIases, along with detailed structural and functional analysis of each type of PPIase found in archaea.

| S-EPMC8530231 | biostudies-literature

A Selective, Cell-Permeable Nonphosphorylated Bicyclic Peptidyl Inhibitor against Peptidyl-Prolyl Isomerase Pin1.

Project description:Pin1 regulates the levels and functions of phosphoproteins by catalyzing phosphorylation-dependent cis/trans isomerization of peptidyl-prolyl bonds. Previous Pin1 inhibitors contained phosphoamino acids, which are metabolically unstable and have poor membrane permeability. In this work, we report a cell-permeable and metabolically stable nonphosphorylated bicyclic peptide as a potent and selective Pin1 inhibitor, which inhibited the intracellular Pin1 activity in cultured mammalian cells but had little effect on other isomerases such as Pin4, FKBP12, or cyclophilin A.

| S-EPMC4594195 | biostudies-literature

Activities of prolyl hydroxylase, lysyl hydroxylase, collagen galactosyltransferase and collagen glucosyltransferase in the liver of rats with hepatic injury.

Project description:The activities of four enzymes catalysing post-translational modifications of the collagen polypeptide chains were assayed in the livers of rats with experimental hepatic injury. The liver injury was induced by injecting carbon tetrachloride twice weekly, and assays of the enzymic activities were carried out 2 and 4 weeks after commencement of administration of carbon tetrachloride. The liver homogenates were preincubated with Triton X-100 before the assays, because such treatment was found to increase the activities of all four enzymes in the supernatants of liver homogenates. The activities of all four enzymes had increased by 2 weeks after commencement of carbon tetrachloride administration. No increase was found in the collagen content of the livers at this stage and thus an increase in all four enzyme activities preceded an increase in the collagen content of the liver. A further slight increase was found in three of the enzyme activities during the subsequent 2 weeks of the experiment, whereas no further increase was found in the collagen galactosyltransferase activity. A statistically significant correlation was found between all four enzyme activities, but the magnitude of the increases varied considerably. The largest increase was found in lysyl hydroxylase activity, and at 4 weeks the magnitude of this was about three times that of the collagen galactosyltransferase activity. The results thus indicate that the increased enzyme activities cannot be explained simply by an increase in the number of collagen-producing cells having similar enzyme activity patterns to those of the cells initially present in the liver.

| S-EPMC1168471 | biostudies-other

Pathologic role of peptidyl-prolyl isomerase Pin1 in pulmonary artery remodeling.

Project description:Peptidyl-prolyl isomerase Pin1 is crucial for cell proliferation, but its role in pulmonary artery remodeling (PAR) is unclear. In the present study, we aimed to evaluate the expression and contribution of Pin1 in PAR. Treatment with Pin1 inhibitor Juglone or Pin1-specific siRNAs ameliorated the expression of Pin1 and proliferating cell nuclear antigen (PCNA) in human pulmonary artery smooth muscle cells (PASMCs) in vitro, and Juglone treatment arrested the cell cycle at the G1 phase. Treatment with transforming growth factor β1 (TGF-β1) also enhanced Pin1 expression and PASMC proliferation. Immunohistochemical staining revealed that Pin1 and PCNA expression levels were increased and positively correlated with each other in PAR samples from humans and monocrotaline-treated Sprague-Dawley rats; these proteins were mainly localized in arteries undergoing remodeling, as well as inflammatory cells, and hyperplastic bronchial epithelial cells. Intraperitoneal injection of Juglone also led to morphologic and hemodynamic changes in PAR rats. Additionally, PAR rats displayed higher serum and lung TGF-β1 levels compared with controls, while administration of Juglone to PAR rats suppressed serum and lung TGF-β1 levels. The findings in this study suggest that TGF-β1 and Pin1 constitute a positive feedback loop, which plays an important role in the pathophysiology of PAR.

| S-EPMC8581927 | biostudies-literature

Regulation of eukaryotic protein kinases by Pin1, a peptidyl-prolyl isomerase.

Project description:The peptidyl-prolyl isomerase Pin1 cooperates with proline-directed kinases and phosphatases to regulate multiple oncogenic pathways. Pin1 specifically recognizes phosphorylated Ser/Thr-Pro motifs in proteins and catalyzes their cis-trans isomerization. The Pin1-catalyzed conformational changes determine the stability, activity, and subcellular localization of numerous protein substrates. We conducted a survey of eukaryotic protein kinases that are regulated by Pin1 and whose Pin1 binding sites have been identified. Our analyses reveal that Pin1 target sites in kinases do not fall exclusively within the intrinsically disordered regions of these enzymes. Rather, they fall into three groups based on their location: (i) within the catalytic kinase domain, (ii) in the C-terminal kinase region, and (iii) in regulatory domains. Some of the kinases downregulated by Pin1 activity are tumor-suppressing, and all kinases upregulated by Pin1 activity are functionally pro-oncogenic. These findings further reinforce the rationale for developing Pin1-specific inhibitors as attractive pharmaceuticals for cancer therapy.

| S-EPMC9992314 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data