Structure and Activity of the Peptidyl-Prolyl Isomerase Domain from the Histone Chaperone Fpr4 toward Histone H3 Proline Isomerization

Monneau, Yoan R.; Soufari, Heddy; Nelson, Christopher J.; Mackereth, Cameron D.

doi:10.1074/jbc.m113.479964

Cited by 19 publications

(18 citation statements)

References 56 publications

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“…The C-terminal PPI of FKBP39, which has a pI of 10, did not show in our hands any interaction with histones in vitro . On the other hand, the PPI domain of Fpr4, which is similarly positively charged, does turn over H3 histone peptides and has a charge-compatible active site [12,14] . In order to establish which part of FKBP39 is responsible for the abovementioned interactions, two further protein A pull-down experiments were carried out: one with the amino-terminal half and the other one with the carboxy-terminal half of the protein (including the PPI domain).…”

Section: Resultsmentioning

confidence: 99%

“…Perhaps due to its unique role, nucleoplasmin's similarity to a group of proteins implicated in chromatin regulation, such as the plant type 2 histone deacetylases, or HD-tuins [7–11] , and the yeast Fpr3 and Fpr4 proteins [12–14] , has never been noticed. The family's defining feature is an N-terminal domain of unknown structure with a signature motif of conserved hydrophobic and two potentially catalytic residues—a histidine and an aspartate [15] .…”

Section: Introductionmentioning

confidence: 99%

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The Pentameric Nucleoplasmin Fold Is Present in Drosophila FKBP39 and a Large Number of Chromatin-Related Proteins

Edlich‐Muth

Artero

Callow

et al. 2015

Journal of Molecular Biology

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Nucleoplasmin is a histone chaperone that consists of a pentameric N-terminal domain and an unstructured C-terminal tail. The pentameric core domain, a doughnut-like structure with a central pore, is only found in the nucleoplasmin family. Here, we report the first structure of a nucleoplasmin-like domain (NPL) from the unrelated Drosophila protein, FKBP39, and we present evidence that this protein associates with chromatin. Furthermore, we show that two other chromatin proteins, Arabidopsis thaliana histone deacetylase type 2 (HD2) and Saccharomyces cerevisiae Fpr4, share the NPL fold and form pentamers, or a dimer of pentamers in the case of HD2. Thus, we propose a new family of proteins that share the pentameric nucleoplasmin-like NPL domain and are found in protists, fungi, plants and animals.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Pentameric Nucleoplasmin Fold Is Present in Drosophila FKBP39 and a Large Number of Chromatin-Related Proteins

Edlich‐Muth

Artero

Callow

et al. 2015

Journal of Molecular Biology

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“…While there are good examples to support this model ( 9 , 10 , 96 , 97 ), a growing body of literature demonstrates that these proteins also have non-catalytic impacts on biological processes, presumably via direct binding events ( 27 , 28 , 98 , 99 ). For example, we recently showed that the FKBP domain of yeast Fpr4, which can target histone prolines ( 10 , 100 ) could also affect chromatin fiber self-association independently of catalytic function ( 101 ). This illustrates that targets of catalytic action may reside close to or within binding partners of FKBPs.…”

Section: Discussionmentioning

confidence: 99%

The prolyl isomerase FKBP25 regulates microtubule polymerization impacting cell cycle progression and genomic stability

Dilworth

Gudavicius

et al. 2018

Nucleic Acids Research

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FK506 binding proteins (FKBPs) catalyze the interconversion of cis-trans proline conformers in proteins. Importantly, FK506 drugs have anti-cancer and neuroprotective properties, but the effectors and mechanisms underpinning these properties are not well understood because the cellular function(s) of most FKBP proteins are unclear. FKBP25 is a nuclear prolyl isomerase that interacts directly with nucleic acids and is associated with several DNA/RNA binding proteins. Here, we show the catalytic FKBP domain binds microtubules (MTs) directly to promote their polymerization and stabilize the MT network. Furthermore, FKBP25 associates with the mitotic spindle and regulates entry into mitosis. This interaction is important for mitotic spindle dynamics, as we observe increased chromosome instability in FKBP25 knockdown cells. Finally, we provide evidence that FKBP25 association with chromatin is cell-cycle regulated by Protein Kinase C phosphorylation. This disrupts FKBP25–DNA contacts during mitosis while maintaining its interaction with the spindle apparatus. Collectively, these data support a model where FKBP25 association with chromatin and MTs is carefully choreographed to ensure faithful genome duplication. Additionally, they highlight that FKBP25 is a MT-associated FK506 receptor and potential therapeutic target in MT-associated diseases.

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“…Given these findings, histone H1 may be a target for prolyl isomerization by FKBP25 in the regulation of DNA repair. If true, this would imply that FKBP25's catalytic activity might promote HR through remodeling the chromatin environment, which would be similar to the histone-binding/chromatin targets and recombination checkpoint functions of the orthologous nuclear FKBPs in yeast (Hochwagen et al 2005;Nelson et al 2006;Macqueen and Roeder 2009;Monneau et al 2013;Ohkuni et al 2014;Edlich-Muth et al 2015;Leung et al 2017). While further work is required, a role in DNA damage repair may explain FKBP25's, so far inexplicable, association with chromatin.…”

Section: Discussionmentioning

confidence: 99%

FKBP25 participates in DNA double-strand break repair

Dilworth

Gong

Miller

et al. 2020

Biochem. Cell Biol.

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FK506-binding proteins (FKBPs) alter the conformation of proteins via cis–trans isomerization of prolyl-peptide bonds. While this activity can be demonstrated in vitro, the intractability of detecting prolyl isomerization events in cells has limited our understanding of the biological processes regulated by FKBPs. Here we report that FKBP25 is an active participant in the repair of DNA double-strand breaks (DSBs). FKBP25 influences DSB repair pathway choice by promoting homologous recombination (HR) and suppressing single-strand annealing (SSA). Consistent with this observation, cells depleted of FKBP25 form fewer Rad51 repair foci in response to etoposide and ionizing radiation, and they are reliant on the SSA repair factor Rad52 for viability. We find that FKBP25’s catalytic activity is required for promoting DNA repair, which is the first description of a biological function for this enzyme activity. Consistent with the importance of the FKBP catalytic site in HR, rapamycin treatment also impairs homologous recombination, and this effect is at least in part independent of mTor. Taken together these results identify FKBP25 as a component of the DNA DSB repair pathway.

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Structure and Activity of the Peptidyl-Prolyl Isomerase Domain from the Histone Chaperone Fpr4 toward Histone H3 Proline Isomerization

Cited by 19 publications

References 56 publications

The Pentameric Nucleoplasmin Fold Is Present in Drosophila FKBP39 and a Large Number of Chromatin-Related Proteins

The Pentameric Nucleoplasmin Fold Is Present in Drosophila FKBP39 and a Large Number of Chromatin-Related Proteins

The prolyl isomerase FKBP25 regulates microtubule polymerization impacting cell cycle progression and genomic stability

FKBP25 participates in DNA double-strand break repair

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