Affinage

TP53RK

EKC/KEOPS complex subunit TP53RK · UniProt Q96S44

Length
253 aa
Mass
28.2 kDa
Annotated
2026-06-10
25 papers in source corpus 19 papers cited in narrative 19 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TP53RK (PRPK/Bud32) is an atypical RIO-family Ser/Thr protein kinase that is a core, evolutionarily conserved subunit of the KEOPS complex, where its principal contribution to tRNA t6A modification is enzymatic ATPase rather than classical kinase activity (PMID:12023889, PMID:35525560). Within KEOPS — a linear heteropentamer (Gon7–Pcc1–Kae1–Bud32–Cgi121) — TP53RK contacts and is held in an inactive kinase configuration by its partner Kae1/OSGEP, while its ATPase activity drives tRNA substrate recruitment and positions the A37 base in the Kae1 active site, with a C-terminal-tail arginine contacting a flipped-out tRNA base to enable the modification-competent conformation (PMID:19172740, PMID:25735745, PMID:35525560, PMID:39639027). Crystallography of the human PRPK–TPRKB complex shows PRPK in an active, nucleotide-bound conformation and maps the Galloway-Mowat-associated truncation K238Nfs*2 to the OSGEP-binding interface required for complex assembly; loss-of-function TP53RK variants cause Galloway-Mowat syndrome (PMID:33547416, PMID:36116039). Beyond KEOPS, TP53RK acts as a kinase whose activity is switched on by upstream Akt/PKB phosphorylation at Ser-250 and by TOPK, phosphorylates substrates including p53 at Ser-15 and survivin/Birc5 at Thr-34 to control survivin stability and nuclear translocation, and supports CDC7 stability and replication-fork progression, linking it to apoptosis restraint, cancer progression, renal fibrosis, and DNA replication (PMID:12914926, PMID:17712528, PMID:29904102, PMID:29483219, PMID:37382161, PMID:41102525). Its substrate preference is unusual among Ser/Thr kinases, favoring acidic, carboxylate-flanked seryl residues (PMID:12207926).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2002 High

    Established that the TP53RK ortholog Bud32 is a genuine, if atypical, Ser/Thr protein kinase, defining the catalytic machinery later found to be unconventional.

    Evidence Recombinant yeast Bud32 with site-directed mutagenesis and in vitro kinase/mobility-shift assays

    PMID:12023889

    Open questions at the time
    • Physiological substrates not identified
    • Functional consequence of lacking the canonical ATP-binding lysine unresolved
  2. 2002 Medium

    Defined the kinase's unusual substrate specificity for acidic, carboxylate-flanked sites, distinguishing it from basophilic and proline-directed kinases.

    Evidence In vitro kinase assays on acidic proteins and synthetic peptides

    PMID:12207926

    Open questions at the time
    • Specificity determinants on the enzyme not mapped
    • In vivo relevance of acidic preference untested
  3. 2003 Medium

    Linked human PRPK to p53 by showing it phosphorylates p53 Ser-15 and binds p53, with conservation back to yeast Bud32, framing an early tumor-suppressor signaling role.

    Evidence In vitro kinase assay, protein interaction assay, and yeast complementation

    PMID:12914926

    Open questions at the time
    • In-cell p53 phosphorylation not demonstrated
    • Later work reports PRPK does not phosphorylate p53 directly, leaving the relationship unsettled
  4. 2003 Medium

    Identified TPRKB/CGI-121 as a direct PRPK partner that can inhibit PRPK–p53 association, introducing a regulatory binding partner.

    Evidence Yeast two-hybrid, reciprocal in vivo and in vitro co-IP, recombinant competition assay

    PMID:12659830

    Open questions at the time
    • Mechanism of inhibition (steric vs allosteric) unresolved
    • Effect on kinase catalysis vs substrate binding not separated
  5. 2004 Medium

    Connected Bud32 to the glycoprotease Kae1 and revealed non-kinase functions, foreshadowing the structural/enzymatic partnership at the heart of KEOPS.

    Evidence Yeast two-hybrid, in vitro kinase assay with phosphosite mapping (Grx4 Ser-134), and complementation

    PMID:14519092

    Open questions at the time
    • Functional significance of the Grx4 phosphorylation unknown
    • Nature of the non-catalytic role not defined
  6. 2006 Medium

    Showed the Rab-family GTPase Ray/Rab35 binds PRPK and, in a GTP-dependent manner, relocalizes it and suppresses PRPK-driven p53 transcriptional activity, adding spatial regulation.

    Evidence Co-IP, immunofluorescence localization, and transcriptional reporter assays with GTPase mutants

    PMID:16600182

    Open questions at the time
    • Physiological trigger for relocalization unknown
    • Relationship to KEOPS function not addressed
  7. 2007 High

    Placed PRPK downstream of Akt/PKB by identifying Ser-250 phosphorylation as an activating input, establishing an upstream regulatory kinase.

    Evidence In vitro Akt kinase assay, phospho-specific antibody, Ser250Ala mutant, cell co-transfection, and LY294002 inhibition

    PMID:17712528

    Open questions at the time
    • Whether Akt regulates KEOPS-associated PRPK function untested
    • Stimuli driving Akt-PRPK signaling not defined
  8. 2009 High

    Provided the structural basis for KEOPS regulation, showing Kae1 holds the Bud32 kinase site inactive and that the Kae1–Bud32 interface is required for complex function.

    Evidence X-ray crystallography of archaeal Kae1/Bud32 fusion, in vitro kinase repression assay, and yeast interface mutagenesis

    PMID:19172740

    Open questions at the time
    • Catalytic role of Bud32 within KEOPS not yet redefined as ATPase
    • Mechanism linking kinase site to telomere/transcription functions unclear
  9. 2015 High

    Defined the architecture and stoichiometry of the eukaryotic KEOPS complex as a linear heteropentamer and captured Bud32 with ADP in a canonical active site.

    Evidence X-ray crystallography of Bud32/Cgi121–ADP and analytical ultracentrifugation

    PMID:25735745

    Open questions at the time
    • Catalytic mechanism (kinase vs ATPase) within the assembled complex not resolved
    • tRNA-bound state not captured
  10. 2018 Medium

    Identified TOPK as an additional upstream kinase activating PRPK and linked active PRPK to skin carcinogenesis, supporting therapeutic targeting.

    Evidence siRNA knockdown, phosphorylation analysis, mouse cutaneous SCC model, and pharmacological inhibitors

    PMID:29904102

    Open questions at the time
    • TOPK phosphosite on PRPK not mapped
    • Relationship between TOPK and Akt inputs unresolved
  11. 2018 Medium

    Reassigned a key PRPK substrate by showing it does not phosphorylate p53 directly but phosphorylates survivin/Birc5 at Thr-34 to stabilize it and drive metastasis.

    Evidence In vitro kinase assay (negative for p53), knockdown, and in vivo colon cancer metastasis model

    PMID:29483219

    Open questions at the time
    • Contradiction with earlier p53 Ser-15 data not reconciled
    • How survivin phosphorylation confers stability mechanistically unclear
  12. 2019 Medium

    Revealed PRPK stabilizes TPRKB and that TPRKB has TP53-dependent, complex-independent behavior, dissecting subunit-specific functions.

    Evidence shRNA knockdown, proteasome-inhibition and PRPK co-expression rescue, proliferation assays

    PMID:31110156

    Open questions at the time
    • Mechanism of PRPK-mediated TPRKB stabilization unknown
    • Generalizability beyond tested cell models untested
  13. 2021 High

    Delivered the human PRPK–TPRKB structure in an active conformation and mapped a Galloway-Mowat truncation to the OSGEP-binding interface critical for KEOPS assembly.

    Evidence 2.53 Å crystal structure, PRPK-mutant OSGEP binding assay, and human KEOPS modeling

    PMID:33547416

    Open questions at the time
    • Catalytic output of the active conformation in human KEOPS not assayed
    • How disrupted assembly causes disease phenotype not shown
  14. 2022 High

    Redefined Bud32's primary KEOPS role as an ATPase required for t6A modification and tRNA recruitment/positioning, resolving the long-standing kinase-vs-enzyme question.

    Evidence In vitro ATPase, tRNA binding, and t6A modification assays plus yeast complementation

    PMID:35525560

    Open questions at the time
    • Whether the kinase activity has any KEOPS-independent in vivo role unsettled
    • Coupling between ATP hydrolysis and tRNA positioning mechanistically incomplete
  15. 2022 Medium

    Functionally validated TP53RK missense variants as loss-of-function causes of Galloway-Mowat syndrome using an in vivo developmental model.

    Evidence Xenopus morpholino knockdown with wild-type vs mutant human TP53RK mRNA rescue

    PMID:36116039

    Open questions at the time
    • Tissue-specific basis of the developmental phenotype unknown
    • Whether variants impair ATPase or assembly not separated
  16. 2023 High

    Connected TP53RK kinase activity to disease by showing it phosphorylates Birc5 to drive its nuclear translocation and downstream PI3K/Akt and MAPK signaling in renal fibrosis.

    Evidence Conditional cell-type-specific knockout mice, in vitro kinase assay, subcellular fractionation, and pharmacological inhibition

    PMID:37382161

    Open questions at the time
    • Direct mechanism of Birc5 nuclear import via phosphorylation not detailed
    • Relationship to KEOPS/t6A function unaddressed
  17. 2024 High

    Provided substrate-bound cryo-EM snapshots showing how a Bud32 C-terminal-tail arginine contacts a flipped-out tRNA base to enable the conformational change required for modification, clarifying its substrate-specificity contribution.

    Evidence Cryo-EM of KEOPS ± tRNA with C-terminal-tail mutagenesis and t6A/ATPase assays

    PMID:39639027

    Open questions at the time
    • Dynamics of ATPase cycle coupled to tRNA flipping not fully resolved
    • Human-complex equivalence of the tRNA contact untested
  18. 2025 Medium

    Linked TP53RK to DNA replication by showing it stabilizes CDC7 to sustain MCM phosphorylation and fork progression, with depletion causing replication stress independent of p53.

    Evidence CRISPR screen, knockdown/knockout, MCM ChIP, DNA fiber assay, co-expression analysis

    PMID:41102525

    Open questions at the time
    • Whether stabilization is kinase-dependent or via direct binding unclear
    • Connection to KEOPS/t6A activity not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TP53RK's two activities — KEOPS-embedded ATPase for tRNA modification versus free kinase phosphorylating survivin/CDC7-related targets — are partitioned in cells, and which underlies Galloway-Mowat pathology, remains unresolved.
  • No experiment separates KEOPS-dependent from kinase-dependent phenotypes in disease
  • Conflicting reports on p53 as a direct substrate not reconciled
  • Spatial/temporal control of substrate choice undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0003723 RNA binding 2 GO:0016740 transferase activity 2 GO:0016787 hydrolase activity 2 GO:0140657 ATP-dependent activity 2
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-8953854 Metabolism of RNA 2 R-HSA-69306 DNA Replication 1
Partners
AKT1BIRC5CDC7OSGEPPBKRAB35TPRKB
Complex memberships
KEOPS/EKC complex

Evidence

Reading pass · 19 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Yeast piD261/Bud32 (ortholog of TP53RK) is a Ser/Thr protein kinase; mutational analysis showed that despite low sequence similarity, invariant residues of protein kinases are conserved. Autophosphorylation at Ser-187 and Ser-189 in the activation loop is required for full catalytic activity; Ser→Ala mutation abolished the upshifted SDS/PAGE band and reduced catalytic activity. Notably, the protein lacks the canonical lysyl residue that interacts with ATP gamma-phosphate, replaced by a threonine. Recombinant protein expression in E. coli, site-directed mutagenesis, in vitro kinase assay, SDS/PAGE mobility shift The Biochemical journal High 12023889
2002 Yeast piD261/Bud32 preferentially phosphorylates acidic substrates in vitro, recognizing seryl residues specified by adjacent carboxylic side chains, distinguishing it from most Ser/Thr kinases that favor basic or proline-directed sites. In vitro kinase assay with acidic proteins and synthetic peptides Biochemical and biophysical research communications Medium 12207926
2003 Human PRPK (TP53RK) phosphorylates p53 at Ser-15 in vitro and interacts with p53 protein; yeast Bud32 also phosphorylates human p53 in vitro and interacts with it, demonstrating functional conservation across distant organisms. PRPK partially complements the growth defect of yeast lacking BUD32. In vitro kinase assay, protein-protein interaction assay, yeast complementation FEBS letters Medium 12914926
2003 CGI-121 (TPRKB) directly interacts with PRPK (TP53RK) both in vivo and in vitro. Recombinant CGI-121 inhibits the coprecipitation of p53 by recombinant PRPK in vitro, indicating CGI-121 can act as an inhibitor of PRPK–p53 binding. Yeast two-hybrid, co-immunoprecipitation in vivo and in vitro, recombinant protein competition assay Biochemical and biophysical research communications Medium 12659830
2004 Yeast Bud32 directly phosphorylates the glutaredoxin Grx4 at Ser-134 in vitro. Bud32 also interacts with the putative glycoprotease Kae1 (Ykr038/Kae1) and this interaction is evolutionarily conserved. The phosphotransferase activity of Bud32 is relevant to its in vivo function, but non-catalytic mutants that retain native conformation can partially complement gene deletion, indicating additional non-kinase roles. Yeast two-hybrid, in vitro kinase assay, phosphosite mapping, complementation of deletion mutant The Biochemical journal Medium 14519092
2006 The small Ras-like GTPase Ray/Rab1c (Rab35) directly binds PRPK and redistributes overexpressed PRPK from nucleus to cytosol. Both wild-type Ray and a GTP-binding locked mutant (Ray-Q67L), but not a guanine nucleotide-unstable mutant (Ray-N120I), suppressed PRPK-induced p53 transcriptional activity, indicating GTP binding to Ray is required for this regulatory function. Co-immunoprecipitation, subcellular localization by immunofluorescence, transcriptional reporter assay with mutant analysis Biochemical and biophysical research communications Medium 16600182
2007 PRPK (TP53RK) is phosphorylated and activated by Akt/PKB at Ser-250. Recombinant PRPK is phosphorylated in vitro by Akt; co-transfection of Akt with wild-type PRPK but not Ser250Ala mutant increased PRPK phosphorylation. Akt co-expression increased PRPK-dependent p53 Ser-15 phosphorylation, which was abolished by the Akt pathway inhibitor LY294002, establishing Akt as an upstream activating kinase for PRPK. In vitro kinase assay, phospho-specific antibody, site-directed mutagenesis (Ser250Ala), cell co-transfection, pharmacological inhibition (LY294002) Cellular and molecular life sciences : CMLS High 17712528
2008 Crystal structure of the archaeal Kae1/Bud32 fusion protein MJ1130 revealed that Kae1 (Kae1p) maintains the Bud32 kinase ATP-binding site in an inactive configuration. Yeast Kae1p was shown to repress the kinase activity of yeast Bud32p in vitro. Mutations disrupting the Kae1p/Bud32p interaction in yeast abolished both transcription and telomere homeostasis functions of the EKC/KEOPS complex. X-ray crystallography, in vitro kinase repression assay, site-directed mutagenesis of protein-protein interface, yeast genetics The EMBO journal High 19172740
2010 siRNA-mediated knockdown of TP53RK accelerated caspase-3/7 activation and cell death after mitotic arrest induced by paclitaxel or PLK1 inhibitor, without affecting mitotic entry kinetics. This places TP53RK as a restrainer of apoptosis specifically after mitotic stress. siRNA knockdown, caspase-3/7 activation assay, time-lapse microscopy Cancer research Medium 20647325
2015 Crystal structure of the yeast Bud32/Cgi121 complex with ADP showed ADP bound in the Bud32 catalytic site in a canonical PKA-family manner. The full yeast KEOPS complex exists as a linear heteropentamer (Gon7–Pcc1–Kae1–Bud32–Cgi121), distinct from the archaeal homodimeric Pcc1 arrangement. X-ray crystallography, analytical ultracentrifugation, structural modeling Nucleic acids research High 25735745
2018 PRPK (TP53RK) is phosphorylated by TOPK (T-LAK cell-originated protein kinase); knockdown of TOPK inhibited PRPK phosphorylation in vivo. Active phospho-PRPK promoted skin carcinogenesis; topical PRPK inhibitors (rocuronium bromide or betamethasone 17-valerate) attenuated TOPK-dependent PRPK signaling and reduced cutaneous SCC development in mice. siRNA knockdown, in vivo mouse carcinogenesis model, pharmacological inhibition, phosphorylation analysis Oncogene Medium 29904102
2018 Active PRPK does not phosphorylate p53 directly (negative result in in vitro kinase assay). Instead, PRPK phosphorylates survivin (Birc5) at Thr-34, which is important for survivin stability, and this promotes colon cancer metastasis. In vitro kinase assay, knockdown, in vivo metastasis mouse model Molecular cancer therapeutics Medium 29483219
2019 TP53 indirectly mediates degradation of TPRKB (CGI-121); this degradation was rescued by co-expression of PRPK (TP53RK), indicating PRPK stabilizes TPRKB. Depletion of other EKC/KEOPS members had TP53-independent effects, supporting complex-independent functions of TPRKB distinct from those of PRPK. shRNA knockdown, proteasome inhibition rescue experiment, cell proliferation assay, co-expression rescue Molecular cancer research : MCR Medium 31110156
2021 Crystal structure of the human PRPK–TPRKB complex at 2.53 Å resolution revealed PRPK in an active conformation with AMPPNP coordinated, despite lacking a conventional activation loop. Structural mapping showed the disease-associated mutation PRPK K238Nfs*2 abolishes binding to OSGEP (Kae1), positioning this interaction as critical for complex assembly. X-ray crystallography, binding assay (PRPK mutant vs. OSGEP), structural modeling of full human KEOPS complex Communications biology High 33547416
2022 Bud32 (TP53RK ortholog) functions primarily as an ATPase rather than a classical protein kinase within the KEOPS complex; its ATPase activity is required for t6A tRNA modification. Bud32 also facilitates tRNA substrate recruitment to KEOPS and helps position tRNA A37 in the Kae1 active site. In vitro ATPase assay, tRNA binding assay, t6A modification assay, yeast complementation growth assay Methods in enzymology High 35525560
2022 A novel homozygous TP53RK missense variant (p.Arg55Gly) causing Galloway-Mowat syndrome was functionally validated: morpholino knockdown of tp53rk in Xenopus laevis caused abnormal eye and head development, rescued by wild-type human TP53RK but not by the p.Arg55Gly mutant or a previously described p.Gly42Asp mutant, demonstrating loss of function for these variants. Xenopus morpholino knockdown, mRNA rescue experiment with wild-type and mutant TP53RK Human mutation Medium 36116039
2023 TP53RK phosphorylates Birc5 (survivin) and facilitates its nuclear translocation; nuclear Birc5 activates PI3K/Akt and MAPK pathways to promote renal fibrosis. Specific deletion of TP53RK in renal tubular cells or fibroblasts in mice mitigated renal fibrosis, and pharmacological inhibition with fusidic acid ameliorated kidney fibrosis. Conditional gene knockout in mice, in vitro kinase assay, subcellular fractionation, pharmacological inhibition, CKD mouse models Advanced science High 37382161
2024 Cryo-EM structures of KEOPS with and without tRNA substrate revealed distinct tRNA flexibility and a conformational change enabling tRNA modification by Kae1. A contact between a flipped-out base of tRNA and an arginine in the C-terminal tail of Bud32 correlates with the tRNA conformational change. Contact surfaces within the KEOPS-tRNA holo-enzyme were identified that are required for Bud32 ATPase regulation and t6A modification activity, clarifying how Bud32 contributes to substrate specificity. Cryo-electron microscopy, mutagenesis of Bud32 C-terminal tail, t6A modification assay, ATPase assay Nature communications High 39639027
2025 TP53RK stabilizes CDC7 (cell division cycle 7 kinase), ensuring MCM complex phosphorylation and replication fork progression; TP53RK depletion reduced MCM2 enrichment at replication origins and induced DNA replication stress, apoptosis, and cell cycle arrest independent of p53 status. CRISPR screen, TP53RK knockdown/knockout, MCM ChIP, DNA fiber assay, co-expression analysis Scientific reports Medium 41102525

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Analysis of the interaction between piD261/Bud32, an evolutionarily conserved protein kinase of Saccharomyces cerevisiae, and the Grx4 glutaredoxin. The Biochemical journal 61 14519092
2008 Structure of the archaeal Kae1/Bud32 fusion protein MJ1130: a model for the eukaryotic EKC/KEOPS subcomplex. The EMBO journal 55 19172740
2015 Crystal structures of the Gon7/Pcc1 and Bud32/Cgi121 complexes provide a model for the complete yeast KEOPS complex. Nucleic acids research 38 25735745
2002 Structure-function analysis of yeast piD261/Bud32, an atypical protein kinase essential for normal cell life. The Biochemical journal 35 12023889
2018 Targeting PRPK and TOPK for skin cancer prevention and therapy. Oncogene 33 29904102
2009 The universal Kae1 protein and the associated Bud32 kinase (PRPK), a mysterious protein couple probably essential for genome maintenance in Archaea and Eukarya. Biochemical Society transactions 32 19143597
2003 Functional homology between yeast piD261/Bud32 and human PRPK: both phosphorylate p53 and PRPK partially complements piD261/Bud32 deficiency. FEBS letters 30 12914926
2010 A chemosensitization screen identifies TP53RK, a kinase that restrains apoptosis after mitotic stress. Cancer research 28 20647325
2007 Phosphorylation and activation of the atypical kinase p53-related protein kinase (PRPK) by Akt/PKB. Cellular and molecular life sciences : CMLS 22 17712528
2006 A Small Ras-like protein Ray/Rab1c modulates the p53-regulating activity of PRPK. Biochemical and biophysical research communications 22 16600182
2003 Identification of CGI-121, a novel PRPK (p53-related protein kinase)-binding protein. Biochemical and biophysical research communications 20 12659830
2018 Targeting PRPK Function Blocks Colon Cancer Metastasis. Molecular cancer therapeutics 16 29483219
2018 A familial case of Galloway-Mowat syndrome due to a novel TP53RK mutation: a case report. BMC medical genetics 15 30053862
2021 Crystal structure of the human PRPK-TPRKB complex. Communications biology 14 33547416
2019 Identification of TP53RK-Binding Protein (TPRKB) Dependency in TP53-Deficient Cancers. Molecular cancer research : MCR 13 31110156
2002 Acidophilic character of yeast PID261/BUD32, a putative ancestor of eukaryotic protein kinases. Biochemical and biophysical research communications 13 12207926
2023 TP53RK Drives the Progression of Chronic Kidney Disease by Phosphorylating Birc5. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 11 37382161
2022 Functional characterization of a novel TP53RK mutation identified in a family with Galloway-Mowat syndrome. Human mutation 10 36116039
2024 Structures of KEOPS bound to tRNA reveal functional roles of the kinase Bud32. Nature communications 3 39639027
2023 Novel TP53RK variants cause varied clinical features of Galloway-Mowat syndrome without nephrotic syndrome in three unrelated Chinese patients. Frontiers in molecular neuroscience 3 36873107
2025 Identifying TP53RK as a key regulator of colorectal cancer survival and a potential therapeutic target. Scientific reports 2 41102525
2025 Ethanol extract from Ziziphus nummularia stem inhibits MCF-7 breast cancer cell proliferation through TP53 regulating kinase (TP53RK)-mediated p53 activation: In silico and genes expression investigations. Narra J 1 40352177
2022 A suite of in vitro and in vivo assays for monitoring the activity of the pseudokinase Bud32. Methods in enzymology 1 35525560
2025 The kinase Bud32 regulates iron homeostasis in fungal pathogen Cryptococcus neoformans. Frontiers in immunology 0 40787456
2025 The Role of the Prpk Gene in the Body Development of Apis cerana. Life (Basel, Switzerland) 0 41465844

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