{"gene":"OLA1","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":2007,"finding":"Human OLA1 (hOLA1) is an ATPase that binds and hydrolyzes ATP more efficiently than GTP, distinguishing it from other Obg-family GTPases. X-ray crystal structure of hOLA1 bound to the non-hydrolyzable ATP analogue AMPPCP explains the altered nucleotide specificity of the YchF/OLA1 subfamily.","method":"Biochemical nucleotide hydrolysis assays, X-ray crystallography (structure with AMPPCP)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro biochemical assay + crystal structure in a single rigorous study","pmids":["17430889"],"is_preprint":false},{"year":2009,"finding":"OLA1 functions as a negative regulator of the cellular antioxidant response through nontranscriptional mechanisms. Knockdown of OLA1 increases resistance to oxidizing agents (tBH, diamide), decreases intracellular ROS, and reduces glutathione depletion, without changing mRNA levels of antioxidant genes or requiring de novo protein synthesis.","method":"RNAi knockdown, cell viability assays, ROS measurement, glutathione assay, cycloheximide block experiment","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods in a single study, replicated in follow-up papers","pmids":["19706404"],"is_preprint":false},{"year":2009,"finding":"Knockdown of OLA1 inhibits breast cancer cell migration and invasion through modulation of intracellular ROS levels, as treatment with the ROS scavenger N-acetylcysteine phenocopies OLA1 knockdown.","method":"siRNA knockdown, wound-healing assay, Transwell migration/invasion assay, ROS measurement, NAC treatment","journal":"Journal of Zhejiang University. Science. B","confidence":"Medium","confidence_rationale":"Tier 2 — defined cellular phenotype with pathway placement via ROS modulation, single lab","pmids":["19882753"],"is_preprint":false},{"year":2013,"finding":"OLA1 stabilizes HSP70 by binding to the HSP70 carboxyl-terminus variable domain, thereby preventing recruitment of the E3 ubiquitin ligase CHIP and blocking CHIP-mediated ubiquitination and degradation of HSP70. OLA1 knockdown reduces HSP70 levels and impairs thermotolerance; overexpression elevates HSP70 and improves heat-shock survival.","method":"RNAi knockdown, gene disruption, overexpression, co-immunoprecipitation, ubiquitination assay, heat-shock survival assay","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, ubiquitination assay, gain/loss-of-function with defined molecular mechanism","pmids":["23412384"],"is_preprint":false},{"year":2013,"finding":"OLA1 localizes to centrosomes in interphase and spindle poles in mitosis, directly binds to BRCA1 (amino-terminal region) and γ-tubulin, and is required for centrosome number regulation. OLA1 knockdown causes centrosome amplification and microtubule aster formation. A cancer-associated OLA1 mutant (E168Q) fails to bind BRCA1 and cannot rescue centrosome amplification. BRCA1 variant I42V also abrogates BRCA1-OLA1 binding.","method":"Mass spectrometry, co-immunoprecipitation, immunofluorescence/confocal microscopy, siRNA knockdown, centrosome counting, mutagenesis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (MS, Co-IP, imaging, mutagenesis), clean KO phenotype with molecular mechanism","pmids":["24289923"],"is_preprint":false},{"year":2014,"finding":"OLA1 negatively regulates cell adhesion and spreading. OLA1-deficient cells show elevated FAK protein levels and decreased Ser3 phosphorylation of cofilin; OLA1-overexpressing cells show the opposite. OLA1 thus regulates actin dynamics and cell-matrix adhesion through FAK and cofilin.","method":"RNAi knockdown, gene overexpression, cell adhesion/spreading assays, Western blot for FAK and phospho-cofilin","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 — defined cellular phenotype and molecular correlates, single lab, no direct binding to FAK shown","pmids":["24486488"],"is_preprint":false},{"year":2015,"finding":"OLA1 inhibits protein synthesis and promotes the integrated stress response (ISR) by binding eIF2, hydrolyzing GTP, and interfering with eIF2 ternary complex (TC) formation. OLA1 depletion causes hypoactive ISR and reduces CHOP-mediated apoptosis, while promoting tumor growth and metastasis in vivo.","method":"Co-immunoprecipitation, GTPase assay, polysome profiling, ATF4/CHOP reporter assays, siRNA knockdown, xenograft tumor models","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro GTPase assay, co-IP, translational assays, and in vivo validation in a single study","pmids":["26283179"],"is_preprint":false},{"year":2016,"finding":"OLA1 contributes to epithelial-mesenchymal transition (EMT) in lung cancer by interacting with GSK3β and inhibiting GSK3β activity via promotion of its Ser9 phosphorylation. This suppresses GSK3β-mediated degradation of Snail, which in turn downregulates E-cadherin.","method":"Co-immunoprecipitation, kinase activity assay, siRNA knockdown, Western blot, TGF-β-induced EMT assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP and kinase assay support the mechanism, single lab","pmids":["26863455"],"is_preprint":false},{"year":2016,"finding":"OLA1 is required for normal cell cycle progression and organismal development in mice. Ola1-/- MEFs accumulate p21 due to enhanced mRNA translation mediated through an eIF2-dependent mechanism. Knockout of p21 partially rescues growth retardation of Ola1-/- embryos, placing OLA1 upstream of translational p21 control.","method":"Knockout mouse model, primary MEF culture, cell cycle analysis, polysome/translation assays, double-knockout epistasis (p21-/- Ola1-/-), immunohistochemistry","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — genetic epistasis in double-KO mice, translational assays, multiple orthogonal methods","pmids":["27481995"],"is_preprint":false},{"year":2018,"finding":"OLA1 requires interaction with BARD1 for proper centrosome number regulation. Five OLA1 missense mutants deficient in centrosome regulation were identified; three failed to bind BARD1. Phosphomimetic mutations restored BARD1 binding and rescued centrosome amplification. BARD1 knockdown or cancer-derived BARD1 mutants that fail to bind OLA1 also caused centrosome amplification.","method":"Co-immunoprecipitation, overexpression of OLA1 mutants, centrosome counting, BARD1 knockdown","journal":"Molecular cancer research : MCR","confidence":"High","confidence_rationale":"Tier 2 — systematic mutagenesis with binding and functional readouts, multiple mutants tested","pmids":["29858377"],"is_preprint":false},{"year":2019,"finding":"OLA1 is N-terminally methylated in vivo by the N-terminal methyltransferase NTMT1, as demonstrated by activity-based substrate profiling using the SAM analogue Hey-SAM and validated in NTMT1 knockout HEK293FT cells.","method":"Activity-based substrate profiling with Hey-SAM analogue, CRISPR-Cas9 NTMT1 KO cell validation, mass spectrometry","journal":"Chemical science","confidence":"High","confidence_rationale":"Tier 1-2 — chemical biology profiling confirmed in KO cells, in vivo PTM identification","pmids":["31857877"],"is_preprint":false},{"year":2019,"finding":"Decreased OLA1 expression in pulmonary artery cells of PPHN enhances CHIP affinity for Hsp70-SOD2 complexes, facilitating SOD2 ubiquitination and proteasomal degradation, impairing mitochondrial H2O2 generation. OLA1-deficient lambs and ola1-/- mice show downregulated SOD2, pulmonary arterial remodeling, and right ventricular hypertrophy.","method":"Co-immunoprecipitation, ubiquitination assay, OLA1 knockout mouse model, fetal lamb PPHN model, echocardiography","journal":"Hypertension (Dallas, Tex. : 1979)","confidence":"High","confidence_rationale":"Tier 2 — mechanism defined by co-IP and ubiquitination assay, confirmed in two animal models","pmids":["31476900"],"is_preprint":false},{"year":2020,"finding":"OLA1 localizes to spindles in mouse oocyte meiosis and is required for normal spindle assembly and spindle assembly checkpoint (SAC) activation. OLA1 knockdown causes multipolar spindles, premature anaphase onset, and precocious SAC inactivation.","method":"Immunofluorescence/confocal microscopy, nocodazole treatment, siRNA microinjection into oocytes, chromosome spreading","journal":"PeerJ","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization linked to functional loss-of-function phenotype, single lab","pmids":["31915569"],"is_preprint":false},{"year":2020,"finding":"HIV p17 protein interacts with OLA1 and disrupts the OLA1-GSK3β complex, leading to GSK3β hyperactivation, suppression of autophagy, and enhanced T cell proliferation under nutrient starvation.","method":"Co-immunoprecipitation, GSK3β activity assay, autophagy flux assay, T cell proliferation assay","journal":"Journal of medical virology","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP and functional assay, single lab","pmids":["32790080"],"is_preprint":false},{"year":2021,"finding":"ZFAS1 lncRNA recognizes the OBG-type functional domain of OLA1, facilitates exposure of its ATP-binding sites (NVGKST, residues 32–37), enhances OLA1 ATPase activity, and accelerates ATP hydrolysis and the Warburg effect in colorectal cancer cells. This axis is stabilized by the m6A reader IMP2.","method":"RNA pull-down, RIP, ATP hydrolysis assay, ECAR/lactate assay, co-immunoprecipitation, Western blot","journal":"Journal of hematology & oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 — RNA-protein interaction assay with functional enzymatic readout, single lab","pmids":["34743750"],"is_preprint":false},{"year":2022,"finding":"BARD1 acts as an ATPase activating protein for OLA1 via its BRCT domain binding to the OLA1 TGS domain through a conserved BUDR motif, increasing OLA1 ATPase kcat. A cancer-related BARD1 mutation V695L reduces BARD1-mediated OLA1 activation by perturbing the OLA1 binding site, as shown in a 1.88 Å crystal structure.","method":"Enzyme kinetics (ATPase assay), X-ray crystallography (1.88 Å), co-immunoprecipitation, mutagenesis","journal":"Biochimica et biophysica acta. General subjects","confidence":"High","confidence_rationale":"Tier 1 — crystal structure combined with enzyme kinetics and mutagenesis, multiple orthogonal methods","pmids":["35134491"],"is_preprint":false},{"year":2023,"finding":"Aurora A binds to OLA1 and polyubiquitinates it, targeting it for proteasomal degradation. NEK2 phosphorylates OLA1 at T124, which increases OLA1 binding to Aurora A and Aurora A-mediated polyubiquitination. Reduction of centrosomal OLA1 in G2 phase promotes pericentriolar material protein recruitment and centrosome maturation. Aurora A's E3 ligase activity is required for centrosome amplification induced by its overexpression.","method":"Co-immunoprecipitation, in vitro and in vivo ubiquitination assays, kinase assay, mutagenesis, centrosome imaging","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro and in vivo ubiquitination assays plus mutagenesis and functional imaging","pmids":["37481721"],"is_preprint":false},{"year":2023,"finding":"OLA1 phosphorylation at Ser232/Tyr236 triggers translocation from cytoplasm/mitochondria to the nucleus, and subsequent phosphorylation at Thr325 switches its biochemical activity from ATPase to GTPase, promoting transcription of nuclear-encoded mitochondrial bioenergetic genes. This process is regulated by ERK1/2 and restrained by PP1A. A phosphoresistant T325A OLA1 mutant fails to translocate and leads to cellular energy depletion.","method":"Phosphomimetic/phosphoresistant mutants, subcellular fractionation, nuclear translocation imaging, metabolic gene expression assays, ERK1/2 knockdown, PP1A assay, OLA1 knockout mice","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods including mutagenesis and in vivo KO, single lab","pmids":["36481055"],"is_preprint":false},{"year":2024,"finding":"HIV-1 p17 promotes STING signaling by binding OLA1 and inhibiting OLA1's regulation of STING. OLA1 normally interacts with STING and inhibits STING translocation and phosphorylation upon cGAMP stimulation. HIV-1 p17 (but not HIV-2 or SIV p17) also specifically promotes the ATPase and GTPase activities of OLA1.","method":"Co-immunoprecipitation, STING phosphorylation/translocation assay, cGAMP stimulation, ATPase/GTPase assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP and enzymatic assay with species-specific controls, single lab","pmids":["38132845"],"is_preprint":false},{"year":2025,"finding":"OLA1 interacts with Keap1 and disrupts the Keap1-Nrf2 interaction; when STING is activated, STING binds OLA1 and disrupts OLA1-Keap1 interactions, freeing Keap1 to promote Nrf2 degradation and thereby suppressing antioxidant defense and promoting ferroptosis.","method":"Co-immunoprecipitation, siRNA knockdown, Nrf2 activity assay, in vivo mouse model of POF","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP with functional readout, confirmed in vivo, single lab","pmids":["41352507"],"is_preprint":false},{"year":2026,"finding":"Bi-allelic loss-of-function variants in OLA1 in humans cause a neurodevelopmental disorder with joint hypermobility. Proband-derived fibroblasts recapitulate impaired migration and proliferation. Neurons derived from proband fibroblasts show impaired adhesion and cytoskeletal control. In C. elegans, ola-1 deficiency reduces neurite numbers and suppresses microtubule dynamics and axon regrowth.","method":"Human genetics (biallelic variants), proband-derived fibroblast functional assays, neuron differentiation assays, C. elegans ola-1 knockout with neurite imaging and transcriptomics","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — human genetics validated by multiple cellular and organismal models with defined molecular pathway","pmids":["41887223"],"is_preprint":false}],"current_model":"OLA1 is a conserved Obg-family P-loop ATPase (with secondary GTPase activity) that acts as a multifunctional regulatory hub: it inhibits eIF2 ternary complex formation to suppress global translation and promote the integrated stress response, stabilizes HSP70 by blocking CHIP-mediated ubiquitination, localizes to centrosomes where it works with the BRCA1/BARD1 complex to restrain centriole duplication (with BARD1 serving as an ATPase-activating protein and Aurora A/NEK2 targeting OLA1 for proteasomal degradation to drive centrosome maturation), negatively regulates cell-matrix adhesion via FAK and cofilin, modulates the antioxidant response through nontranscriptional ROS control, undergoes NTMT1-mediated N-terminal methylation, and couples redox/stress signals to nuclear metabolic gene expression via phosphorylation-dependent nuclear translocation that switches its ATPase to GTPase activity."},"narrative":{"teleology":[{"year":2007,"claim":"Establishing that OLA1 is an ATPase rather than a canonical GTPase resolved its enzymatic identity and explained the divergent nucleotide specificity of the YchF/OLA1 subfamily through structural determination.","evidence":"Biochemical nucleotide hydrolysis assays and X-ray crystallography of hOLA1 with AMPPCP","pmids":["17430889"],"confidence":"High","gaps":["No cellular substrate or downstream effector identified","Whether GTPase activity is biologically relevant was not addressed"]},{"year":2009,"claim":"Demonstrating that OLA1 negatively regulates the antioxidant response through a nontranscriptional mechanism positioned it as a post-translational modulator of cellular redox homeostasis and linked it to cancer cell migration via ROS.","evidence":"RNAi knockdown with ROS/glutathione measurements and cycloheximide block; migration/invasion assays with NAC rescue","pmids":["19706404","19882753"],"confidence":"High","gaps":["Direct molecular target mediating ROS regulation was not identified","Whether ATPase activity is required for redox function was untested"]},{"year":2013,"claim":"Identifying OLA1 as an HSP70 stabilizer that blocks CHIP-mediated ubiquitination defined a chaperone-protection mechanism, while discovery of OLA1 at centrosomes in complex with BRCA1 and γ-tubulin revealed its role in restraining centriole duplication.","evidence":"Reciprocal co-IP, ubiquitination assays, heat-shock survival (HSP70 axis); mass spectrometry, co-IP, centrosome counting, cancer-associated mutant analysis (centrosome axis)","pmids":["23412384","24289923"],"confidence":"High","gaps":["Whether HSP70 stabilization and centrosome regulation are linked through a common ATPase mechanism was unknown","The E168Q mutant's effect on ATPase activity was not measured"]},{"year":2015,"claim":"Showing that OLA1 inhibits eIF2 ternary complex formation via GTP hydrolysis established a direct translational control mechanism and explained how OLA1 promotes the integrated stress response and CHOP-mediated apoptosis.","evidence":"Co-IP with eIF2, GTPase assays, polysome profiling, ATF4/CHOP reporters, xenograft models","pmids":["26283179"],"confidence":"High","gaps":["Whether ATP or GTP hydrolysis is the physiologically dominant activity in translational regulation was not resolved","Structural basis for eIF2 binding was not determined"]},{"year":2016,"claim":"Genetic epistasis in Ola1-knockout mice confirmed in vivo translational control: Ola1-/- MEFs accumulated p21 via eIF2-dependent translation, and p21 knockout partially rescued embryonic growth retardation, placing OLA1 upstream of translational p21 regulation.","evidence":"Ola1-/- and Ola1-/-;p21-/- double-knockout mouse models, polysome/translation assays","pmids":["27481995"],"confidence":"High","gaps":["Whether additional mRNAs beyond p21 are selectively regulated was not catalogued","Tissue-specific requirements for OLA1 translational control were not fully mapped"]},{"year":2018,"claim":"Systematic mutagenesis demonstrated that OLA1–BARD1 interaction is essential for centrosome number control, with phosphomimetic OLA1 mutants restoring BARD1 binding and rescuing centrosome amplification, defining phosphorylation as a regulatory switch.","evidence":"Co-IP of five OLA1 missense mutants, BARD1 knockdown, cancer-derived BARD1 mutant analysis, centrosome counting","pmids":["29858377"],"confidence":"High","gaps":["The kinase responsible for phosphorylation that promotes BARD1 binding was not identified at this stage","How the BRCA1/BARD1 E3 ligase activity integrates with OLA1 ATPase function was unclear"]},{"year":2019,"claim":"OLA1's role in HSP70-CHIP biology was extended to SOD2 regulation in pulmonary hypertension, showing that OLA1 deficiency enhances CHIP-mediated SOD2 ubiquitination, linking the chaperone-protection mechanism to vascular pathology in two animal models.","evidence":"Co-IP and ubiquitination assays in pulmonary artery cells, Ola1-/- mice and fetal lamb PPHN model","pmids":["31476900"],"confidence":"High","gaps":["Whether OLA1 directly binds SOD2 or acts solely through HSP70 was not distinguished","Therapeutic reversibility of pulmonary phenotype by OLA1 restoration was not tested"]},{"year":2019,"claim":"Identification of OLA1 as a substrate of NTMT1 N-terminal methyltransferase established a new post-translational modification on OLA1, expanding its regulatory input layer.","evidence":"Activity-based Hey-SAM profiling, CRISPR NTMT1 KO validation, mass spectrometry in HEK293FT cells","pmids":["31857877"],"confidence":"High","gaps":["Functional consequence of N-terminal methylation on OLA1 activity or localization was not determined"]},{"year":2022,"claim":"Structural and kinetic demonstration that BARD1 BRCT domain acts as an ATPase-activating protein for OLA1 via the conserved BUDR motif explained how BRCA1/BARD1 mechanistically controls OLA1 enzymatic output, with the cancer mutation V695L reducing activation.","evidence":"1.88 Å crystal structure of BARD1 BRCT-OLA1 TGS complex, enzyme kinetics, mutagenesis","pmids":["35134491"],"confidence":"High","gaps":["Whether ATPase activation by BARD1 is required in vivo for centrosome regulation was not directly tested with catalytic-dead mutants","Full-length complex structure is lacking"]},{"year":2023,"claim":"Discovery that Aurora A ubiquitinates OLA1 and NEK2 phosphorylates OLA1 at T124 to promote this degradation resolved how centrosomal OLA1 is removed during G2 to permit centrosome maturation, completing the regulatory circuit.","evidence":"In vitro and in vivo ubiquitination assays, kinase assays, phosphomutants, centrosome imaging","pmids":["37481721"],"confidence":"High","gaps":["Whether other centrosomal substrates of Aurora A E3 ligase activity exist was not addressed","Temporal coordination between BARD1-mediated ATPase activation and Aurora A-mediated degradation at centrosomes is undefined"]},{"year":2023,"claim":"Phosphorylation-dependent nuclear translocation of OLA1 (Ser232/Tyr236) and a subsequent activity switch from ATPase to GTPase (Thr325) coupled stress/redox sensing to transcriptional control of mitochondrial bioenergetic genes, regulated by ERK1/2 and PP1A.","evidence":"Phosphomimetic/phosphoresistant mutants, subcellular fractionation, nuclear imaging, metabolic gene expression, ERK1/2 knockdown, Ola1-/- mice","pmids":["36481055"],"confidence":"Medium","gaps":["Structural basis for the ATPase-to-GTPase switch is unknown","Nuclear binding partners or chromatin targets of GTPase-active OLA1 were not identified","Independent replication in a second laboratory is needed"]},{"year":2024,"claim":"OLA1 was shown to interact with STING and inhibit its translocation and phosphorylation, placing OLA1 in the cGAS-STING innate immune pathway; HIV-1 p17 disrupts this interaction to promote STING signaling.","evidence":"Co-IP, STING phosphorylation/translocation assays, cGAMP stimulation, species-specific p17 controls","pmids":["38132845"],"confidence":"Medium","gaps":["Whether OLA1 ATPase or GTPase activity is required for STING inhibition was not determined","Physiological relevance outside HIV infection context is untested"]},{"year":2025,"claim":"OLA1 was found to sequester Keap1 away from Nrf2, promoting antioxidant defense; STING activation disrupts OLA1-Keap1 binding, freeing Keap1 to degrade Nrf2 and promote ferroptosis, linking OLA1's redox role to the Keap1-Nrf2 axis.","evidence":"Co-IP, Nrf2 activity assay, siRNA, in vivo mouse POF model","pmids":["41352507"],"confidence":"Medium","gaps":["Direct binding domain on OLA1 for Keap1 is unmapped","Whether this mechanism accounts for the nontranscriptional antioxidant phenotype reported in 2009 remains unconnected"]},{"year":2026,"claim":"Bi-allelic OLA1 loss-of-function variants were identified as causal for a human neurodevelopmental disorder with joint hypermobility, validated by impaired migration and adhesion in proband fibroblasts/neurons and reduced neurite dynamics in C. elegans, establishing OLA1 as essential for nervous system development.","evidence":"Human genetics (biallelic variants in multiple families), proband-derived fibroblast and neuron assays, C. elegans ola-1 knockout with neurite imaging","pmids":["41887223"],"confidence":"High","gaps":["Genotype-phenotype correlation across different variant types is limited","Whether translational, centrosomal, or cytoskeletal functions of OLA1 drive the neurodevelopmental phenotype is undetermined"]},{"year":null,"claim":"Key unresolved questions include the structural basis for OLA1's phosphorylation-dependent ATPase-to-GTPase switch, how its multiple functions (translational control, centrosome regulation, redox modulation, STING inhibition) are coordinately regulated in different cellular contexts, and which specific OLA1 activity underlies the human neurodevelopmental phenotype.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length OLA1 structure in complex with eIF2 or STING","Relative contributions of ATPase vs GTPase activity to distinct cellular functions are unresolved","Cell-type-specific regulation and substrate specificity of OLA1 remain poorly defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,14,15]},{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[6,17]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,6,8,18]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[19]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[4,9,16]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6,17]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[17]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[17]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,8,9,16]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,6,8,10,11]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[6,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[18]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[1,17]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8,20]}],"complexes":["BRCA1/BARD1"],"partners":["BRCA1","BARD1","HSPA1A","STUB1","EIF2S1","AURKA","NEK2","STING1"],"other_free_text":[]},"mechanistic_narrative":"OLA1 is a conserved Obg-family P-loop NTPase that functions as a multifunctional regulatory hub integrating translational control, centrosome homeostasis, redox signaling, and cytoskeletal dynamics. It preferentially hydrolyzes ATP over GTP [PMID:17430889], inhibits eIF2 ternary complex formation to suppress global protein synthesis and promote the integrated stress response — with Ola1 knockout mice accumulating p21 through enhanced eIF2-dependent translation [PMID:26283179, PMID:27481995] — and stabilizes HSP70 by competitively blocking CHIP-mediated ubiquitination, a mechanism also governing SOD2 turnover in pulmonary vascular disease [PMID:23412384, PMID:31476900]. OLA1 localizes to centrosomes where BARD1 serves as its ATPase-activating protein, and Aurora A/NEK2-dependent phosphorylation and ubiquitination of OLA1 drive its degradation during G2 to permit centrosome maturation; phosphorylation-dependent nuclear translocation switches its NTPase specificity from ATPase to GTPase, coupling redox and stress signals to mitochondrial bioenergetic gene transcription [PMID:24289923, PMID:35134491, PMID:37481721, PMID:36481055]. Bi-allelic loss-of-function OLA1 variants cause a neurodevelopmental disorder with joint hypermobility in humans [PMID:41887223]."},"prefetch_data":{"uniprot":{"accession":"Q9NTK5","full_name":"Obg-like ATPase 1","aliases":["DNA damage-regulated overexpressed in cancer 45","DOC45","GTP-binding protein 9"],"length_aa":396,"mass_kda":44.7,"function":"Hydrolyzes ATP, and can also hydrolyze GTP with lower efficiency. Has lower affinity for GTP","subcellular_location":"Cytoplasm; Nucleus; Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/Q9NTK5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OLA1","classification":"Not Classified","n_dependent_lines":40,"n_total_lines":1208,"dependency_fraction":0.033112582781456956},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SAR1B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/OLA1","total_profiled":1310},"omim":[{"mim_id":"611175","title":"OBG-LIKE ATPase 1; OLA1","url":"https://www.omim.org/entry/611175"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Cytosol","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/OLA1"},"hgnc":{"alias_symbol":["PTD004"],"prev_symbol":["GTPBP9"]},"alphafold":{"accession":"Q9NTK5","domains":[{"cath_id":"3.40.50.300","chopping":"23-301","consensus_level":"medium","plddt":89.0069,"start":23,"end":301},{"cath_id":"3.10.20.30","chopping":"305-386","consensus_level":"medium","plddt":96.3243,"start":305,"end":386}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NTK5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NTK5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NTK5-F1-predicted_aligned_error_v6.png","plddt_mean":88.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OLA1","jax_strain_url":"https://www.jax.org/strain/search?query=OLA1"},"sequence":{"accession":"Q9NTK5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NTK5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NTK5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NTK5"}},"corpus_meta":[{"pmid":"34743750","id":"PMC_34743750","title":"N6-methyladenosine reader IMP2 stabilizes the ZFAS1/OLA1 axis and activates the Warburg effect: implication in colorectal cancer.","date":"2021","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34743750","citation_count":96,"is_preprint":false},{"pmid":"17430889","id":"PMC_17430889","title":"Human OLA1 defines an ATPase subfamily in the Obg family of GTP-binding proteins.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17430889","citation_count":90,"is_preprint":false},{"pmid":"19706404","id":"PMC_19706404","title":"OLA1, an Obg-like ATPase, suppresses antioxidant response via nontranscriptional mechanisms.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19706404","citation_count":62,"is_preprint":false},{"pmid":"24289923","id":"PMC_24289923","title":"The BRCA1/BARD1-interacting protein OLA1 functions in centrosome regulation.","date":"2013","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/24289923","citation_count":61,"is_preprint":false},{"pmid":"23412384","id":"PMC_23412384","title":"OLA1 protects cells in heat shock by stabilizing HSP70.","date":"2013","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/23412384","citation_count":55,"is_preprint":false},{"pmid":"26283179","id":"PMC_26283179","title":"OLA1 regulates protein synthesis and integrated stress response by inhibiting eIF2 ternary complex formation.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26283179","citation_count":38,"is_preprint":false},{"pmid":"19882753","id":"PMC_19882753","title":"Knockdown of OLA1, a regulator of oxidative stress response, inhibits motility and invasion of breast cancer cells.","date":"2009","source":"Journal of Zhejiang University. Science. 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X-ray crystal structure of hOLA1 bound to the non-hydrolyzable ATP analogue AMPPCP explains the altered nucleotide specificity of the YchF/OLA1 subfamily.\",\n      \"method\": \"Biochemical nucleotide hydrolysis assays, X-ray crystallography (structure with AMPPCP)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemical assay + crystal structure in a single rigorous study\",\n      \"pmids\": [\"17430889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"OLA1 functions as a negative regulator of the cellular antioxidant response through nontranscriptional mechanisms. Knockdown of OLA1 increases resistance to oxidizing agents (tBH, diamide), decreases intracellular ROS, and reduces glutathione depletion, without changing mRNA levels of antioxidant genes or requiring de novo protein synthesis.\",\n      \"method\": \"RNAi knockdown, cell viability assays, ROS measurement, glutathione assay, cycloheximide block experiment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in a single study, replicated in follow-up papers\",\n      \"pmids\": [\"19706404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Knockdown of OLA1 inhibits breast cancer cell migration and invasion through modulation of intracellular ROS levels, as treatment with the ROS scavenger N-acetylcysteine phenocopies OLA1 knockdown.\",\n      \"method\": \"siRNA knockdown, wound-healing assay, Transwell migration/invasion assay, ROS measurement, NAC treatment\",\n      \"journal\": \"Journal of Zhejiang University. Science. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined cellular phenotype with pathway placement via ROS modulation, single lab\",\n      \"pmids\": [\"19882753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"OLA1 stabilizes HSP70 by binding to the HSP70 carboxyl-terminus variable domain, thereby preventing recruitment of the E3 ubiquitin ligase CHIP and blocking CHIP-mediated ubiquitination and degradation of HSP70. OLA1 knockdown reduces HSP70 levels and impairs thermotolerance; overexpression elevates HSP70 and improves heat-shock survival.\",\n      \"method\": \"RNAi knockdown, gene disruption, overexpression, co-immunoprecipitation, ubiquitination assay, heat-shock survival assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, ubiquitination assay, gain/loss-of-function with defined molecular mechanism\",\n      \"pmids\": [\"23412384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"OLA1 localizes to centrosomes in interphase and spindle poles in mitosis, directly binds to BRCA1 (amino-terminal region) and γ-tubulin, and is required for centrosome number regulation. OLA1 knockdown causes centrosome amplification and microtubule aster formation. A cancer-associated OLA1 mutant (E168Q) fails to bind BRCA1 and cannot rescue centrosome amplification. BRCA1 variant I42V also abrogates BRCA1-OLA1 binding.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, immunofluorescence/confocal microscopy, siRNA knockdown, centrosome counting, mutagenesis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (MS, Co-IP, imaging, mutagenesis), clean KO phenotype with molecular mechanism\",\n      \"pmids\": [\"24289923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"OLA1 negatively regulates cell adhesion and spreading. OLA1-deficient cells show elevated FAK protein levels and decreased Ser3 phosphorylation of cofilin; OLA1-overexpressing cells show the opposite. OLA1 thus regulates actin dynamics and cell-matrix adhesion through FAK and cofilin.\",\n      \"method\": \"RNAi knockdown, gene overexpression, cell adhesion/spreading assays, Western blot for FAK and phospho-cofilin\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — defined cellular phenotype and molecular correlates, single lab, no direct binding to FAK shown\",\n      \"pmids\": [\"24486488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"OLA1 inhibits protein synthesis and promotes the integrated stress response (ISR) by binding eIF2, hydrolyzing GTP, and interfering with eIF2 ternary complex (TC) formation. OLA1 depletion causes hypoactive ISR and reduces CHOP-mediated apoptosis, while promoting tumor growth and metastasis in vivo.\",\n      \"method\": \"Co-immunoprecipitation, GTPase assay, polysome profiling, ATF4/CHOP reporter assays, siRNA knockdown, xenograft tumor models\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro GTPase assay, co-IP, translational assays, and in vivo validation in a single study\",\n      \"pmids\": [\"26283179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"OLA1 contributes to epithelial-mesenchymal transition (EMT) in lung cancer by interacting with GSK3β and inhibiting GSK3β activity via promotion of its Ser9 phosphorylation. This suppresses GSK3β-mediated degradation of Snail, which in turn downregulates E-cadherin.\",\n      \"method\": \"Co-immunoprecipitation, kinase activity assay, siRNA knockdown, Western blot, TGF-β-induced EMT assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP and kinase assay support the mechanism, single lab\",\n      \"pmids\": [\"26863455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"OLA1 is required for normal cell cycle progression and organismal development in mice. Ola1-/- MEFs accumulate p21 due to enhanced mRNA translation mediated through an eIF2-dependent mechanism. Knockout of p21 partially rescues growth retardation of Ola1-/- embryos, placing OLA1 upstream of translational p21 control.\",\n      \"method\": \"Knockout mouse model, primary MEF culture, cell cycle analysis, polysome/translation assays, double-knockout epistasis (p21-/- Ola1-/-), immunohistochemistry\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic epistasis in double-KO mice, translational assays, multiple orthogonal methods\",\n      \"pmids\": [\"27481995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"OLA1 requires interaction with BARD1 for proper centrosome number regulation. Five OLA1 missense mutants deficient in centrosome regulation were identified; three failed to bind BARD1. Phosphomimetic mutations restored BARD1 binding and rescued centrosome amplification. BARD1 knockdown or cancer-derived BARD1 mutants that fail to bind OLA1 also caused centrosome amplification.\",\n      \"method\": \"Co-immunoprecipitation, overexpression of OLA1 mutants, centrosome counting, BARD1 knockdown\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic mutagenesis with binding and functional readouts, multiple mutants tested\",\n      \"pmids\": [\"29858377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"OLA1 is N-terminally methylated in vivo by the N-terminal methyltransferase NTMT1, as demonstrated by activity-based substrate profiling using the SAM analogue Hey-SAM and validated in NTMT1 knockout HEK293FT cells.\",\n      \"method\": \"Activity-based substrate profiling with Hey-SAM analogue, CRISPR-Cas9 NTMT1 KO cell validation, mass spectrometry\",\n      \"journal\": \"Chemical science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — chemical biology profiling confirmed in KO cells, in vivo PTM identification\",\n      \"pmids\": [\"31857877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Decreased OLA1 expression in pulmonary artery cells of PPHN enhances CHIP affinity for Hsp70-SOD2 complexes, facilitating SOD2 ubiquitination and proteasomal degradation, impairing mitochondrial H2O2 generation. OLA1-deficient lambs and ola1-/- mice show downregulated SOD2, pulmonary arterial remodeling, and right ventricular hypertrophy.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, OLA1 knockout mouse model, fetal lamb PPHN model, echocardiography\",\n      \"journal\": \"Hypertension (Dallas, Tex. : 1979)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanism defined by co-IP and ubiquitination assay, confirmed in two animal models\",\n      \"pmids\": [\"31476900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"OLA1 localizes to spindles in mouse oocyte meiosis and is required for normal spindle assembly and spindle assembly checkpoint (SAC) activation. OLA1 knockdown causes multipolar spindles, premature anaphase onset, and precocious SAC inactivation.\",\n      \"method\": \"Immunofluorescence/confocal microscopy, nocodazole treatment, siRNA microinjection into oocytes, chromosome spreading\",\n      \"journal\": \"PeerJ\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization linked to functional loss-of-function phenotype, single lab\",\n      \"pmids\": [\"31915569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HIV p17 protein interacts with OLA1 and disrupts the OLA1-GSK3β complex, leading to GSK3β hyperactivation, suppression of autophagy, and enhanced T cell proliferation under nutrient starvation.\",\n      \"method\": \"Co-immunoprecipitation, GSK3β activity assay, autophagy flux assay, T cell proliferation assay\",\n      \"journal\": \"Journal of medical virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP and functional assay, single lab\",\n      \"pmids\": [\"32790080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZFAS1 lncRNA recognizes the OBG-type functional domain of OLA1, facilitates exposure of its ATP-binding sites (NVGKST, residues 32–37), enhances OLA1 ATPase activity, and accelerates ATP hydrolysis and the Warburg effect in colorectal cancer cells. This axis is stabilized by the m6A reader IMP2.\",\n      \"method\": \"RNA pull-down, RIP, ATP hydrolysis assay, ECAR/lactate assay, co-immunoprecipitation, Western blot\",\n      \"journal\": \"Journal of hematology & oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — RNA-protein interaction assay with functional enzymatic readout, single lab\",\n      \"pmids\": [\"34743750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"BARD1 acts as an ATPase activating protein for OLA1 via its BRCT domain binding to the OLA1 TGS domain through a conserved BUDR motif, increasing OLA1 ATPase kcat. A cancer-related BARD1 mutation V695L reduces BARD1-mediated OLA1 activation by perturbing the OLA1 binding site, as shown in a 1.88 Å crystal structure.\",\n      \"method\": \"Enzyme kinetics (ATPase assay), X-ray crystallography (1.88 Å), co-immunoprecipitation, mutagenesis\",\n      \"journal\": \"Biochimica et biophysica acta. General subjects\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure combined with enzyme kinetics and mutagenesis, multiple orthogonal methods\",\n      \"pmids\": [\"35134491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Aurora A binds to OLA1 and polyubiquitinates it, targeting it for proteasomal degradation. NEK2 phosphorylates OLA1 at T124, which increases OLA1 binding to Aurora A and Aurora A-mediated polyubiquitination. Reduction of centrosomal OLA1 in G2 phase promotes pericentriolar material protein recruitment and centrosome maturation. Aurora A's E3 ligase activity is required for centrosome amplification induced by its overexpression.\",\n      \"method\": \"Co-immunoprecipitation, in vitro and in vivo ubiquitination assays, kinase assay, mutagenesis, centrosome imaging\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro and in vivo ubiquitination assays plus mutagenesis and functional imaging\",\n      \"pmids\": [\"37481721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"OLA1 phosphorylation at Ser232/Tyr236 triggers translocation from cytoplasm/mitochondria to the nucleus, and subsequent phosphorylation at Thr325 switches its biochemical activity from ATPase to GTPase, promoting transcription of nuclear-encoded mitochondrial bioenergetic genes. This process is regulated by ERK1/2 and restrained by PP1A. A phosphoresistant T325A OLA1 mutant fails to translocate and leads to cellular energy depletion.\",\n      \"method\": \"Phosphomimetic/phosphoresistant mutants, subcellular fractionation, nuclear translocation imaging, metabolic gene expression assays, ERK1/2 knockdown, PP1A assay, OLA1 knockout mice\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including mutagenesis and in vivo KO, single lab\",\n      \"pmids\": [\"36481055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HIV-1 p17 promotes STING signaling by binding OLA1 and inhibiting OLA1's regulation of STING. OLA1 normally interacts with STING and inhibits STING translocation and phosphorylation upon cGAMP stimulation. HIV-1 p17 (but not HIV-2 or SIV p17) also specifically promotes the ATPase and GTPase activities of OLA1.\",\n      \"method\": \"Co-immunoprecipitation, STING phosphorylation/translocation assay, cGAMP stimulation, ATPase/GTPase assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP and enzymatic assay with species-specific controls, single lab\",\n      \"pmids\": [\"38132845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OLA1 interacts with Keap1 and disrupts the Keap1-Nrf2 interaction; when STING is activated, STING binds OLA1 and disrupts OLA1-Keap1 interactions, freeing Keap1 to promote Nrf2 degradation and thereby suppressing antioxidant defense and promoting ferroptosis.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, Nrf2 activity assay, in vivo mouse model of POF\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP with functional readout, confirmed in vivo, single lab\",\n      \"pmids\": [\"41352507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Bi-allelic loss-of-function variants in OLA1 in humans cause a neurodevelopmental disorder with joint hypermobility. Proband-derived fibroblasts recapitulate impaired migration and proliferation. Neurons derived from proband fibroblasts show impaired adhesion and cytoskeletal control. In C. elegans, ola-1 deficiency reduces neurite numbers and suppresses microtubule dynamics and axon regrowth.\",\n      \"method\": \"Human genetics (biallelic variants), proband-derived fibroblast functional assays, neuron differentiation assays, C. elegans ola-1 knockout with neurite imaging and transcriptomics\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human genetics validated by multiple cellular and organismal models with defined molecular pathway\",\n      \"pmids\": [\"41887223\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OLA1 is a conserved Obg-family P-loop ATPase (with secondary GTPase activity) that acts as a multifunctional regulatory hub: it inhibits eIF2 ternary complex formation to suppress global translation and promote the integrated stress response, stabilizes HSP70 by blocking CHIP-mediated ubiquitination, localizes to centrosomes where it works with the BRCA1/BARD1 complex to restrain centriole duplication (with BARD1 serving as an ATPase-activating protein and Aurora A/NEK2 targeting OLA1 for proteasomal degradation to drive centrosome maturation), negatively regulates cell-matrix adhesion via FAK and cofilin, modulates the antioxidant response through nontranscriptional ROS control, undergoes NTMT1-mediated N-terminal methylation, and couples redox/stress signals to nuclear metabolic gene expression via phosphorylation-dependent nuclear translocation that switches its ATPase to GTPase activity.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"OLA1 is a conserved Obg-family P-loop NTPase that functions as a multifunctional regulatory hub integrating translational control, centrosome homeostasis, redox signaling, and cytoskeletal dynamics. It preferentially hydrolyzes ATP over GTP [PMID:17430889], inhibits eIF2 ternary complex formation to suppress global protein synthesis and promote the integrated stress response — with Ola1 knockout mice accumulating p21 through enhanced eIF2-dependent translation [PMID:26283179, PMID:27481995] — and stabilizes HSP70 by competitively blocking CHIP-mediated ubiquitination, a mechanism also governing SOD2 turnover in pulmonary vascular disease [PMID:23412384, PMID:31476900]. OLA1 localizes to centrosomes where BARD1 serves as its ATPase-activating protein, and Aurora A/NEK2-dependent phosphorylation and ubiquitination of OLA1 drive its degradation during G2 to permit centrosome maturation; phosphorylation-dependent nuclear translocation switches its NTPase specificity from ATPase to GTPase, coupling redox and stress signals to mitochondrial bioenergetic gene transcription [PMID:24289923, PMID:35134491, PMID:37481721, PMID:36481055]. Bi-allelic loss-of-function OLA1 variants cause a neurodevelopmental disorder with joint hypermobility in humans [PMID:41887223].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing that OLA1 is an ATPase rather than a canonical GTPase resolved its enzymatic identity and explained the divergent nucleotide specificity of the YchF/OLA1 subfamily through structural determination.\",\n      \"evidence\": \"Biochemical nucleotide hydrolysis assays and X-ray crystallography of hOLA1 with AMPPCP\",\n      \"pmids\": [\"17430889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No cellular substrate or downstream effector identified\", \"Whether GTPase activity is biologically relevant was not addressed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrating that OLA1 negatively regulates the antioxidant response through a nontranscriptional mechanism positioned it as a post-translational modulator of cellular redox homeostasis and linked it to cancer cell migration via ROS.\",\n      \"evidence\": \"RNAi knockdown with ROS/glutathione measurements and cycloheximide block; migration/invasion assays with NAC rescue\",\n      \"pmids\": [\"19706404\", \"19882753\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular target mediating ROS regulation was not identified\", \"Whether ATPase activity is required for redox function was untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identifying OLA1 as an HSP70 stabilizer that blocks CHIP-mediated ubiquitination defined a chaperone-protection mechanism, while discovery of OLA1 at centrosomes in complex with BRCA1 and γ-tubulin revealed its role in restraining centriole duplication.\",\n      \"evidence\": \"Reciprocal co-IP, ubiquitination assays, heat-shock survival (HSP70 axis); mass spectrometry, co-IP, centrosome counting, cancer-associated mutant analysis (centrosome axis)\",\n      \"pmids\": [\"23412384\", \"24289923\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HSP70 stabilization and centrosome regulation are linked through a common ATPase mechanism was unknown\", \"The E168Q mutant's effect on ATPase activity was not measured\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showing that OLA1 inhibits eIF2 ternary complex formation via GTP hydrolysis established a direct translational control mechanism and explained how OLA1 promotes the integrated stress response and CHOP-mediated apoptosis.\",\n      \"evidence\": \"Co-IP with eIF2, GTPase assays, polysome profiling, ATF4/CHOP reporters, xenograft models\",\n      \"pmids\": [\"26283179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ATP or GTP hydrolysis is the physiologically dominant activity in translational regulation was not resolved\", \"Structural basis for eIF2 binding was not determined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Genetic epistasis in Ola1-knockout mice confirmed in vivo translational control: Ola1-/- MEFs accumulated p21 via eIF2-dependent translation, and p21 knockout partially rescued embryonic growth retardation, placing OLA1 upstream of translational p21 regulation.\",\n      \"evidence\": \"Ola1-/- and Ola1-/-;p21-/- double-knockout mouse models, polysome/translation assays\",\n      \"pmids\": [\"27481995\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether additional mRNAs beyond p21 are selectively regulated was not catalogued\", \"Tissue-specific requirements for OLA1 translational control were not fully mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Systematic mutagenesis demonstrated that OLA1–BARD1 interaction is essential for centrosome number control, with phosphomimetic OLA1 mutants restoring BARD1 binding and rescuing centrosome amplification, defining phosphorylation as a regulatory switch.\",\n      \"evidence\": \"Co-IP of five OLA1 missense mutants, BARD1 knockdown, cancer-derived BARD1 mutant analysis, centrosome counting\",\n      \"pmids\": [\"29858377\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The kinase responsible for phosphorylation that promotes BARD1 binding was not identified at this stage\", \"How the BRCA1/BARD1 E3 ligase activity integrates with OLA1 ATPase function was unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"OLA1's role in HSP70-CHIP biology was extended to SOD2 regulation in pulmonary hypertension, showing that OLA1 deficiency enhances CHIP-mediated SOD2 ubiquitination, linking the chaperone-protection mechanism to vascular pathology in two animal models.\",\n      \"evidence\": \"Co-IP and ubiquitination assays in pulmonary artery cells, Ola1-/- mice and fetal lamb PPHN model\",\n      \"pmids\": [\"31476900\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether OLA1 directly binds SOD2 or acts solely through HSP70 was not distinguished\", \"Therapeutic reversibility of pulmonary phenotype by OLA1 restoration was not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of OLA1 as a substrate of NTMT1 N-terminal methyltransferase established a new post-translational modification on OLA1, expanding its regulatory input layer.\",\n      \"evidence\": \"Activity-based Hey-SAM profiling, CRISPR NTMT1 KO validation, mass spectrometry in HEK293FT cells\",\n      \"pmids\": [\"31857877\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of N-terminal methylation on OLA1 activity or localization was not determined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Structural and kinetic demonstration that BARD1 BRCT domain acts as an ATPase-activating protein for OLA1 via the conserved BUDR motif explained how BRCA1/BARD1 mechanistically controls OLA1 enzymatic output, with the cancer mutation V695L reducing activation.\",\n      \"evidence\": \"1.88 Å crystal structure of BARD1 BRCT-OLA1 TGS complex, enzyme kinetics, mutagenesis\",\n      \"pmids\": [\"35134491\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ATPase activation by BARD1 is required in vivo for centrosome regulation was not directly tested with catalytic-dead mutants\", \"Full-length complex structure is lacking\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery that Aurora A ubiquitinates OLA1 and NEK2 phosphorylates OLA1 at T124 to promote this degradation resolved how centrosomal OLA1 is removed during G2 to permit centrosome maturation, completing the regulatory circuit.\",\n      \"evidence\": \"In vitro and in vivo ubiquitination assays, kinase assays, phosphomutants, centrosome imaging\",\n      \"pmids\": [\"37481721\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other centrosomal substrates of Aurora A E3 ligase activity exist was not addressed\", \"Temporal coordination between BARD1-mediated ATPase activation and Aurora A-mediated degradation at centrosomes is undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Phosphorylation-dependent nuclear translocation of OLA1 (Ser232/Tyr236) and a subsequent activity switch from ATPase to GTPase (Thr325) coupled stress/redox sensing to transcriptional control of mitochondrial bioenergetic genes, regulated by ERK1/2 and PP1A.\",\n      \"evidence\": \"Phosphomimetic/phosphoresistant mutants, subcellular fractionation, nuclear imaging, metabolic gene expression, ERK1/2 knockdown, Ola1-/- mice\",\n      \"pmids\": [\"36481055\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis for the ATPase-to-GTPase switch is unknown\", \"Nuclear binding partners or chromatin targets of GTPase-active OLA1 were not identified\", \"Independent replication in a second laboratory is needed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"OLA1 was shown to interact with STING and inhibit its translocation and phosphorylation, placing OLA1 in the cGAS-STING innate immune pathway; HIV-1 p17 disrupts this interaction to promote STING signaling.\",\n      \"evidence\": \"Co-IP, STING phosphorylation/translocation assays, cGAMP stimulation, species-specific p17 controls\",\n      \"pmids\": [\"38132845\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether OLA1 ATPase or GTPase activity is required for STING inhibition was not determined\", \"Physiological relevance outside HIV infection context is untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"OLA1 was found to sequester Keap1 away from Nrf2, promoting antioxidant defense; STING activation disrupts OLA1-Keap1 binding, freeing Keap1 to degrade Nrf2 and promote ferroptosis, linking OLA1's redox role to the Keap1-Nrf2 axis.\",\n      \"evidence\": \"Co-IP, Nrf2 activity assay, siRNA, in vivo mouse POF model\",\n      \"pmids\": [\"41352507\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding domain on OLA1 for Keap1 is unmapped\", \"Whether this mechanism accounts for the nontranscriptional antioxidant phenotype reported in 2009 remains unconnected\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Bi-allelic OLA1 loss-of-function variants were identified as causal for a human neurodevelopmental disorder with joint hypermobility, validated by impaired migration and adhesion in proband fibroblasts/neurons and reduced neurite dynamics in C. elegans, establishing OLA1 as essential for nervous system development.\",\n      \"evidence\": \"Human genetics (biallelic variants in multiple families), proband-derived fibroblast and neuron assays, C. elegans ola-1 knockout with neurite imaging\",\n      \"pmids\": [\"41887223\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype-phenotype correlation across different variant types is limited\", \"Whether translational, centrosomal, or cytoskeletal functions of OLA1 drive the neurodevelopmental phenotype is undetermined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for OLA1's phosphorylation-dependent ATPase-to-GTPase switch, how its multiple functions (translational control, centrosome regulation, redox modulation, STING inhibition) are coordinately regulated in different cellular contexts, and which specific OLA1 activity underlies the human neurodevelopmental phenotype.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length OLA1 structure in complex with eIF2 or STING\", \"Relative contributions of ATPase vs GTPase activity to distinct cellular functions are unresolved\", \"Cell-type-specific regulation and substrate specificity of OLA1 remain poorly defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 14, 15]},\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [6, 17]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 6, 8, 18]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [4, 9, 16]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6, 17]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 8, 9, 16]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 6, 8, 10, 11]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [1, 17]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8, 20]}\n    ],\n    \"complexes\": [\n      \"BRCA1/BARD1\"\n    ],\n    \"partners\": [\n      \"BRCA1\",\n      \"BARD1\",\n      \"HSPA1A\",\n      \"STUB1\",\n      \"EIF2S1\",\n      \"AURKA\",\n      \"NEK2\",\n      \"STING1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}