OLA1 (Obg-like ATPase 1) in Human: Functions, Conservation, and Interactions

Molecular Functions of OLA1 in Humans

Biochemical Activity and Domains: OLA1 is a P-loop NTP-binding protein belonging to the TRAFAC class of translation-factor related GTPases, classified specifically in the Obg family and YchF subfamily[1]. It contains a conserved core NTPase domain (with Walker motifs for nucleotide binding and hydrolysis), an inserted helical domain essential for its function, and a C-terminal TGS domain (named for ThrRS, GTPase, SpoT) often implicated in RNA binding[1]. Notably, human OLA1 has evolved a unique nucleotide specificity: it hydrolyzes ATP as its primary substrate and can also hydrolyze GTP with much lower efficiency[2][3]. This altered specificity is due to a mutation in the conserved GTP-binding signature (the G4 motif) of the YchF/OLA1 subfamily, which in OLA1 is (N/T)(M/L/V)xE instead of the typical GTPase motif, resulting in a lower affinity for GTP and preference for ATP[4]. The crystal structure of human OLA1 bound to a nonhydrolyzable ATP analog confirmed the structural basis for this ATP specificity, making the OLA1/YchF subfamily a striking example of an ATPase that arose within a broader family of GTP-binding proteins[3]. In summary, OLA1 is an ATPase by biochemical activity, despite being evolutionarily related to GTPases, and it retains the typical Obg-family domains that enable nucleotide binding and potential RNA/protein interactions.

Functional Annotations and Cellular Roles: In the cell, OLA1 is predominantly a cytosolic protein that associates with ribosomes and stress-related complexes. Gene Ontology annotations for human OLA1 include GTP binding and ribosome binding[5], reflecting its ability to interact with the protein synthesis machinery. Indeed, OLA1 is a ribosome-interacting protein: it binds to 80S ribosomes in human cells and can associate with both the large and small ribosomal subunits[6]. This ribosome binding appears to be nucleotide-independent (as seen with bacterial homologs) and the presence of ribosomes can stimulate OLA1’s ATPase activity[6]. Through these interactions, OLA1 directly influences translation. One known molecular function of OLA1 is the regulation of translation initiation. Human OLA1 can bind to the eukaryotic initiation factor eIF2, preventing the loading of the initiator Met-tRNA_i onto the ribosome, thereby acting as a negative modulator of canonical translation initiation under normal conditions[7]. Consistent with this, down-regulation of OLA1 (such as under stress conditions) leads to enhanced translation initiation and can alleviate the translational repression of the integrated stress response (ISR)[7]. In essence, OLA1 acts as a translational “brake” that is lifted during stress to allow selective mRNA translation.

Beyond translation, OLA1 has emerging roles in multiple stress response pathways. It has been characterized as an intrinsic regulator of the cellular oxidative stress response and heat shock response. OLA1 functions as a negative regulator of antioxidant defenses: studies have shown that OLA1 depletion enhances cellular resistance to oxidative stress, whereas OLA1 overexpression can suppress the antioxidant response[8][9]. Mechanistically, this occurs via non-transcriptional means – for example, OLA1 knockdown cells show improved survival against reactive oxygen species without requiring new gene expression[10]. In contrast, during heat shock, OLA1 plays a protective role by stabilizing molecular chaperones. OLA1 binds directly to the C-terminus of the major heat shock protein HSP70, protecting HSP70 from ubiquitination and proteasomal degradation[11]. This results in elevated HSP70 levels in cells with active OLA1, promoting cell survival during acute heat stress[12]. Consistently, loss of OLA1 leads to accelerated HSP70 turnover and greater heat sensitivity, indicating OLA1 is a positive regulator of the heat shock response[12]. These findings illustrate that OLA1’s molecular functions are closely tied to managing protein homeostasis under stress: it fine-tunes translation and chaperone availability to help cells cope with changing conditions.

Additional Cellular Functions: OLA1 has been implicated in other cellular processes through its interaction partners. For instance, OLA1 interacts with the tumor suppressor BRCA1 and its partner BARD1 (BRCA1-associated RING domain protein 1)[13]. This interaction localizes OLA1 to the centrosome and has been linked to the regulation of centrosome function[13]. Dysregulation of OLA1–BRCA1 binding is suspected to contribute to centrosome amplification and genomic instability, which can promote carcinogenesis in hereditary breast and ovarian cancer contexts[13]. Additionally, OLA1 has been found overexpressed in many cancers (including breast, lung, and liver cancers) and is associated with tumor progression[14]. High OLA1 levels correlate with poor prognosis in certain cancers, making it a candidate biomarker; conversely, OLA1 knockdown in cancer cells can dampen stress pathways (like the ISR) and reduce apoptosis, potentially aiding tumor cell survival[14][7]. OLA1 has also been connected to cell adhesion pathways[15] and cytoskeletal dynamics, although these roles are less well characterized. In summary, human OLA1 is a multifunctional ATPase: biochemically adept at ATP hydrolysis and ribosome binding, and biologically involved in translational control, protein quality control, and cellular stress adaptation.

Evolutionary Conservation of OLA1 Across Species

Conservation and Phylogeny: OLA1 is a highly conserved protein across the tree of life, found in organisms ranging from bacteria to humans. It belongs to an ancient lineage of Obg-family P-loop NTPases that are present in all kingdoms of life[16]. The specific subfamily comprising OLA1 and its orthologs is often referred to as the YchF/Ola1 subfamily, named after the E. coli protein YchF (the bacterial homolog of OLA1)[17]. Members of this subfamily share more than \~40% sequence identity across bacteria, plants, and animals[18], indicating strong evolutionary pressure to maintain their structure and function. All OLA1/YchF proteins contain the hallmark features described in humans: the P-loop NTPase domain, the helical insertion, and the C-terminal TGS domain[1]. Importantly, the unique G4 motif that confers ATP preference is conserved in this subfamily, meaning that even bacterial YchF proteins are ATPases rather than classical GTPases[2]. This represents a notable divergence in nucleotide specificity that occurred within the Obg family, distinguishing the OLA1/YchF branch from other Obg proteins that remain GTP-dependent[19].

Orthologs in Model Organisms: Functional homologs of human OLA1 have been identified in many model organisms. In bacteria, Escherichia coli YchF (363 amino acids) is the prototypical member of this subfamily and was initially presumed to be a GTP-binding protein, but it in fact hydrolyzes ATP similarly to human OLA1[17]. E. coli YchF binds to the 70S ribosome (and specifically can attach to the 50S subunit) in a nucleotide-independent manner[6]. Loss-of-function studies in bacteria suggest YchF is involved in stress adaptation: for example, E. coli downregulates YchF under oxidative stress, and ΔychF mutant bacteria show enhanced survival under oxidative conditions[20], implying a conserved role in modulating the oxidative stress response (in bacteria, YchF depletion leads to a higher tolerance to stress, analogous to OLA1’s negative regulatory role in eukaryotic antioxidant responses). In yeast (Saccharomyces cerevisiae), the OLA1 ortholog (Ola1p, encoded by gene YBR025C) is a 394 amino acid protein that closely mirrors the human protein in domain architecture and function. Yeast Ola1p associates with ribosomes and has been shown to act as a positive regulator of the heat shock response – yeast cells lacking Ola1p upregulate certain stress-protective proteins during heat shock, indicating that, as in humans, Ola1p helps promote chaperone function and proteostasis under thermal stress[21].

Orthologs are also present in multicellular eukaryotes. In plants, such as Arabidopsis thaliana, an OLA1 homolog exists and is highly conserved (sharing >40% identity with human OLA1)[18]. Plant Ola1 is expected to bind plant ribosomes and partake in stress responses; indeed, the ribosome association of OLA1/YchF has been observed in plant systems as well[6], though detailed functional studies in plants are still emerging. In the fruit fly (Drosophila melanogaster), a single OLA1 ortholog (CG1354) is present and is predicted to encode an ATP-hydrolyzing protein active in the cytoplasm[22]. While not extensively characterized, the conservation suggests it performs similar roles in fly development and stress physiology. In nematode worms (C. elegans) and other metazoans, OLA1 homologs are likewise annotated, underscoring a ubiquitous presence in animal lineages. Notably, in mice and other mammals, OLA1 is functionally conserved: mouse OLA1 is \~396 amino acids (essentially the same size as human) and targeted deletion of Ola1 in mice leads to physiological defects, including perinatal lethality, developmental delays, and heightened sensitivity to stress, consistent with the idea that OLA1 is required for normal stress resilience and homeostasis[23][24]. This phenotypic conservation underlines that OLA1’s role is fundamentally important across species.

Distant Taxa and Divergence: Even in more distant eukaryotes and single-celled organisms, OLA1 orthologs are present and largely maintain their function. For instance, the parasite Trypanosoma brucei possesses an OLA1 homolog (TbOLA1) that binds to ribosomes[6] and is thought to be essential for protein synthesis in this organism. Minimalist bacteria provide another perspective: a recent study in Mycoplasma (Mollicutes), which have highly reduced genomes, identified YchF as one of only \~104 core proteins required to sustain ribosome biogenesis and the translation apparatus[25], underscoring how fundamental this protein is even in the simplest self-replicating cells. Overall, no major organisms lack an OLA1/YchF gene, reflecting its universal conservation. While the core biochemical activity of OLA1/YchF is preserved (ATP binding/hydrolysis and ribosome association), some mechanistic nuances diverge between bacteria and eukaryotes. In bacteria, YchF appears to primarily influence the translation of leaderless mRNAs and may interact with different ribosomal factors, whereas in humans OLA1 directly interacts with initiation factor eIF2 and integrates with the eIF2α-mediated stress response[7]. Despite these differences, a common theme across evolution is that OLA1/YchF proteins modulate translation under stress conditions, often restraining protein synthesis under normal conditions and being down-regulated or inactivated to unleash alternative translation programs during stress[26][7]. The table below summarizes OLA1 orthologs in select species and their known features:

(Table: OLA1/YchF orthologs in representative species, highlighting their conservation and roles.)

Key Molecular Mechanisms and Interaction Partners

Ribosome Interaction and Translation Regulation: A central mechanism of OLA1’s action is through its interaction with the ribosome and control of translation. Structural and biochemical studies have shed light on how OLA1 (and YchF) engages the ribosome. A recent cryo-EM structure of E. coli YchF bound to the 50S ribosomal subunit reveals that YchF contacts ribosomal proteins uL14 and bL19 as well as rRNA helix H62 on the large subunit[29]. This binding site lies at the interface of the ribosomal subunits, positioning OLA1/YchF to influence ribosome dynamics. Notably, the inserted helical domain of OLA1 is critical for this interaction and function[30]. Through these contacts, OLA1/YchF can promote the splitting of ribosomes into subunits when translation is stalled, particularly on mRNAs with runs of acidic (Asp/Glu-rich) residues[31]. Such D/E-rich sequences in nascent peptides tend to slow translation and can cause ribosome stalling; OLA1 helps to resolve these stalls by dissociating the ribosome, which in turn allows translation to restart on these difficult mRNAs[31]. This mechanism ensures efficient translation of certain stress-related or tumor-associated mRNAs that encode D/E-rich protein domains[31]. In essence, OLA1 acts as a ribosome rescue factor, maintaining the translation of specific proteins under conditions that would otherwise induce pausing. This activity is somewhat analogous to known ribosome rescue systems in bacteria, though OLA1’s method (ATP-driven subunit splitting) is distinct.

In addition to resolving stalls during elongation, OLA1 influences the initiation phase of translation. As mentioned, human OLA1 interacts with eIF2, the GTP-binding initiation factor that delivers initiator tRNA to the 40S ribosomal subunit[7]. OLA1 binding to eIF2 prevents eIF2 from assembling the translation pre-initiation complex (specifically, it hinders eIF2–Met-tRNA_i binding)[7]. Under normal growth conditions, this activity of OLA1 likely serves to keep a check on unwarranted translation initiation, possibly to conserve resources or ensure proper start codon selection. However, under stress conditions such as the integrated stress response (ISR) – where eIF2 is phosphorylated and general translation is dampened – cells that reduce OLA1 levels can bypass some of the translational inhibition. Experiments have shown that knocking down OLA1 permits higher translation of mRNAs during stress and blunts the effect of ISR signaling[7]. In cancer cells, loss of OLA1 leads to an ISR-deficient state with reduced levels of the pro-apoptotic factor CHOP, thereby promoting survival under stress[32]. These findings highlight OLA1 as a modulator of the translation initiation machinery, acting through direct protein–protein interaction with eIF2 and perhaps other initiation factors. It is worth noting that in bacteria, which lack eIF2, YchF may interact instead with analogous factors or the 30S subunit to influence initiation on leaderless mRNAs[26]. Despite mechanistic differences, both bacteria and human cells see increased non-canonical translation initiation when OLA1/YchF is absent or inactivated, pointing to a conserved role in restraining certain forms of translation and a release of that restraint during stress[26].

Protein Quality Control and Stress Partnerships: OLA1 also interfaces with the protein quality control network via its interaction with molecular chaperones. A key binding partner is Heat Shock Protein 70 (HSP70), a chaperone vital for protein folding and stress resistance. OLA1 binds to HSP70’s C-terminal domain, the same region that co-chaperones and ubiquitin ligases often recognize[11]. By occupying this site, OLA1 protects HSP70 from ubiquitination and subsequent proteasomal degradation[11]. One identified E3 ubiquitin ligase for HSP70 is CHIP; OLA1 likely competes with CHIP or similar factors, thereby stabilizing HSP70 levels during and after heat shock. Consistent with this mechanism, cells lacking OLA1 show a marked increase in HSP70 ubiquitination and turnover, resulting in lower HSP70 steady-state levels[12]. Consequently, OLA1-deficient cells cannot sustain adequate HSP70 under stress and suffer higher rates of protein aggregation and cell death during heat shock[12]. Conversely, normal OLA1 function leads to robust HSP70 availability, which enhances cell survival upon sudden temperature elevations[12]. This molecular mechanism explains OLA1’s role as a positive regulator of the heat shock response and illustrates how it links nucleotide-dependent machinery (its ATPase activity) with the preservation of chaperone proteins. It also connects to OLA1’s effect on oxidative stress: HSP70 levels can influence the stability of antioxidant enzymes like SOD2 (Mn-superoxide dismutase)[33]. In OLA1-null conditions, rapid HSP70 degradation can reduce SOD2 expression or activity, paradoxically lowering intracellular ROS and making cells more resistant to external oxidative stress despite having a generally compromised chaperone capacity[34]. Thus, OLA1’s interaction with HSP70 creates a complex trade-off in stress responses, balancing proteostasis and reactive oxygen species levels.

Cell Cycle and DNA Damage Interactions: Another set of notable OLA1 interactions involves proteins linked to genome maintenance. Human OLA1 was found to interact with BRCA1, a tumor suppressor involved in DNA repair, and with BARD1, BRCA1’s partner in a ubiquitin ligase complex[13]. These interactions suggest that OLA1 might be recruited to nuclear or perinuclear sites (like centrosomes) during the cell cycle. BRCA1-BARD1 plays a role in restraining centrosome duplication; intriguingly, perturbation of OLA1 is associated with centrosome amplification in cells[13]. It is proposed that OLA1, via binding BRCA1/BARD1, influences centrosome dynamics – perhaps by modulating the local availability or activity of this complex. In mouse models, partial loss of Ola1 leads to centrosome amplification and has been linked with the development of lymphomas in older mice[28], aligning with the idea that OLA1 helps safeguard normal cell division. Additionally, OLA1’s negative regulation of antioxidant responses could intersect with DNA damage signaling, since oxidative stress impacts genomic stability. While the precise molecular details remain to be fully elucidated, the OLA1–BRCA1 interaction connects OLA1 to DNA damage response pathways and cancer susceptibility, independent of its ribosomal functions. This may explain why OLA1 is frequently upregulated in cancers and why its genetic variants have been studied in relation to cancer risk and other diseases[14][35]. For example, certain SNPs in the human OLA1 gene have been associated with increased carotid atherosclerosis, potentially due to OLA1’s role in vascular cell migration and response to oxidative stress in the endothelium[36][37].

Summary of Interaction Network: In summary, OLA1 operates at the crossroads of translation regulation, protein quality control, and cellular stress defense by interacting with diverse molecular partners. Its ribosome binding and ATPase activity allow it to act on the translation apparatus directly, controlling ribosome splitting and initiation factor function. Through protein–protein interactions with factors like eIF2, HSP70, BRCA1/BARD1, and likely others (e.g., components of the stress granule or integrated stress response pathways), OLA1 coordinates cellular responses to heat shock, oxidative stress, and DNA damage. These interactions help explain OLA1’s broad influence on cell physiology – from ensuring efficient translation of stress-protective proteins to modulating the cell’s decision between survival and death under extreme conditions. Ongoing research continues to uncover how this universally conserved ATPase can impact such a wide array of processes, solidifying OLA1’s status as an important regulatory node coupling metabolism (ATP/GTP usage), the translation machinery, and stress signaling in cells[26][15].

Sources:

1. Koller-Eichhorn et al., J. Biol. Chem. 282(27):19928-37 (2007). (Original identification of human OLA1 as an ATPase subfamily member in the Obg family)[3][19].

2. Yu et al., Nat. Commun. 16:1549 (2025). (Structural and functional analysis of OLA1/YchF in ribosome binding and translation of D/E-rich mRNAs)[1][31].

3. Landwehr et al., Cells 11(3):374 (2022). (Review: Role of universally conserved YchF/Ola1 ATPase in translation regulation under stress)[38][12].

4. Zhang et al., PNAS 106(36):15356-61 (2009). (OLA1 as a negative regulator of the antioxidant response via non-transcriptional mechanisms)[8][39].

5. Mao et al., Cell Death Dis. 4:e491 (2013). (OLA1 protects cells from heat shock by binding HSP70 and preventing its degradation)[11][40].

6. Lin et al., Int. J. Mol. Sci. 23(19):11511 (2022). (Genetic variants in OLA1 and links to oxidative stress in vascular disease; notes OLA1-BRCA1 interaction)[36][35].

7. Balasingam et al., Biochem. Cell Biol. 98(1):1-11 (2020). (Review of cellular roles of human OLA1 and YchF homologs)[9][41].

8. Rosler et al., J. Biol. Chem. 290(30):18650-61 (2015). (Biochemical dissection of the ATP hydrolysis mechanism in E. coli YchF)[42].

9. Gradia et al., Biochem. Biophys. Res. Commun. 408(3):459-464 (2011). (Ribosome-binding and catalytic analysis of YchF)[41].

10. UniProtKB – OLA1_HUMAN (Q9NTK5): Functional and structural annotations[43][44]. (Accessed 2025)

[1] [2] [4] [6] [7] [13] [14] [15] [18] [25] [29] [30] [31] Conserved GTPase OLA1 promotes efficient translation on D/E-rich mRNA | Nature Communications

https://www.nature.com/articles/s41467-025-56797-8?error=cookies_not_supported\&code=95fce6c4-698b-4c19-8a96-a77f44c8ff76

[3] [16] [17] [19] Human OLA1 defines an ATPase subfamily in the Obg family of GTP-binding proteins - PubMed

https://pubmed.ncbi.nlm.nih.gov/17430889/

[5] [43] [44] OLA1 Gene - GeneCards | OLA1 Protein | OLA1 Antibody

https://www.genecards.org/cgi-bin/carddisp.pl?gene=OLA1

[8] OLA1, an Obg-like ATPase, Suppresses Antioxidant Response via ...

https://pubmed.ncbi.nlm.nih.gov/19706404/

[9] [11] [12] [21] [26] [27] [33] [34] [38] [40] [41] [42] The Role of the Universally Conserved ATPase YchF/Ola1 in Translation Regulation during Cellular Stress - PMC

https://pmc.ncbi.nlm.nih.gov/articles/PMC8779481/

[10] The Universally Conserved ATPase YchF Regulates Translation of ...

https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2021.643696/full

[20] The Universally Conserved ATPase YchF Regulates Translation of ...

https://pmc.ncbi.nlm.nih.gov/articles/PMC8138138/

[22] CG1354 | Drosophila melanogaster gene

https://www.alliancegenome.org/gene/FB:FBgn0030151

[23] [24] Ola1 MGI Mouse Gene Detail - MGI:1914309 - Obg-like ATPase 1

https://www.informatics.jax.org/marker/MGI:1914309

[28] Knockout of Brca1-interacting factor Ola1 in female mice induces ...

https://www.sciencedirect.com/science/article/pii/S0925443924001273

[32] OLA1 regulates protein synthesis and integrated stress response by ...

https://www.nature.com/articles/srep13241

[35] [36] [37] Association of Common Variants in OLA1 Gene with Preclinical Atherosclerosis

https://ouci.dntb.gov.ua/en/works/9JOG0nE7/

[39] Control of a chemical chaperone by a universally conserved ATPase

https://www.sciencedirect.com/science/article/pii/S2589004224014408