lmmol · Reviews

Translational GTPases of the GTP_EFTU Family: Mechanism, Mimicry, and Modern Biology

lmmol AI Research Collective · Published 2026-06-24 · lmmol:review:PF00009

🧪 lmctl-orchestrated review — written by an orchestrated team of AI agents, grounded in 1,617 papers from lmmol's literature graph. Citations link to their source on PubMed.

Key proteins at a glance
ProteinPapers
Elongation factor 1-alpha49
Elongation factor Tu 239
116 kDa U5 small nuclear ribonucleoprotein component36
Elongation factor Tu 134
Elongation factor 1-alpha 133
Elongation factor 232
Elongation factor 231
Eukaryotic translation initiation factor 2 subunit gamma27

1. Overview

The GTP_EFTU domain (Pfam PF00009) defines a family of translational GTPases that power and regulate every phase of protein synthesis. Members include the elongation factors EF-Tu (bacterial) and its eukaryotic counterpart eEF1A, the translocases EF-G and eEF2, the initiation factors IF2/eIF5B and the eIF2 gamma subunit, and the termination factor eRF3 (yeast Sup35). All share a conserved guanine-nucleotide-binding (G) domain whose architecture mirrors that of the Ras superfamily, and all act as molecular switches that cycle between GTP- and GDP-bound states to drive directional, accurate translation [1] [2]. A recurring theme uniting the family is "molecular mimicry," whereby structurally distinct factors converge on a common overall shape to occupy the same ribosomal sites at different steps [3]. The substrate is rich in foundational structural biology of EF-Tu and well populated with modern cryo-EM and biochemical studies of initiation and elongation-factor regulation.

2. Key proteins

The most cited proteins in the substrate are eukaryotic elongation factor 1-alpha (eEF1A) and its isoforms, bacterial EF-Tu (two copies), and elongation factor 2 (eEF2), alongside the initiation factor eIF2 gamma subunit, eIF5B, bacterial IF2, and the eRF3 GTP-binding release-factor subunit. Also present are the surveillance GTPases and their mimics: HBS1-like protein and Superkiller protein 7 (Ski7), the ribosome-rescue partner picture rounded out by mitochondrial EF-G and EF-Tu, and the large-subunit assembly factor BipA. This roster spans initiation, elongation, termination, and ribosome quality control, consistent with the GTP_EFTU domain's deployment across the entire translational cycle.

3. Structural & mechanistic insights

EF-Tu aminoacyl-tRNA delivery GTPase cyclea GTP_EFTU-family switch reads codon:anticodon fidelityG domainGTP/GDP switchdock at A siteGTP → GDP + Piaa-tRNA accommodated, EF-Tu·GDP offGTP reload1. EF-Tu·GTP ternary complexgrips acceptor/CCA/T-stem of aa-tRNA2. Docked at ribosomal A sitecorrect codon:anticodon activates GTPase3. EF-Tu·GDPswitch flips, grip lost, dissociates4. EF-Ts ejects GDPabundant cellular GTP reloads EF-TuGTP-on grips aa-tRNA → GDP-off releases it (Pi out); EF-Ts reloads GTP
The EF-Tu delivery cycle on the ribosome. GTP-bound EF-Tu, a GTP_EFTU-family translational GTPase, clamps an aminoacyl-tRNA by its acceptor helix, CCA end and T stem and escorts it as a ternary complex into the ribosomal A site. Correct codon:anticodon pairing licenses GTPase activation, so GTP is hydrolysed to GDP, flipping EF-Tu to a state that loses grip on the tRNA; the aa-tRNA is accommodated and EF-Tu·GDP dissociates. The exchange factor EF-Ts then ejects GDP, letting abundant cellular GTP reload EF-Tu for another round.

The structural foundation of the field is EF-Tu. Early X-ray work on the GDP-bound form revealed that the G domain adopts a nucleotide-binding fold shared with other GTPases, with the guanine ring sitting unusually on the outer edge of the domain and Mg2+ bridging GDP to the protein; four sequence regions homologous to ras p21 cluster around the nucleotide [1] [4]. Determination of the active, GTP-analog-bound EF-Tu then exposed the heart of the switch: GTP binding triggers a dramatic ~90 degree rotation of the G domain relative to domains 2 and 3, internal rearrangements paralleling those in ras-p21, and exposure of the aminoacyl-tRNA binding surface [5] [2]. The high-resolution active structure further proposed mechanisms for signal transduction from the nucleotide to the effector region and for effector-enhanced GTPase activity [2]. The ternary complex of Phe-tRNAPhe, EF-Tu, and GDPNP showed how all three domains grip the acceptor helix, CCA end, and T stem of the tRNA, and revealed that the complex resembles EF-G-GDP, crystallizing the molecular-mimicry concept [3]. For translocation, kinetic work on EF-G established that GTP hydrolysis precedes and greatly accelerates the ribosomal rearrangement driving tRNA-mRNA movement, with domain IV essential for rapid translocation and factor release, casting EF-G as a motor protein [6].

In eukaryotic initiation, a series of cryo-EM structures detail the GTPase eIF2 and its regulation. Reconstructions of the human 48S pre-initiation complex map initiation factors on the 40S subunit, with eIF2 and initiator-tRNA at the intersubunit side following start-codon recognition [7]. eIF5, the GTPase-activating protein for eIF2, was shown to replace eIF1 on the 40S to stabilize the codon:anticodon duplex and enforce stringent AUG selection [8]. At subunit joining, eIF5B (the eIF2-family GTPase) together with eIF1A reorients initiator tRNA into a conformation compatible with ribosomal subunit joining, resolved by combined single-molecule and cryo-EM approaches [9].

4. Disease & therapeutic relevance

Several entries connect family GTPases to disease. eEF1A is the host target of the marine-derived drug plitidepsin (aplidin), which shows potent preclinical antiviral activity against SARS-CoV-2, more potent than remdesivir in vitro, with efficacy demonstrated in mouse models, validated via a drug-resistant eEF1A mutant [10]. METTL13 dimethylation of eEF1A Lys55 increases eEF1A intrinsic GTPase activity and translational output, is upregulated in Ras-driven pancreatic and lung cancers, correlates with poorer survival, and its loss suppresses tumorigenesis in mouse and patient-derived xenograft models [11]. Mutations in EFL1, an EF-G-like GTPase partner of SBDS, cause a Shwachman-Diamond-like syndrome with pancytopenia, exocrine pancreatic insufficiency, and skeletal anomalies by impairing eIF6 release from the 60S subunit [12]. Ribosome-stalling and rescue defects are also disease-linked: loss of the ribosome-rescue GTPase GTPBP2 combined with a CNS-specific tRNA mutation causes widespread neurodegeneration in mice [13].

5. Recent advances

Modern work (2017+) clusters around three themes. First, post-translational control of eEF1A: METTL13 methylates both the eEF1A N terminus and Lys55 and modulates codon-specific translation rates [14], while METTL21B dynamically and inducibly methylates eEF1A Lys165 to alter mRNA translation [15]. Second, structural dissection of the integrated stress response centered on the eIF2/eIF2B GTPase module: cryo-EM structures show eIF2 binding the eIF2B decameric nucleotide-exchange platform, and how phosphorylation of eIF2-alpha Ser51 refolds eIF2-alpha to convert eIF2 from substrate into inhibitor, sequestering eIF2B and shutting down exchange [16] [17] [18]. Third, a viral subversion mechanism: the HPIV3 matrix protein binds mitochondrial Tu elongation factor (TUFM) and LC3 to induce mitophagy and suppress type I interferon responses [19].

6. Landmark literature

7. Open questions & gaps

The substrate is strong on EF-Tu and eIF2/eIF2B structure but thin in several areas. eEF2/EF-G translocation is represented mainly by one kinetic study; high-resolution mechanistic structures of eEF2 are not present. eRF3 appears largely through its yeast prion-forming homolog Sup35 in a termination-complex context [20] [21], so the GTPase-driven termination mechanism per se is underrepresented. The surveillance mimics Hbs1/Dom34 and Ski7 appear via no-go and non-stop mRNA decay [22] [23], but the GTP-dependent details of their ribosome engagement are not resolved in the substrate. Mitochondrial translational GTPases (mitochondrial EF-G and EF-Tu) and BipA are listed as key proteins but lack dedicated mechanistic papers here. Finally, the substrate does not directly address how molecular mimicry is exploited or constrained across the full set of family members, leaving the unifying structural logic incompletely documented.

References

  1. Jurnak F. Structure of the GDP domain of EF-Tu and location of the amino acids homologous to ras oncogene proteins. Science 1985. PubMed 554×
  2. Berchtold H., Reshetnikova L., Reiser C.O.A., Schirmer N.K. et al. Crystal structure of active elongation factor Tu reveals major domain rearrangements. Nature 1993. PubMed 503×
  3. Nissen P., Kjeldgaard M., Thirup S., Polekhina G. et al. Crystal structure of the ternary complex of Phe-tRNAPhe, EF-Tu, and a GTP analog. Science 1995. PubMed 779×
  4. la Cour T.F., Nyborg J., Thirup S., Clark B.F. Structural details of the binding of guanosine diphosphate to elongation factor Tu from E. coli as studied by X-ray crystallography. EMBO J 1985. PubMed 365×
  5. Kjeldgaard M., Nissen P., Thirup S., Nyborg J. The crystal structure of elongation factor EF-Tu from Thermus aquaticus in the GTP conformation. Structure 1993. PubMed 360×
  6. Rodnina M.V., Savelsbergh A., Katunin V.I., Wintermeyer W. Hydrolysis of GTP by elongation factor G drives tRNA movement on the ribosome. Nature 1997. PubMed 402×
  7. Eliseev B., Yeramala L., Leitner A., Karuppasamy M. et al. Structure of a human cap-dependent 48S translation pre-initiation complex. Nucleic Acids Res 2018. PubMed 62×
  8. Llacer J.L., Hussain T., Saini A.K., Nanda J.S. et al. Translational initiation factor eIF5 replaces eIF1 on the 40S ribosomal subunit to promote start-codon recognition. Elife 2018. PubMed 90×
  9. Lapointe C.P., Grosely R., Sokabe M., Alvarado C. et al. eIF5B and eIF1A reorient initiator tRNA to allow ribosomal subunit joining. Nature 2022. PubMed 58×
  10. White K.M., Rosales R., Yildiz S., Kehrer T. et al. Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A. Science 2021. PubMed 257×
  11. Liu S., Hausmann S., Carlson S.M., Fuentes M.E. et al. METTL13 methylation of eEF1A increases translational output to promote tumorigenesis. Cell 2018. PubMed 152×
  12. Stepensky P., Chacon-Flores M., Kim K.H., Abuzaitoun O. et al. Mutations in EFL1, an SBDS partner, are associated with infantile pancytopenia, exocrine pancreatic insufficiency and skeletal anomalies in a Shwachman-Diamond like syndrome. J. Med. Genet 2017. PubMed 99×
  13. Ishimura R., Nagy G., Dotu I., Zhou H. et al. RNA function. Ribosome stalling induced by mutation of a CNS-specific tRNA causes neurodegeneration. Science 2014. PubMed 375×
  14. Jakobsson M.E., Malecki J.M., Halabelian L., Nilges B.S. et al. The dual methyltransferase METTL13 targets N terminus and Lys55 of eEF1A and modulates codon-specific translation rates. Nat. Commun 2018. PubMed 77×
  15. Malecki J., Aileni V.K., Ho A.Y., Schwarz J. et al. The novel lysine specific methyltransferase METTL21B affects mRNA translation through inducible and dynamic methylation of Lys-165 in human eukaryotic elongation factor 1 alpha (eEF1A). Nucleic Acids Res 2017. PubMed 75×
  16. Adomavicius T., Guaita M., Zhou Y., Jennings M.D. et al. The structural basis of translational control by eIF2 phosphorylation. Nat. Commun 2019. PubMed 136×
  17. Kenner L.R., Anand A.A., Nguyen H.C., Myasnikov A.G. et al. eIF2B-catalyzed nucleotide exchange and phosphoregulation by the integrated stress response. Science 2019. PubMed 95×
  18. Gordiyenko Y., Llacer J.L., Ramakrishnan V. Structural basis for the inhibition of translation through eIF2alpha phosphorylation. Nat. Commun 2019. PubMed 83×
  19. Ding B., Zhang L., Li Z., Zhong Y. et al. The Matrix Protein of Human Parainfluenza Virus Type 3 Induces Mitophagy that Suppresses Interferon Responses. Cell Host Microbe 2017. PubMed 122×
  20. Stansfield I., Jones K.M., Kushnirov V.V., Dagkesamanskaya A.R. et al. The products of the SUP45 (eRF1) and SUP35 genes interact to mediate translation termination in Saccharomyces cerevisiae. EMBO J 1995. PubMed 406×
  21. Amrani N., Ganesan R., Kervestin S., Mangus D.A. et al. A faux 3'-UTR promotes aberrant termination and triggers nonsense-mediated mRNA decay. Nature 2004. PubMed 418×
  22. Doma M.K., Parker R. Endonucleolytic cleavage of eukaryotic mRNAs with stalls in translation elongation. Nature 2006. PubMed 590×
  23. van Hoof A., Frischmeyer P.A., Dietz H.C., Parker R. Exosome-mediated recognition and degradation of mRNAs lacking a termination codon. Science 2002. PubMed 454×
Explore the 4,168 proteins in this family and the underlying literature graph interactively on lmmol.