Affinage

EFL1

Elongation factor-like GTPase 1 · UniProt Q7Z2Z2

Length
1120 aa
Mass
125.4 kDa
Annotated
2026-06-09
19 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EFL1 is a eukaryote-specific GTPase that catalyzes the final cytoplasmic maturation step of the 60S ribosomal subunit, cooperating with SBDS to drive release of the anti-association factor eIF6 (yeast Tif6) and thereby license the large subunit for translation (PMID:28331068, PMID:31151987). SBDS functions as a guanine nucleotide exchange factor for EFL1, dramatically accelerating GDP dissociation without altering GTP affinity or hydrolysis rate, which promotes EFL1 activation; the disease-associated SBDS S143L substitution weakens its affinity for EFL1 and impairs this exchange (PMID:23831625, PMID:25991726), an interaction mediated by the intrinsically disordered insertion domain of EFL1 and domains II–III of SBDS (PMID:24406167). In human patients, biallelic loss-of-function EFL1 mutations cause defective eIF6 eviction, impaired subunit joining, and attenuated global translation, with Efl1-deficient mice recapitulating Shwachman-Diamond syndrome phenotypes (PMID:31151987); loss of EFL1 selectively impairs 80S assembly on TOP-element ribosomal protein transcripts, linking it to translational control of this mRNA class (PMID:34115847). A central mechanistic theme is allosteric control: SDS-associated missense mutations such as R1095Q and M882K leave steady-state GTPase activity and SBDS stimulation intact yet abolish the conformational changes required for eIF6 release (PMID:28331068, PMID:36009035), acting through a long-range intramolecular communication network connecting the GTPase domain (domain I) to domain IV whose disruption is rescued by second-site suppressors in the same allosteric pathway (PMID:31838967, PMID:41848393).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2005 Medium

    Established a functional link between EFL1 and 60S maturation by showing its loss perturbs the GTPase-associated center of the large subunit and that it competes with the elongation machinery for a shared ribosome-binding site.

    Evidence rRNA chemical probing, TAP purification of Tif6-pre-60S, and EF-2 GTPase inhibition assays in wild-type and Δefl1 yeast

    PMID:16095611

    Open questions at the time
    • Did not define the catalytic event EFL1 performs on the subunit
    • Causal role of Tif6/eIF6 in the rRNA defect inferred indirectly
    • No human protein characterized
  2. 2013 High

    Resolved how SBDS regulates EFL1 enzymatically by demonstrating it acts as a GEF rather than a GTPase-activating partner, lowering the Km for GTP without changing kcat.

    Evidence Steady-state kinetic analyses of GTP hydrolysis with purified human and yeast EFL1 ± SBDS/Sdo1

    PMID:23831625

    Open questions at the time
    • Did not directly measure nucleotide exchange rates
    • Did not connect GEF activity to eIF6 release
  3. 2014 High

    Mapped the physical EFL1–SBDS interface, showing the EFL1 disordered insertion domain and SBDS domains II–III mediate complex formation with coupled folding.

    Evidence ITC, size exclusion chromatography, gel shift, and CD with domain-truncated EFL1 and SBDS

    PMID:24406167

    Open questions at the time
    • Interface mapped by truncation, not residue-resolution structure
    • Functional consequence of insertion-domain folding not established
  4. 2015 High

    Defined the kinetic mechanism of SBDS as a GEF, showing it accelerates GDP dissociation specifically, and linked a disease variant to defective EFL1 binding.

    Evidence Stopped-flow spectroscopy with fluorescent nucleotide analogs and anisotropy of WT vs S143L SBDS binding EFL1

    PMID:25991726

    Open questions at the time
    • Did not address how exchange couples to subunit binding
    • S143L effect on eIF6 release not directly tested
  5. 2017 High

    Dissociated GTPase activity from biological function, showing patient mutations preserve catalysis and SBDS stimulation yet block eIF6 eviction from the 60S subunit.

    Evidence GTPase colorimetric assay, Tif6-GFP localization microscopy, CD/SAXS, and yeast complementation of mutant EFL1

    PMID:28331068

    Open questions at the time
    • Molecular basis of how eviction is uncoupled from GTP turnover unknown
    • Structural model of the active conformation lacking
  6. 2019 High

    Confirmed in humans and mice that EFL1 loss-of-function causes defective eIF6 release, impaired subunit joining, and reduced translation, establishing EFL1 as a Shwachman-Diamond-syndrome gene.

    Evidence Patient-cell subunit-joining and polysome assays plus Efl1 knockout mouse phenotyping across three families

    PMID:31151987

    Open questions at the time
    • Tissue-specific bases of phenotype not resolved
    • Did not define which transcripts are most translationally affected
  7. 2019 Medium

    Characterized the allosteric coupling of Sdo1 and guanine nucleotides on EFL1's conformational landscape and noted the solution conformation differs from the 60S-bound state.

    Evidence ITC of Efl1 with GDP, GTP, and Sdo1 separately and combined, with structure-based energetic analysis

    PMID:30780079

    Open questions at the time
    • Interpretive/model-building from a single method and lab
    • Functional readout of the conformational change not assayed
  8. 2019 Medium

    Localized the structural defect of SDS mutations to a rotation of domain IV relative to domains I/II, implicating concerted GTPase-domain/domain-IV action.

    Evidence Molecular dynamics simulations of WT and three mutant EFL1 proteins validated by SAXS

    PMID:31838967

    Open questions at the time
    • Mechanistic interpretation relies heavily on computation
    • Single lab; high-resolution structure of mutants absent
  9. 2021 Medium

    Placed EFL1 evolutionarily as an EF-2 duplicate specialized for ribosome maturation and showed EFL1•SBDS cooperation is species-specific and non-interchangeable.

    Evidence Phylogenetics, GTPase assays of orthologues, and yeast complementation with orthologous/chimeric EFL1 and SBDS

    PMID:34453201

    Open questions at the time
    • Structural basis of species specificity unresolved
    • Role of SBDS domain 2 mechanistically undefined
  10. 2021 Medium

    Identified a specialized translational role, showing EFL1 loss selectively impairs 80S assembly on TOP-element ribosomal protein mRNAs.

    Evidence 80S assembly assays on TOP-containing transcripts in EFL1-loss cell and animal models

    PMID:34115847

    Open questions at the time
    • Mechanism of TOP-transcript selectivity unknown
    • Single lab/single study
  11. 2014 Medium

    Linked EFL1 (EFTUD1) depletion to cellular consequences of disrupted ribosome biogenesis, including G1 arrest, apoptosis, and protective autophagy in glioma cells.

    Evidence siRNA knockdown with cell-cycle, apoptosis, autophagy assays and chloroquine combination in glioma lines

    PMID:25015090

    Open questions at the time
    • Causality between specific maturation defect and phenotype not isolated
    • Single cell-type context
  12. 2022 Medium

    Demonstrated that the R1095Q/R1086Q mutation disrupts a long-distance intramolecular network so Sdo1 and nucleotides no longer trigger eIF6-release conformations, without affecting GTPase kinetics.

    Evidence Enzyme kinetics, ITC of nucleotide and Sdo1 binding, and conformational analysis of WT vs R1086Q Efl1

    PMID:36009035

    Open questions at the time
    • Limited to one mutant
    • Topology of the communication network not yet mapped experimentally
  13. 2026 High

    Mapped the allosteric communication network experimentally, showing the domain-IV R1086Q mutation propagates changes to domain I and the nucleotide pocket, and that a second-site suppressor in the pathway rescues function.

    Evidence X-ray hydroxyl radical footprinting, yeast growth complementation with suppressor mutations, and Tif6-GFP localization

    PMID:41848393

    Open questions at the time
    • Atomic-resolution structure of the active and mutant states still lacking
    • How the network couples to eIF6 displacement on the ribosome unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How EFL1's GTP cycle, allosteric domain-IV motion, and SBDS GEF activity are mechanically coupled to physical eviction of eIF6 from the 60S subunit, and the structural basis of TOP-mRNA selectivity, remain unresolved.
  • No high-resolution structure of the active EFL1•SBDS•60S•eIF6 transition state
  • Mechanism linking conformational change to eIF6 release undefined
  • Basis of TOP-transcript specificity unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 5 GO:0098772 molecular function regulator activity 3
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-392499 Metabolism of proteins 2
Partners
EIF6SBDS
Complex memberships
pre-60S ribosomal particle

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 SBDS (yeast: Sdo1) acts as a guanine nucleotide exchange factor (GEF) for EFL1: in the presence of SBDS/Sdo1, the Km for GTP of EFL1 decreases approximately 2-fold while kcat remains unchanged, indicating that SBDS facilitates nucleotide exchange rather than stimulating hydrolysis. Steady-state kinetic analyses of GTP hydrolysis in vitro; circular dichroism and fluorescence-based assays with purified human and yeast EFL1 alone and in presence of SBDS/Sdo1 Biochemical and biophysical research communications High 23831625
2015 SBDS acts as a guanine nucleotide exchange factor for EFL1 by dramatically increasing the GDP dissociation rate without altering GTP affinity, thereby promoting EFL1 activation. The SDS-associated S143L mutation in SBDS reduces its affinity for EFL1, impairing this nucleotide exchange regulation. Fluorescence stopped-flow spectroscopy with fluorescent guanine nucleotide analogs; fluorescence anisotropy measurements of EFL1–SBDS interaction with wild-type and S143L mutant SBDS The Journal of biological chemistry High 25991726
2014 EFL1 directly interacts with SBDS; this interaction is mediated by the intrinsically disordered insertion domain of EFL1 (which adopts a more fixed conformation upon complex formation) and domains II–III of SBDS, as determined by ITC, size exclusion chromatography, and gel shift assays. Isothermal titration calorimetry (ITC), size exclusion chromatography, gel shift assay, circular dichroism spectroscopy using domain-truncated mutants of EFL1 and SBDS Biochemical and biophysical research communications High 24406167
2005 Deletion of EFL1 in yeast results in heterogeneous rRNA conformations in the GTPase-associated center of free 60S subunits (domains II and VI of 25S rRNA), and EFL1 inhibits EF-2 GTPase activity, suggesting EFL1 and EF-2 share a ribosome-binding site. The rRNA conformational changes in Δefl1 60S subunits are attributable to nucleolar Tif6 deficit during 60S assembly. Chemical probing of rRNA conformation in wild-type, Δefl1, and dominant suppressor (R1) yeast strains; TAP-tag purification of Tif6-associated pre-60S ribosomes; EF-2 GTPase activity assay in the presence/absence of EFL1 Journal of molecular biology Medium 16095611
2017 Pathogenic missense mutations in EFL1 (p.R1095Q and p.M882K) do not affect EFL1 GTPase activity or its stimulation by SBDS, but abolish the ability of EFL1 to promote cytoplasmic release of eIF6 (Tif6) from the 60S subunit, as shown by mislocalization of Tif6-GFP to the cytoplasm in yeast expressing the mutant proteins. Green malachite colorimetric GTPase assay; fluorescence microscopy of Tif6-GFP localization in complemented efl1Δ yeast; circular dichroism and SAXS of mutant EFL1 proteins; yeast growth complementation assay Journal of medical genetics High 28331068
2019 Biallelic loss-of-function mutations in EFL1 in human patients cause defective eIF6 eviction from 60S ribosomal subunits, impaired ribosomal subunit joining, and attenuated global protein translation. In mice, Efl1 deficiency recapitulates key SDS phenotypes. Patient-derived cell studies: ribosomal subunit joining assays, global translation assays (polysome profiling); Efl1 knockout mouse model phenotyping Blood High 31151987
2019 Sdo1 (yeast SBDS) and guanine nucleotides exert cooperative allosteric effects on Efl1 conformational landscape in solution, modulating Efl1 in a way consistent with GTPase activation, as characterized by calorimetric binding analysis. EFL1 in solution adopts an inverted orientation relative to the 60S-bound cryo-EM conformation. Isothermal titration calorimetry (ITC) characterizing Efl1 interactions with GDP, GTP, and Sdo1 separately and in combination; structural-based energetic analysis Biophysical chemistry Medium 30780079
2019 Molecular dynamics simulations supported by SAXS reveal that SDS-associated EFL1 mutations (T127A, M882K, R1095Q) cause a distinctive rotation of domain IV relative to domains I and II, suggesting EFL1 function is governed by an allosteric mechanism involving the concerted action of the GTPase domain (domain I) and domain IV. Comparative molecular dynamics simulations on wild-type and three mutant EFL1 proteins, validated by small-angle X-ray scattering (SAXS) experiments Journal of biomolecular structure & dynamics Medium 31838967
2022 The SDS-associated EFL1 R1095Q mutation (R1086Q in yeast) disrupts a long-distance intramolecular network such that Sdo1 and guanine nucleotides no longer elicit the conformational changes required for eIF6 release, without altering steady-state GTPase kinetics. Enzyme kinetics assays; isothermal titration calorimetry of nucleotide and Sdo1 binding to wild-type vs. R1086Q Efl1; conformational analysis Biomolecules Medium 36009035
2021 EFL1 proteins are exclusive to eukaryotes and originated by gene duplication from EF-2 proteins, specializing in ribosome maturation. Functional complementation assays show species-specific cooperation: no EFL1 orthologue or cross-species EFL1•SBDS combination could rescue the function of the corresponding yeast EFL1•SBDS pair. SBDS domain 2 is vital for function with EFL1 and the 60S subunit. Phylogenetic analysis; GTPase activity assays with orthologous EFL1 proteins; yeast complementation assays with orthologous and chimeric EFL1 and SBDS proteins Molecular genetics and genomics Medium 34453201
2021 Loss of EFL1 specifically impairs assembly of 80S ribosomes on terminal oligopyrimidine (TOP) element-containing ribosomal protein transcripts, demonstrating a role for EFL1 in translational control of this specific mRNA class. Cell line and animal models with EFL1 loss; 80S ribosome assembly assays on TOP-element containing transcripts Blood Medium 34115847
2014 Knockdown of EFTUD1 (EFL1) in glioma cell lines impairs ribosome biogenesis, induces G1 cell-cycle arrest and apoptosis, and triggers protective autophagy as an adaptive response. siRNA knockdown of EFTUD1 in glioma cell lines; Western blot; cell cycle analysis; apoptosis and autophagy assays; autophagy inhibitor (chloroquine) combination experiments Neuro-oncology Medium 25015090
2026 X-ray hydroxyl radical footprinting of yeast Efl1 R1086Q (equivalent to human R1095Q) reveals widespread conformational changes across the protein despite the mutation being located in domain IV, particularly affecting domain I, demonstrating long-range intramolecular communication. A compensatory second-site mutation in the allosteric pathway rescued growth defects and restored nuclear localization of Tif6, confirming that R1086Q disrupts a structural communication network spanning from the nucleotide-binding pocket to domain IV. X-ray hydroxyl radical footprinting (synchrotron-based); yeast growth complementation with second-site suppressor mutations; fluorescence microscopy of Tif6-GFP nuclear localization Protein science High 41848393

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 dpl-1 DP and efl-1 E2F act with lin-35 Rb to antagonize Ras signaling in C. elegans vulval development. Molecular cell 151 11463372
2017 Mutations in EFL1, an SBDS partner, are associated with infantile pancytopenia, exocrine pancreatic insufficiency and skeletal anomalies in aShwachman-Diamond like syndrome. Journal of medical genetics 99 28331068
2019 EFL1 mutations impair eIF6 release to cause Shwachman-Diamond syndrome. Blood 58 31151987
2007 DPL-1 DP, LIN-35 Rb and EFL-1 E2F act with the MCD-1 zinc-finger protein to promote programmed cell death in Caenorhabditis elegans. Genetics 37 17237514
2018 Further evidence for the involvement of EFL1 in a Shwachman-Diamond-like syndrome and expansion of the phenotypic features. Cold Spring Harbor molecular case studies 30 29970384
2013 Guanine nucleotide exchange in the ribosomal GTPase EFL1 is modulated by the protein mutated in the Shwachman-Diamond syndrome. Biochemical and biophysical research communications 19 23831625
2014 Direct interaction between EFL1 and SBDS is mediated by an intrinsically disordered insertion domain. Biochemical and biophysical research communications 17 24406167
2005 Deletion of EFL1 results in heterogeneity of the 60 S GTPase-associated rRNA conformation. Journal of molecular biology 17 16095611
2021 Somatic uniparental disomy mitigates the most damaging EFL1 allele combination in Shwachman-Diamond syndrome. Blood 16 34115847
2015 Defective Guanine Nucleotide Exchange in the Elongation Factor-like 1 (EFL1) GTPase by Mutations in the Shwachman-Diamond Syndrome Protein. The Journal of biological chemistry 16 25991726
2018 Evolutionary freedom in the regulation of the conserved itaconate cluster by Ria1 in related Ustilaginaceae. Fungal biology and biotechnology 13 30065845
2019 Cooperative energetic effects elicited by the yeast Shwachman-Diamond syndrome protein (Sdo1) and guanine nucleotides modulate the complex conformational landscape of the elongation factor-like 1 (Efl1) GTPase. Biophysical chemistry 8 30780079
2014 Functional analysis of a novel glioma antigen, EFTUD1. Neuro-oncology 8 25015090
2019 Exploring the role of elongation Factor-Like 1 (EFL1) in Shwachman-Diamond syndrome through molecular dynamics. Journal of biomolecular structure & dynamics 7 31838967
2024 Shwachman-Diamond syndrome due to biallelic EFL1 variants with complex and fatal clinical course in early infancy. British journal of haematology 3 39379149
2022 Altered Conformational Landscape upon Sensing Guanine Nucleotides in a Disease Mutant of Elongation Factor-like 1 (EFL1) GTPase. Biomolecules 2 36009035
2021 Evolutionary and functional relationships in the ribosome biogenesis SBDS and EFL1 protein families. Molecular genetics and genomics : MGG 1 34453201
2026 Hydroxyl radical footprinting modification reveals an intradomain communication pathway in EFL1 disrupted by a Shwachman-Diamond syndrome-associated mutation. Protein science : a publication of the Protein Society 0 41848393
2026 Homozygous Pathogenic Variant in Elongation Factor-Like 1 (EFL1) as a Causal Factor in Shwachman-Diamond Syndrome 2 in a Palestinian Child, With Distinct Ocular Manifestations. Molecular genetics & genomic medicine 0 42043893

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