Affinage

AK2

Adenylate kinase 2, mitochondrial · UniProt P54819

Length
239 aa
Mass
26.5 kDa
Annotated
2026-06-09
28 papers in source corpus 12 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AK2 is a monomeric phosphotransferase of the mitochondrial intermembrane space that catalyzes the reversible interconversion ATP + AMP ⇌ 2 ADP, sharing the catalytic core (His-36, Asp-93) of cytosolic AK1 but carrying an additional ~50-residue 'wing' segment linked to its mitochondrial localization (PMID:6086335, PMID:3002789). It is imported via the MIA40 disulfide relay and positioned within a central intermembrane-space energy-metabolism platform, where binding of the AK2A isoform to the AIFM1 C-terminus locks AIFM1 in an active NADH oxidoreductase dimer and reciprocally stabilizes AK2A, coupling local ADP regeneration to the OXPHOS machinery (PMID:40312560). Through this role in adenine-nucleotide and ATP homeostasis, AK2 supports mitochondrial oxidative phosphorylation and energy distribution required for hematopoietic stem/progenitor differentiation, with loss causing oxidative stress, energy depletion (elevated AMP/ADP), reduced nuclear ATP supply, and lineage maturation arrest (PMID:26270350, PMID:26150473, PMID:29462620); AK2 deficiency underlies the differentiation block seen in reticular dysgenesis, and hypomorphic variants reveal a particularly strict B-cell dependence on AK2-mediated mitochondrial respiration during activation (PMID:31862378). AK2 function is also essential in vivo, as null mice are embryonic lethal and cardiac-specific deletion precipitates heart failure with metabolite buildup before compensatory adenylate-kinase and creatine-kinase upregulation restores pump function (PMID:33571905). Beyond its catalytic role, AK2 acquires signaling functions: during intrinsic apoptosis it translocates to the cytoplasm and nucleates an AK2-FADD-caspase-10 complex that activates caspase-10 and then caspase-3 (PMID:17952061), and it acts as an AMP-sensing negative regulator of BRAF, where AMP binding strengthens the AK2-BRAF interaction to suppress ERK signaling while RAS activation abrogates it (PMID:35585049). Cytosolic AK2 abundance is set by a post-translational switch in which DPP8/9 process its N-terminus to unmask an IAP-binding motif targeting it for proteasomal degradation, countered by NatA N-terminal acetylation (PMID:40312560).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1986 High

    Establishing AK2's primary structure and catalytic chemistry defined it as a distinct intermembrane-space adenylate kinase rather than a redundant copy of cytosolic AK1.

    Evidence Protein sequencing, CNBr fragmentation, cysteine titration, and sedimentation analysis of the 238-residue enzyme

    PMID:3002789 PMID:6086335

    Open questions at the time
    • Mechanistic basis by which the 'wing' segment directs mitochondrial localization not shown
    • Quaternary regulation in cellular context not addressed
  2. 2007 High

    Identifying the AK2-FADD-caspase-10 complex answered how a metabolic enzyme participates in apoptosis, defining a novel intrinsic death pathway distinct from caspase-8 activation.

    Evidence Reciprocal Co-IP, purified-protein reconstitution in extracts, Apaf-1 knockdown epistasis, and Bcl-2/Bcl-XL overexpression

    PMID:17952061

    Open questions at the time
    • Whether catalytic activity is required for caspase activation unresolved
    • Trigger for AK2 mitochondrial release not defined at molecular level
  3. 2015 High

    Linking AK2 loss to disrupted nucleotide homeostasis, oxidative stress, and lineage arrest explained the hematopoietic basis of reticular dysgenesis and showed the defect is metabolic.

    Evidence shRNA knockdown in human progenitors, zebrafish ak2 mutant, RD patient iPSC differentiation, AMP/ADP profiling, and antioxidant rescue

    PMID:26150473 PMID:26270350

    Open questions at the time
    • Why myeloid/lymphoid lineages are selectively vulnerable not fully explained
    • Direct link between energy state and transcriptional arrest not yet mapped
  4. 2018 Medium

    Demonstrating decreased nuclear ATP distribution in AK2-deficient progenitors refined the model from global energy failure to stage-specific intracellular ATP redistribution controlling fate.

    Evidence FRET-based ATP biosensor imaging and transcriptional profiling in RD patient iPSC-derived hemo-angiogenic progenitors

    PMID:29462620

    Open questions at the time
    • Mechanism coupling AK2 activity to nuclear ATP pools unknown
    • Single-lab iPSC model
  5. 2019 High

    Characterizing hypomorphic AK2 variants revealed a tunable dependency, showing B cells require AK2-mediated respiration more strictly than T cells.

    Evidence Patient variant sequencing, tandem MS enzymatic activity, proliferation/Ig-secretion assays, mitochondrial respiration and membrane potential measurement

    PMID:31862378

    Open questions at the time
    • Molecular basis of B-cell-specific sensitivity not defined
    • Threshold of residual activity sufficient for each lineage not mapped
  6. 2021 High

    Identifying AK2 as an AMP-sensing BRAF inhibitor connected cellular metabolic state to MAPK/ERK signaling, extending AK2 beyond bioenergetics into signal regulation.

    Evidence Reciprocal Co-IP, in vitro BRAF kinase assays, AMP addition to lysates, AK2 KO with proliferation, and HRASG12V HCC mouse model

    PMID:35585049

    Open questions at the time
    • Structural basis of AMP-enhanced AK2-BRAF binding not resolved
    • Physiological contexts where this regulation dominates not delineated
  7. 2021 Medium

    Conditional knockouts established AK2 as developmentally essential and showed cardiac tissue can transiently compensate via redundant kinases, clarifying organ-level requirements.

    Evidence Constitutive embryonic-lethal and cardiac-specific Ak2 deletion with cardiac function, metabolite profiling, compensatory kinase expression, and ultrastructure imaging

    PMID:33571905

    Open questions at the time
    • Whether compensation occurs in other tissues unknown
    • Trigger for compensatory kinase upregulation not identified
  8. 2023 Medium

    Identifying ODF4-dependent AK2 retention in the sperm flagellar midpiece extended AK2's energy role to a specialized motile structure required for fertility.

    Evidence Reciprocal Co-IP from spermatozoa, immunofluorescence, Odf4-/- mouse with motility analysis, and genetic rescue

    PMID:36804949

    Open questions at the time
    • Whether AK2 catalytic function or structural presence drives motility unresolved
    • Direct ODF4-AK2 binding interface not mapped
  9. 2025 High

    Defining DPP8/9 processing, IBM unmasking, IAP-mediated degradation, and NatA acetylation explained how cytosolic AK2 abundance is controlled post-translationally, and confirmed MIA40-dependent intermembrane-space import.

    Evidence Biochemical IBM identification, DPP8/9 processing assays, IAP-binding and NatA acetylation assays, MIA40-dependent import and subcellular fractionation

    PMID:40312560

    Open questions at the time
    • Conditions that partition AK2 between mitochondrial import and cytosolic processing not defined
    • Physiological signals controlling DPP8/9 vs NatA balance unknown
  10. 2024 High

    Structural and biochemical analysis of the AIFM1-AK2A complex placed AK2 within a NADH-sensing intermembrane-space platform that positions it for local ADP regeneration adjacent to OXPHOS.

    Evidence AIFM1 interactome MS, cryo-EM of AIFM1-AK2A, NADH oxidoreductase and binding assays, glycolytic manipulation, and C. elegans genetic interference (preprint)

    Open questions at the time
    • Findings remain in preprint, not yet peer-reviewed
    • Quantitative contribution of AIFM1-positioned AK2 to ATP synthase substrate supply in vivo not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how AK2's catalytic, apoptotic, BRAF-regulatory, and degradation-control functions are coordinately partitioned across mitochondrial and cytosolic pools within a single cell.
  • No unified model of pool partitioning
  • Signals governing functional state transitions undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 2 GO:0060090 molecular adaptor activity 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 1 R-HSA-392499 Metabolism of proteins 1 R-HSA-5357801 Programmed Cell Death 1
Partners
AIFM1BRAFCASP10DPP8DPP9FADDMIA40ODF4
Complex memberships
AIFM1-AK2A complexAK2-FADD-caspase-10 (AFAC10) complex

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 AK2 translocates from mitochondria to the cytoplasm during intrinsic apoptosis (blocked by Bcl-2/Bcl-XL and reduced in Apaf-1 knockdown cells), and forms an AK2-FADD-caspase-10 (AFAC10) complex that activates caspase-10 via FADD and subsequently caspase-3, but not caspase-8, defining a novel intrinsic apoptotic pathway. Purified AK2 added to cell extracts reconstituted this caspase activation cascade. Co-immunoprecipitation of AFAC10 complex, purified protein addition to cell extracts, Apaf-1 knockdown epistasis, Bcl-2/Bcl-XL overexpression, caspase activity assays, AK2 siRNA knockdown Nature cell biology High 17952061
1984 AK2 is a monomeric mitochondrial intermembrane space phosphotransferase that catalyzes ATP + AMP ⇌ 2 ADP. Its N-terminal ~100 residues share homology with cytosolic AK1, including catalytic residues His-36 and Asp-93, but AK2 contains an additional ~50-residue 'wing' segment absent in AK1 that is likely related to its mitochondrial localization. Protein sequencing (Laursen sequenator), CNBr fragmentation, peptide mapping, sequence alignment, molecular weight determination European journal of biochemistry High 3002789 6086335
1986 AK2 contains 238 residues with four cysteines: Cys-41 and Cys-233 are free thiols carboxymethylatable without loss of enzymatic activity, while Cys-43/Cys-93 likely form a disulfide bond in native AK2. AK2 and AK1 share similar active-site geometry but differ in antigenic sites, consistent with lack of immunological cross-reactivity. Gas-phase protein sequencing, SH-group titration, sedimentation equilibrium ultracentrifugation, gel filtration, chemical modification of cysteines with enzymatic activity assay European journal of biochemistry High 3002789
2015 AK2 deficiency impairs mitochondrial oxidative phosphorylation and disrupts adenine nucleotide homeostasis in human hematopoietic progenitors, causing a block in lymphoid and granulocyte differentiation. AK2 knockdown progenitors show poor proliferative and survival capacities. AK2 shRNA knockdown in hematopoietic progenitors, mitochondrial function assays (oxidative phosphorylation measurement), proliferation and survival assays, differentiation assays toward lymphoid and granulocyte lineages Cell death & disease Medium 26270350
2015 AK2 deficiency in zebrafish leads to increased oxidative stress and apoptosis in hematopoietic stem and progenitor cells; AK2-deficient human iPSCs show increased AMP/ADP ratio (energy-depleted adenine nucleotide profile) and myeloid maturation arrest. Antioxidant treatment rescues hematopoietic phenotypes in vivo and restores granulocyte differentiation from iPSCs, linking AK2 loss to cellular energy depletion and oxidative stress. Zebrafish ak2 mutant model, RD patient-derived iPSC differentiation, adenine nucleotide profiling (AMP/ADP ratio), antioxidant rescue experiments, in vivo and in vitro differentiation assays The Journal of experimental medicine High 26150473
2018 AK2 maintains ATP supply to the nucleus during hematopoietic differentiation; RD patient-derived iPSC hemo-angiogenic progenitor cells show decreased ATP distribution in the nucleus and altered global transcriptional profiles, indicating a stage-specific role for AK2 in intracellular ATP redistribution controlling hematopoietic progenitor fate. RD patient iPSC-derived hematopoietic differentiation, ATP distribution imaging (FRET-based ATP biosensor), transcriptional profiling Biochemical and biophysical research communications Medium 29462620
2019 Hypomorphic AK2 variants (AK2G100S and AK2A182D) allow residual AK2 protein expression and enzymatic activity with normal neutrophil and lymphocyte counts, but cause B-cell-specific defects in proliferation and immunoglobulin secretion associated with impaired mitochondrial respiration and dysregulated mitochondrial membrane potential upon B-cell activation, revealing that B cells have a stricter dependency on AK2-mediated mitochondrial function than T cells. Next-generation sequencing to identify variants, tandem mass spectrometry for enzymatic activity, lymphocyte proliferation assays, in vitro immunoglobulin secretion, mitochondrial respiration measurement, mitochondrial membrane potential assay, chemical ATP synthesis inhibition in control cells The Journal of allergy and clinical immunology High 31862378
2021 AK2 promotes migration and invasion of lung adenocarcinoma cells through the Smad-dependent TGF-β/EMT signaling pathway. AK2 knockout reduced EMT-like features and metastatic nodule formation in vivo. AK2 siRNA knockdown, CRISPR knockout, AK2 overexpression, cell migration and invasion assays, differential proteomics, western blot and qPCR for EMT markers and Smad pathway components, in vivo mouse metastasis model Frontiers in pharmacology Medium 34630090
2021 AK2 null homozygosity is embryonic lethal in mice; conditional cardiac-specific AK2 deletion causes abrupt heart failure with Krebs cycle and glycolytic metabolite buildup, followed by compensatory upregulation of AK1, AK3, AK4, creatine kinase isoforms, and hexokinase with mitochondrial ultrastructure remodeling that permits recovery of pump function. Transgenic AK2 knockout (constitutive embryonic lethality), conditional organ-specific Ak2 deletion, cardiac function measurement, metabolite profiling, compensatory kinase expression analysis, mitochondrial ultrastructure imaging Biochemical and biophysical research communications Medium 33571905
2022 AK2 physically interacts with BRAF and inhibits BRAF kinase activity and downstream ERK phosphorylation. AMP binding to AK2 strengthens the AK2-BRAF interaction, placing AK2 as an AMP-sensing negative regulator of BRAF that links cellular metabolic state to MAPK signaling. RAS activation abrogates AK2-BRAF interaction. AK2 also binds and attenuates BRAF inhibitor-insensitive BRAF mutants. Co-immunoprecipitation (AK2-BRAF), in vitro kinase assays for BRAF activity, ERK phosphorylation western blot, AMP addition to cell lysates, AK2 KD/KO with proliferation assay, mouse HRASG12V-driven HCC model Cell death & disease High 35585049
2023 ODF4 co-immunoprecipitates with AK2 (and AK1) in mouse spermatozoa; ODF4 localizes to the whole flagellum midpiece region where AK2 is present. Deletion of Odf4 reduces AK2 levels in sperm flagella and causes abnormal flagellar shape (hairpin flagellum) with loss of midpiece motility and male infertility, rescued by Odf4 restoration. Co-immunoprecipitation of ODF4 with AK2/AK1 from spermatozoa, immunofluorescence localization, Odf4-/- mouse model, sperm motility analysis, rescue experiment with Odf4 restoration Scientific reports Medium 36804949
2025 Cytosolic AK2 stability is regulated by sequential post-translational events: DPP8/9 dipeptidyl peptidases process AK2's N-terminus, unmasking an IAP-binding motif (IBM) that targets AK2 for IAP (E3 ligase)-mediated proteasomal degradation. N-terminal acetylation by NatA prevents the AK2-IAP interaction, stabilizing cytosolic AK2. Biochemical identification of IBM, DPP8/9 processing assays, IAP interaction assays, NatA acetylation assays, genome-wide in silico IBM screen, validation with EIF2A as additional substrate EMBO reports High 40312560
2024 AIFM1 interacts with AK2 (specifically isoform AK2A) via its C-terminus, stabilizing AK2A. Cryo-EM and biochemical analyses show that AK2A binding to AIFM1's C-terminal β-strand locks AIFM1 in an active dimer conformation and enhances its NADH oxidoreductase activity. MIA40 binds the same site and additionally affects the cofactor binding site. The AIFM1-AK2A interaction is crucial during respiratory conditions, placing AK2 as part of the central energy metabolism regulatory platform in the mitochondrial intermembrane space. High-confidence AIFM1 interactome (MS), high-resolution cryo-EM structure of AIFM1-AK2A complex, biochemical binding assays, NADH oxidoreductase activity assays, genetic interference in C. elegans bioRxiv (preprint)preprint High
2024 The AIFM1-AK2 interaction is NADH-dependent and influenced by glycolytic state, placing AK2 adjacent to OXPHOS complexes for local ADP regeneration as substrate for ATP synthase. Disruption of AIFM1/AK2 association impairs metabolic adaptation to altered nutrient availability in C. elegans, identifying AIFM1 as a cellular NADH sensor that positions AK2 to balance ATP synthase substrate supply. AIFM1-AK2 binding assays under NADH conditions, glycolytic manipulation, genetic interference in C. elegans (metabolic phenotype), cryo-EM imaging referenced for hinge motion bioRxiv (preprint)preprint Medium
2025 AK2 is localized in the mitochondrial intermembrane space and imported via the MIA40 disulfide relay system. In the cytosol, AK2 undergoes N-terminal processing by DPP8/9 that sensitizes it to proteasomal degradation (confirmed by the IBM-IAP mechanism). Subcellular fractionation, MIA40-dependent import assay, N-terminal processing assays with DPP8/9 EMBO reports Medium 40312560

Source papers

Stage 0 corpus · 28 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 AK2 activates a novel apoptotic pathway through formation of a complex with FADD and caspase-10. Nature cell biology 81 17952061
2015 AK2 deficiency compromises the mitochondrial energy metabolism required for differentiation of human neutrophil and lymphoid lineages. Cell death & disease 66 26270350
2015 Reticular dysgenesis-associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress. The Journal of experimental medicine 49 26150473
1984 Mitochondrial adenylate kinase (AK2) from bovine heart. Homology with the cytosolic isoenzyme in the catalytic region. European journal of biochemistry 37 6086335
1986 Mitochondrial adenylate kinase (AK2) from bovine heart. The complete primary structure. European journal of biochemistry 32 3002789
2019 Hypomorphic variants in AK2 reveal the contribution of mitochondrial function to B-cell activation. The Journal of allergy and clinical immunology 24 31862378
1982 Assignment of ADA, ITPA, AK1, and AK2 to Chinese hamster chromosomes. Genetic and structural evidence for the conservation of mammalian autosomal synteny. The Journal of heredity 24 7153494
2018 Human AK2 links intracellular bioenergetic redistribution to the fate of hematopoietic progenitors. Biochemical and biophysical research communications 16 29462620
2021 Adenylate kinase AK2 isoform integral in embryo and adult heart homeostasis. Biochemical and biophysical research communications 14 33571905
2020 Circ-AK2 is associated with preeclampsia and regulates biological behaviors of trophoblast cells through miR-454-3p/THBS2. Placenta 14 33129036
2012 Adenylate kinase 2 (AK2) promotes cell proliferation in insect development. BMC molecular biology 14 23020757
2021 AK2 Promotes the Migration and Invasion of Lung Adenocarcinoma by Activating TGF-β/Smad Pathway In vitro and In vivo. Frontiers in pharmacology 13 34630090
2024 Ancestral retrovirus envelope protein ERVWE1 upregulates circ_0001810, a potential biomarker for schizophrenia, and induces neuronal mitochondrial dysfunction via activating AK2. Cell & bioscience 12 39543767
1993 Microbial metabolism of quinoline and related compounds. XX. Quinaldic acid 4-oxidoreductase from Pseudomonas sp. AK-2 compared to other procaryotic molybdenum-containing hydroxylases. Biological chemistry Hoppe-Seyler 10 8292263
2019 Quantitative proteomic analysis reveals AK2 as potential biomarker for late normal tissue radiotoxicity. Radiation oncology (London, England) 8 31399108
2023 The association of ODF4 with AK1 and AK2 in mice is essential for fertility through its contribution to flagellar shape. Scientific reports 7 36804949
2022 AK2 is an AMP-sensing negative regulator of BRAF in tumorigenesis. Cell death & disease 6 35585049
1984 Partial purification and properties of thermostable intracellular amylases from a thermophilic Bacillus sp. AK-2. Acta microbiologica Polonica 6 6205552
2025 Andrographolide ameliorates sepsis-induced acute liver injury by attenuating endoplasmic reticulum stress through the FKBP1A-mediated NOTCH1/AK2 pathway. Cell biology and toxicology 4 40053226
2025 DPP8/9 processing of human AK2 unmasks an IAP binding motif. EMBO reports 4 40312560
2024 Quantitative tissue analysis reveals AK2, COL1A1, and PLG protein signatures: targeted therapeutics for meningioma. International journal of surgery (London, England) 4 39288025
2023 UK-5099, a mitochondrial pyruvate carrier inhibitor, recovers impaired neutrophil maturation caused by AK2 deficiency in human pluripotent stem cell models. Biochemical and biophysical research communications 4 37949028
2021 circ_0075943 Dominates the miR-141-3p/AK2 Network to Support the Development of Breast Carcinoma. Journal of oncology 3 34887922
2020 Reticular dysgenesis caused by an intronic pathogenic variant in AK2. Cold Spring Harbor molecular case studies 3 32532877
2025 Early Haploidentical Hematopoietic Stem Cell Transplantation Provides Rapid Leukocyte and Immune Reconstitution in AK2 Patient Identified by TREC Newborn Screening. Journal of clinical immunology 2 39932644
2026 Case Report: Novel AK2 variant causing reticular dysgenesis with hemophagocytic lymphohistiocytosis-like syndrome and invasive aspergillosis. Frontiers in immunology 0 42039167
2026 Reticular dysgenesis caused by AK2 deficiency: clinical spectrum and hematopoietic stem cell transplantation outcomes in 10 patients from a single-center. Frontiers in immunology 0 42112325
2025 AK2-Deficient Mice Recapitulate Impaired Lymphopoiesis of Reticular Dysgenesis Patients, but Also Lack Erythropoiesis. European journal of immunology 0 40654267

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