Affinage

ALG2

Programmed cell death protein 6 · UniProt O75340

Audit flag: wrong gene
Length
191 aa
Mass
21.9 kDa
Annotated
2026-06-09
100 papers in source corpus 53 papers cited in narrative 48 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ALG2 (PDCD6) is a penta-EF-hand Ca2+-sensor protein that couples Ca2+ signaling to membrane-trafficking and cell-death pathways by acting as a Ca2+-gated adaptor (PMID:8560270, PMID:9832622, PMID:11525164). Ca2+ binding (half-maximal ~6 µM) drives a rigid-body conformational change that exposes a hydrophobic surface and opens distinct ligand-binding pockets: Pocket 1 accepts type-1 PPYP motifs (as in ALIX) while a separate Pocket 3 accepts type-2 PXPGF motifs (as in Sec31A), explaining how a single sensor selectively engages different partners (PMID:11525164, PMID:19143629, PMID:20691033, PMID:25667979, PMID:21786200). Through EF5, ALG-2 forms homodimers and heterodimers with peflin; EF5-mediated dimerization is required for protein stability and underlies its bridging function (PMID:10360947, PMID:11278427, PMID:11883899, PMID:27541325). As a Ca2+-dependent adaptor, ALG-2 bridges the ESCRT machinery — directly binding ALIX and the TSG101 proline-rich region and assembling a ternary ESCRT-I/ALIX/ALG-2 complex — and relieves ALIX autoinhibition to support MVB sorting of ubiquitinated EGFR (PMID:9880530, PMID:10200558, PMID:14999017, PMID:16004603, PMID:19520058, PMID:23924735, PMID:27462417). At ER exit sites it binds the Sec31A proline-rich region to stabilize COPII outer-coat assembly and tune ER-to-Golgi export, with peflin availability setting whether secretion is buffered or stimulated; it also recruits TFG and MISSL to ERES (PMID:16957052, PMID:17196169, PMID:20834162, PMID:24069399, PMID:34762908, PMID:27813252, PMID:28864773). Ca2+-dependent membrane binding to acidic phospholipids targets ALG-2 to ERES and lysosomes, where it recruits ESCRT proteins to confer lysosomal membrane resilience and to drive ERES microautophagy under nutrient stress (PMID:38386713, PMID:38781205, PMID:38593803). In the nucleus, ALG-2 partners with CHERP to control alternative splicing of IP3R1 pre-mRNA (PMID:24078636). ALG-2 was originally identified as a Ca2+-binding protein required for T-cell-receptor-, Fas-, and glucocorticoid-induced apoptosis, acting downstream of caspase activation (PMID:8560270, PMID:9164928). Distinctly, the human ALG2 gene also encodes an ER mannosyltransferase activity: it is a bifunctional α1,3/α1,6-mannosyltransferase that elongates Man1GlcNAc2-PP-dolichol on the cytosolic ER face during N-glycan assembly, and loss-of-function mutations cause a congenital disorder of glycosylation and congenital myasthenic syndrome (PMID:12684507, PMID:16878994, PMID:19282279, PMID:35136180, PMID:23404334).

Mechanistic history

Synthesis pass · year-by-year structured walk · 36 steps
  1. 1996 High

    Established ALG-2 as a Ca2+-binding protein functionally required for programmed cell death, defining its first biological role.

    Evidence Death-trap functional screen with antisense depletion in T cell hybridoma

    PMID:8560270

    Open questions at the time
    • No molecular partner or mechanism identified
    • Does not place ALG-2 relative to caspase activation
  2. 1997 High

    Placed ALG-2 downstream of caspase activation, showing it is required for death execution even when caspases are normally activated.

    Evidence Caspase substrate and PARP cleavage assays in ALG-2-depleted clones

    PMID:9164928

    Open questions at the time
    • Effector mechanism downstream of caspases unresolved
    • No biochemical target identified
  3. 1998 Medium

    Defined the biophysical basis of ALG-2 sensing: a Ca2+-concentration-dependent exposure of a hydrophobic surface enabling target binding.

    Evidence TNS hydrophobicity probe and Ca2+-dependent assays with recombinant protein

    PMID:9832622

    Open questions at the time
    • Single-lab in vitro biochemistry
    • Physiological targets of the exposed surface not yet known
  4. 1999 High

    Identified ALIX/AIP1 as the first Ca2+-dependent ALG-2 partner and connected it to the cell-death pathway.

    Evidence Yeast two-hybrid, co-IP, colocalization and overexpression rescue, replicated independently

    PMID:10200558 PMID:9880530

    Open questions at the time
    • Binding motif on ALIX not yet mapped
    • Functional consequence of the interaction unresolved
  5. 1999 High

    Showed EF5-mediated dimerization and dual strong Ca2+ sites define ALG-2 oligomeric state and Ca2+-induced aggregation.

    Evidence Gel filtration, cross-linking, mutagenesis and spectroscopy with truncated/point mutants

    PMID:10360947

    Open questions at the time
    • Functional importance of the dimer for target bridging not yet established
  6. 2000 Medium

    Demonstrated alternative splicing controls target recognition: Gly121/Phe122 are required for ALIX binding.

    Evidence Yeast two-hybrid isoform comparison and Ca2+ binding assays

    PMID:10744743

    Open questions at the time
    • Structural basis for residue requirement not yet defined
    • Single lab
  7. 2001 High

    Crystal structure of Ca2+-loaded ALG-2 revealed the rigid-body rotation exposing a peptide-binding cleft, defining the mechanism of Ca2+-gated target engagement.

    Evidence X-ray crystallography at 2.3 Å of a Ca2+-loaded fragment

    PMID:11525164

    Open questions at the time
    • Apo vs Ca2+-bound comparison incomplete at this stage
    • Specific physiological ligand in the cleft not yet identified
  8. 2001 High

    Identified peflin as a Ca2+-regulated ALG-2 heterodimer partner, introducing combinatorial control of ALG-2 function.

    Evidence Co-IP, gel filtration, fractionation and immunofluorescence

    PMID:11278427

    Open questions at the time
    • Downstream pathway controlled by peflin/ALG-2 not yet known
  9. 2002 Medium

    Expanded the Ca2+-dependent partner set (annexin VII/XI, ASK1) and linked ALG-2 to JNK signaling regulation.

    Evidence Yeast two-hybrid, overlay/GST pulldown, SPR kinetics, co-IP and JNK activity assays

    PMID:11883939 PMID:12372597 PMID:12445460

    Open questions at the time
    • Physiological relevance of annexin and ASK1 interactions in cells limited
    • Mostly single-lab functional readouts
  10. 2002 Medium

    Showed EF5-dependent dimerization governs ALG-2 (and peflin) stability via proteasomal turnover of monomeric forms.

    Evidence Deletion-mutant pulse-chase with MG132 rescue

    PMID:11883899

    Open questions at the time
    • E3 ligase mediating degradation not identified
    • Single lab
  11. 2003 High

    Established the human ALG2 gene as an α1,3-mannosyltransferase whose deficiency causes a congenital disorder of glycosylation, defining a wholly distinct enzymatic role.

    Evidence Enzyme assay in patient fibroblasts, yeast alg2-1 complementation and cDNA rescue

    PMID:12684507

    Open questions at the time
    • Relationship between the mannosyltransferase and the cytosolic Ca2+-adaptor activities not reconciled
    • Catalytic mechanism not yet defined
  12. 2004 High

    Mapped the ALG-2 binding site to the PxY-repeat proline-rich region of ALIX and proved Ca2+-binding-deficient ALG-2 cannot bind, cementing the Ca2+-gated motif-recognition model.

    Evidence Yeast two-hybrid, overlay, co-IP and alanine-scanning mutagenesis

    PMID:14999017

    Open questions at the time
    • Atomic structure of the complex not yet solved at this stage
  13. 2004 High

    Defined organization of the yeast Alg1/Alg2/Alg11 mannosyltransferase complexes, providing biochemical context for Alg2 in N-glycan assembly.

    Evidence Co-purification and dominant-negative yeast genetics

    PMID:15044395

    Open questions at the time
    • Stoichiometry and human relevance of the complex unresolved
  14. 2005 High

    Extended ALG-2 adaptor function to the ESCRT-I subunit TSG101, linking ALG-2 to endosomal sorting machinery.

    Evidence GST pulldown, yeast two-hybrid, overlay and Ca2+-dependent endosomal colocalization

    PMID:16004603

    Open questions at the time
    • Direct contribution to cargo sorting not yet demonstrated
    • Single lab
  15. 2006 High

    Established ALG-2 as a Ca2+-dependent COPII regulator at ER exit sites that binds and stabilizes Sec31A, connecting Ca2+ signaling to ER-to-Golgi trafficking.

    Evidence Co-IP, confocal imaging, RNAi, Ca2+ chelation and direct binding assays, independently replicated; live-cell imaging linked ALG-2 redistribution to Ca2+ oscillations

    PMID:16957052 PMID:17196169 PMID:17214967

    Open questions at the time
    • Functional effect on vesicle budding not yet quantified at this stage
    • Net directional effect on secretion unresolved
  16. 2006 Medium

    Revealed additional ALG-2 partners (POSH/ALIX in Drosophila, RBM22) connecting ALG-2 to JNK signaling and to nuclear shuttling.

    Evidence Co-IP, Drosophila eye-disc genetics with JNK reporter, and fluorescent-fusion colocalization in cells and zebrafish

    PMID:16698022 PMID:17045351

    Open questions at the time
    • Nuclear function of ALG-2 not yet defined
    • Single labs
  17. 2009 High

    Demonstrated the adaptor mechanism directly: Ca2+-loaded ALG-2 homodimer bridges ALIX and TSG101, an association lost on ALG-2 knockdown and restored by recombinant protein.

    Evidence Strep-tag pulldown with ALG-2 knockdown/reconstitution and dimerization-mutant controls

    PMID:19520058

    Open questions at the time
    • Cellular cargo specificity of the bridged complex not yet defined
  18. 2009 High

    Crystal structures of apo, Ca2+-bound and ALIX-peptide-bound ALG-2 explained pocket opening: Ca2+ at EF3 repositions Arg125 to open Pocket 1 for the PPYP motif.

    Evidence X-ray crystallography of multiple ALG-2 states and a complex

    PMID:19143629 PMID:20691033

    Open questions at the time
    • Structural basis for type-2 (Sec31A) motif binding not yet solved at this stage
  19. 2009 High

    Expanded membrane partners to MCOLN1 (lysosomal channel) and identified yeast Alg2 as a bifunctional α1,3/α1,6-mannosyltransferase acting on the cytosolic ER face with an essential active-site Lys.

    Evidence GST pulldown/co-IP/mutagenesis for MCOLN1; in vitro mannosyltransferase assays with topology and active-site mutagenesis for Alg2

    PMID:16878994 PMID:19282279 PMID:19864416

    Open questions at the time
    • Human enzyme topology and order of mannose addition not yet established
    • Functional role of MCOLN1 binding in cells limited
  20. 2010 High

    Quantified the functional consequence of ALG-2–Sec31A binding: the mapped ABS determines the high-affinity, slow-turnover retention of Sec31A at ERES.

    Evidence Overlay-mapping of ABS and FRAP in live cells with deletion mutants

    PMID:20834162

    Open questions at the time
    • Net effect on cargo export rate not yet resolved
    • Single lab
  21. 2011 High

    Unified the partner-recognition logic by defining two distinct motif classes (type-1 PPYP and type-2 PXPGF) read by separate ALG-2 surfaces, rationalizing isoform-specific partner selection.

    Evidence Structural and mutational synthesis with binding assays

    PMID:21786200

    Open questions at the time
    • Crystallographic definition of the type-2 pocket still pending at this stage
  22. 2013 High

    Resolved the directional consequence of ALG-2 in COPII: Ca2+-loaded ALG-2 attenuates budding while enhancing recruitment and stabilizing outer-coat assembly, and bridges ALIX to ESCRT-I as a ternary complex.

    Evidence In vitro COPII budding and liposome recruitment assays with EF-hand mutant; in vitro reconstitution of ESCRT-I/ALIX/ALG-2 with purified proteins

    PMID:23924735 PMID:24069399

    Open questions at the time
    • Reconciliation of budding attenuation with coat stabilization not fully resolved
  23. 2013 High

    Established a nuclear function: the ALG-2/CHERP complex at nuclear speckles controls Ca2+-regulated alternative splicing of IP3R1 pre-mRNA.

    Evidence Co-IP, live imaging, siRNA, RT-PCR splicing analysis and RNA-IP

    PMID:24078636

    Open questions at the time
    • Breadth of ALG-2-regulated splicing events unknown
    • Single lab
  24. 2013 Medium

    Connected ALG2 enzymatic deficiency to human disease beyond CDG, implicating it in congenital myasthenic syndrome via impaired NMJ glycosylation.

    Evidence Linkage/exome sequencing and expression analysis of patient muscle and transfected cells

    PMID:23404334

    Open questions at the time
    • Direct mechanistic link from glycosylation defect to NMJ pathology inferred, not proven
    • Single study
  25. 2015 High

    Defined the structural basis for type-2 motif binding: Sec31A binds a distinct Pocket 3, with Phe85 and Tyr180 mutations dissociating Sec31A and ALIX binding.

    Evidence Crystal structure of ALG-2/Sec31A peptide complex with pocket mutagenesis

    PMID:25667979

    Open questions at the time
    • Whether both pockets can be occupied simultaneously in trafficking not addressed
  26. 2015 High

    Showed ALG-2 activates ALIX by relieving its autoinhibition, specifically enabling CHMP4-dependent membrane recruitment and MVB sorting of ubiquitinated EGFR.

    Evidence Biochemical activation, membrane recruitment and EGFR sorting assays with pathway-specific controls

    PMID:27462417

    Open questions at the time
    • Why activation is selective for MVB sorting vs abscission/budding not fully explained
  27. 2016 High

    Extended ERES regulation to TFG polymerization and defined EF5 as the high-affinity Mg2+ site stabilizing the ALG-2 dimer.

    Evidence Co-IP, live imaging, in vitro cross-linking for TFG; crystallography and calorimetry with D169A mutant for Mg2+

    PMID:27541325 PMID:27813252

    Open questions at the time
    • Physiological role of Mg2+ occupancy versus Ca2+ in cells unresolved
  28. 2017 High

    Placed MISSL in the ALG-2 ERES pathway and identified MAP1B as a downstream negative regulator of secretion, building a multi-component secretion-control module.

    Evidence Co-IP, live imaging, non-additive double knockdown, SEAP and procollagen transport assays

    PMID:28864773

    Open questions at the time
    • Mechanism by which MAP1B negatively regulates secretion not fully defined
  29. 2018 Medium

    Showed competitive partner regulation: MAP1B binds ALG-2 and selectively competes off ABM-2 partners such as Sec31A, providing a tuning mechanism for ALG-2 localization.

    Evidence Pulldown, co-IP and immunofluorescence in MAP1B KO cells with mutagenesis

    PMID:29432744

    Open questions at the time
    • Physiological trigger for MAP1B competition unknown
    • Single lab
  30. 2018 Medium

    Demonstrated a role in plasma membrane damage repair, dependent on Ca2+ binding and ALIX engagement.

    Evidence PDCD6 KO DT-40 cells, electroporation/digitonin sensitivity assays and peptide competition

    PMID:30240438

    Open questions at the time
    • Direct ESCRT recruitment to wounds not yet visualized
    • Single lab
  31. 2020 Medium

    Linked ALG-2 back to apoptosis mechanistically through proteasome regulation (Rpn3/MCL1) and FASLG trafficking, and to SOCE regulation via SARAF.

    Evidence Co-IP, proteasome activity and MCL1 stability assays; FASLG trafficking co-IP; SARAF binding/ubiquitination assays

    PMID:31919392 PMID:32766719 PMID:32878247

    Open questions at the time
    • FASLG interaction rests on a single low-detail Co-IP/trafficking assay
    • Integration of these activities with the COPII/ESCRT roles unclear
  32. 2021 High

    Established ALG-2 as a Ca2+-dependent regulator of STING ER-to-perinuclear trafficking that restrains type I interferon, and as a hetero-bifunctional COPII rheostat with peflin.

    Evidence ALG2 KO THP-1 with IFN reporter and STING imaging; secretion assays in NRK/PC12 with ALG-2/peflin knockdown

    PMID:34762908 PMID:34787301

    Open questions at the time
    • How peflin availability is set physiologically not defined
    • STING mechanism: direct trafficking step controlled not resolved
  33. 2021 Medium

    Connected the ESCRT adaptor function to apoptosis by showing ALG-2 promotes CDIP1–ESCRT-I association to enhance caspase-dependent death.

    Evidence Co-IP, caspase-3/7 assays and co-expression with ESCRT-I subunit variants

    PMID:33503978

    Open questions at the time
    • Endogenous-level relevance limited by overexpression approach
    • Single lab
  34. 2022 High

    Defined human Alg2 enzyme architecture and kinetics, showing a single membrane-binding domain and a substrate-dependent order of α1,3- then α1,6-mannose addition on the cytosolic ER face.

    Evidence LC-MS quantitative kinetics with purified hAlg2, topology and substrate competition

    PMID:35136180

    Open questions at the time
    • In vivo regulation of reaction order not established
  35. 2022 Medium

    Embedded ALG-2 in a lysosomal stress pathway (JIP4–TRPML1–ALG2) controlling retrograde lysosome transport under oxidative stress.

    Evidence Lysosomal positioning assays, JIP4 KO, Ca2+ flux, phosphomimetics and TRPML1 activation

    PMID:36394115

    Open questions at the time
    • Direct ALG-2 effector at lysosomes in this pathway not pinpointed
    • Single lab
  36. 2024 High

    Resolved how ALG-2 reaches its membrane targets: direct Ca2+-dependent acidic-phospholipid binding drives ERES localization, while ESCRT-I binding can substitute for membrane binding at lysosomes; ALG-2 recruits ESCRT to confer lysosomal membrane resilience and to drive ERES microautophagy.

    Evidence GUV reconstitution, MD simulation, charge-reversal mutagenesis, super-resolution imaging, FIB-SEM and ALG2 KO across two independent studies

    PMID:38386713 PMID:38593803 PMID:38781205

    Open questions at the time
    • Quantitative contribution of lipid vs protein recruitment in different compartments not fully partitioned

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the ER-luminal/cytosolic mannosyltransferase activity and the cytosolic Ca2+-adaptor activities are encoded, partitioned, and regulated within cells remains unresolved.
  • No study reconciles the glycosyltransferase and adaptor functions of the same gene
  • Tissue- and stimulus-specific selection among ESCRT, COPII, splicing and lysosomal roles not defined
  • Determinants of partner choice in vivo beyond motif type and isoform poorly characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0016740 transferase activity 4 GO:0140299 molecular sensor activity 3 GO:0008289 lipid binding 1
Localization
GO:0005783 endoplasmic reticulum 5 GO:0005764 lysosome 3 GO:0005829 cytosol 3 GO:0005654 nucleoplasm 2 GO:0005768 endosome 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 5 R-HSA-392499 Metabolism of proteins 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-8953854 Metabolism of RNA 1 R-HSA-9612973 Autophagy 1
Partners
ALIXCHERPMAP1BMCOLN1PEF1SEC31ATFGTSG101
Complex memberships
ALG-2/peflin heterodimerAlg1/Alg2/Alg11 mannosyltransferase complexCOPII outer coat (Sec13/31A) at ERESESCRT-I/ALIX/ALG-2 ternary complex

Evidence

Reading pass · 48 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 ALG-2 (PDCD6) is a Ca2+-binding protein required for T cell receptor-, Fas-, and glucocorticoid-induced cell death in T cell hybridoma; loss-of-function via antisense depletion protects cells from these apoptotic stimuli. Functional genetic screen ('death trap' assay), antisense depletion, cell death assays Science High 8560270
1997 ALG-2 functions downstream of or independently of ICE/Ced-3 caspase activation during apoptosis: ALG-2-depleted T cells show normal caspase activation (PARP cleavage) yet are protected from death, placing ALG-2 downstream of caspases. Fluorogenic caspase substrate assay, PARP cleavage assay in ALG-2-depleted clones Journal of Immunology High 9164928
1999 ALG-2 interacts with AIP1/ALIX in a strictly Ca2+-dependent manner; AIP1 and ALG-2 co-localize in the cytosol; overexpression of a truncated AIP1 protects cells from trophic factor withdrawal-induced death, indicating AIP1 cooperates with ALG-2 in the Ca2+-dependent cell death pathway. Yeast two-hybrid, co-immunoprecipitation, immunofluorescence colocalization, overexpression rescue The Journal of Biological Chemistry High 10200558 9880530
1998 ALG-2 is a penta-EF-hand Ca2+-binding protein that exposes a hydrophobic surface in a Ca2+-concentration-dependent manner (half-maximal ~6 µM Ca2+), consistent with Ca2+-dependent conformational change enabling target binding; Mg2+ is not effective. Fluorescent hydrophobicity probe (TNS), gel filtration, Ca2+-dependent precipitation assay with recombinant ALG-2 Journal of Biochemistry Medium 9832622
1999 Ca2+-free ALG-2 forms a weak homodimer; the fifth EF-hand (EF5) is required for dimerization; ALG-2 possesses two strong Ca2+-binding sites, and Ca2+ binding to both sites is required for Ca2+-induced protein aggregation. Gel filtration, chemical cross-linking, mutagenesis, fluorescence spectroscopy, circular dichroism with truncated and point mutants Biochemistry High 10360947
2000 ALG-2 exists as two alternatively spliced isoforms (ALG-2,5 and ALG-2,1 lacking Gly121/Phe122); ALG-2,5 but not ALG-2,1 interacts with AIP1/Alix, demonstrating that these two residues are required for target recognition. Yeast two-hybrid, sequence analysis of two mRNA clones, Ca2+ binding assays The Journal of Biological Chemistry Medium 10744743
2001 X-ray crystal structure (2.3 Å) of Ca2+-loaded des1-20 ALG-2 revealed eight α-helices forming five EF-hands, dimer formation via EF5, and Ca2+ binding at EF1, EF3, and EF5. Ca2+ induces a rigid-body rotation between N- and C-terminal halves, exposing a hydrophobic patch and a cleft for peptide binding; a Gly/Pro-rich decapeptide occupies this cleft. X-ray crystallography at 2.3 Å resolution, limited proteolysis for crystallizable fragment Structure High 11525164
2001 ALG-2 forms a Ca2+-independent homodimer and a Ca2+-dependent heterodimer with peflin; in the presence of Ca2+, peflin dissociates from ALG-2, suggesting that peflin modulates ALG-2 function in Ca2+ signaling. In Ca2+ conditions, peflin translocates to the membrane/cytoskeletal fraction. Co-immunoprecipitation, gel filtration, immunofluorescence, subcellular fractionation The Journal of Biological Chemistry High 11278427
2002 ALG-2 directly interacts with the N-terminal domains of annexin VII and annexin XI in a strictly Ca2+-dependent manner through their Pro/Gly/Ala/Tyr/Gln-rich regions, with high-affinity Kd ~40–70 nM and a low-affinity site (~500–700 nM). Yeast two-hybrid, biotin-tagged ALG-2 overlay assay, GST pulldown, surface plasmon resonance (SPR) Biochimica et Biophysica Acta High 11883939 12445460
2002 ALG-2 interacts with ASK1 (apoptosis signal-regulating kinase 1) at its C-terminus (aa 941–1375); ALG-2,1 isoform (lacking Gly121/Phe122) does not bind ASK1; co-transfection of ALG-2 causes nuclear localization of ASK1 and inhibits ASK1-induced JNK activation. Co-immunoprecipitation, in vitro binding, co-transfection, immunofluorescence, JNK activity assay FEBS Letters Medium 12372597
2002 EF5 region of both ALG-2 and peflin is essential for their dimerization and protein stability; EF5-deletion mutants are rapidly degraded by the proteasome, demonstrating that dimerization through EF5 is required for protein stability. Transient expression of deletion mutants, pulse-chase, proteasome inhibitor (MG132) treatment, Western blot Archives of Biochemistry and Biophysics Medium 11883899
2003 Human ALG2 (hALG2, gene CDG1I/hALPG2) encodes an α1,3-mannosyltransferase (GDP-Man:Man1GlcNAc2-PP-dolichol mannosyltransferase) that elongates Man1GlcNAc2-PP-dolichol; deficiency causes CDG-Ii with accumulation of Man1- and Man2-GlcNAc2-PP-dolichol; wild-type but not mutant hALG2 cDNA rescues mannosyltransferase activity in patient fibroblasts and yeast alg2-1 mutant. Enzymatic activity assay in patient fibroblast extracts, complementation of yeast alg2-1 mutant, genetic analysis (heterozygous deletion/substitution), cDNA rescue The Journal of Biological Chemistry High 12684507
2004 ALG-2 directly binds to the Pro-rich C-terminal region (aa 794–827, containing four PxY repeats) of Alix/AIP1 in a Ca2+-dependent manner; alanine substitutions of Pro and Tyr residues in PxY repeats reduce binding; ALG-2(E47A/E114A) Ca2+-binding-deficient mutant does not co-immunoprecipitate with Alix. Yeast two-hybrid, biotin-tagged ALG-2 overlay assay, co-immunoprecipitation, fluorescence microscopy Journal of Biochemistry High 14999017
2004 Yeast Alg1, Alg2, and Alg11 mannosyltransferases physically interact to form two distinct complexes in the ER; one complex contains Alg1+Alg2 and another contains Alg1+Alg11; Alg1 self-assembles through a C-terminal domain distinct from its Alg2/Alg11-interaction regions; catalytically inactive Alg1 missense mutants cause dominant-negative phenotypes, providing genetic evidence for functional Alg1-containing complexes. Biochemical co-purification, genetic epistasis (dominant-negative alleles), yeast genetics Glycobiology High 15044395
2005 ALG-2 directly binds to the proline-rich region (PRR) of TSG101 (ESCRT-I component) in a Ca2+-dependent manner; association with hVps28 and hVps37A is indirect, mediated through TSG101; ALG-2 co-localizes with aberrant endosomes (SKD1/Vps4B dominant-negative) in a Ca2+-dependent manner, suggesting a role as a Ca2+-dependent accessory protein of the endosomal sorting machinery. GST pulldown, yeast two-hybrid, biotin-labeled ALG-2 overlay assay, immunofluorescence microscopy, Ca2+ chelator treatment The Biochemical Journal High 16004603
2006 ALG-2 is recruited to ER exit sites (ERES) by binding to the Pro-rich region of Sec31A (COPII outer coat) in a Ca2+-dependent manner; ALG-2 in turn stabilizes Sec31A at ERES; Ca2+-binding-deficient ALG-2 mutant fails to localize to ERES; Sec31A depletion or Ca2+ chelation (BAPTA-AM) abolishes ALG-2 localization at ERES. Co-immunoprecipitation, immunofluorescence confocal microscopy, RNAi, Ca2+ chelator treatment, GST pulldown, biotin-labeled ALG-2 overlay assay Molecular Biology of the Cell / Biochemical and Biophysical Research Communications High 16957052 17196169
2006 ALG-2 subcellular distribution oscillates in synchrony with Ca2+ oscillations induced by physiological stimuli (ATP, EGF, prostaglandin, histamine), redistributing from cytosol to punctate (COPII/ERES) localization; Ca2+-binding-deficient ALG-2 mutant does not redistribute, establishing a direct link between Ca2+ signaling and ER-to-Golgi trafficking. Live-cell fluorescence imaging of tagged ALG-2 combined with Ca2+ indicators, physiological agonist stimulation Biochemical and Biophysical Research Communications Medium 17214967
2006 In Drosophila, POSH (JNK scaffold protein) forms a Ca2+-dependent complex with ALG-2 and ALIX; overexpression of ALG-2 in imaginal eye discs causes eye phenotypes; overexpression of either ALG-2 or ALIX induces ectopic JNK activation, suggesting the POSH/ALG-2/ALIX complex functions in JNK pathway regulation. Co-immunoprecipitation, genetic overexpression in Drosophila eye discs, JNK activity reporter assay FEBS Letters Medium 16698022
2006 ALG-2 interacts with RBM22 (RNA-binding protein); co-expression of RBM22 causes nuclear translocation of ALG-2 from the cytoplasm, establishing that RBM22 shuttles ALG-2 into the nucleus. Yeast two-hybrid, fluorescent fusion protein co-transfection and confocal microscopy in NIH 3T3 cells and zebrafish embryos Biochimica et Biophysica Acta Medium 17045351
2006 In vitro reconstitution with recombinant yeast Alg2 demonstrates that it is a bifunctional enzyme catalyzing both α1,3-mannosylation and α1,6-mannosylation of the dolichylpyrophosphate-linked substrate to form the first branched pentasaccharide intermediate (Man3GlcNAc2-PP-Dol). In vitro enzymatic assay with purified recombinant Alg2 and defined Dol-PP-linked substrates, mass spectrometry product analysis Biochemistry High 16878994
2008 ALG-2 and Alix interact with pro-caspase-8; Alix forms a complex with TNF receptor-1 (TNF-R1) dependent on ESCRT-binding capacity; Alix lacking its ALG-2-binding site fails to support TNF-R1-induced cell death, suggesting ALG-2/Alix recruit pro-caspase-8 to endosomes containing TNF-R1 for caspase activation. Mass spectrometry identification, co-immunoprecipitation, overexpression of deletion mutants, cell death assays The Journal of Biological Chemistry Medium 18936101
2009 ALG-2 directly binds the NH-terminal cytosolic tail of mucolipin-1 (MCOLN1) in a strictly Ca2+-dependent manner via a patch of charged/hydrophobic residues (MCOLN1 residues 37–49); ALG-2/MCOLN1 co-localize on enlarged endosomes; mutation of the ALG-2-binding domain in MCOLN1 reduces accumulation of aberrant endosomes, indicating ALG-2 regulates MCOLN1 function. GST pulldown, co-immunoprecipitation, immunofluorescence colocalization, site-directed mutagenesis of binding domain The Journal of Biological Chemistry High 19864416
2009 Ca2+-loaded ALG-2 bridges Alix and TSG101 as an adaptor protein: ALG-2-dependent Ca2+-mediated pulldown of TSG101 requires the ALG-2-binding site in Alix (not the PSAP motif); ALG-2 knockdown abolishes the Alix-TSG101 association, which is restored by adding recombinant ALG-2. The ALG-2 homodimer (not monomeric or dimerization-defective forms) is required. Strep-tag pulldown assay, ALG-2 knockdown/reconstitution, use of ALG-2 isoforms and dimerization mutants Biochemical and Biophysical Research Communications High 19520058
2009 X-ray crystal structural analysis of Ca2+-free vs. Ca2+-bound ALG-2 and its complex with an Alix PPYP-containing peptide revealed: Ca2+ binding at EF3 repositions the Arg125 side chain to open a primary hydrophobic pocket (Pocket 1) that accepts the PPYP motif; the side chain of F122 forms Pocket 2 interactions with the Alix peptide. X-ray crystallography of Ca2+-free and Ca2+-bound ALG-2 and ALG-2/Alix peptide complex Biochemical Society Transactions / BMC Structural Biology High 19143629 20691033
2009 Yeast Alg2 is a bifunctional α1,3- and α1,6-mannosyltransferase that adds both mannose residues to Man1GlcNAc2-PP-Dol on the cytosolic face of the ER membrane; Alg2 has only two functional N-terminal transmembrane segments; Lys230 (not an EX7E motif) is essential for catalytic activity, likely involved in GDP-phosphate binding. In vitro mannosyltransferase assay, site-directed mutagenesis (including K230 and EX7E motif), topology analysis, truncation mutants The Journal of Biological Chemistry High 19282279
2010 The ALG-2-binding site (ABS) in Sec31A is defined as residues 839–851 in the Pro-rich region; FRAP analysis shows ABS deletion reduces the high-affinity (slow-turnover) population of Sec31A at ERES, establishing that ALG-2 binding to Sec31A determines Sec31A retention kinetics at ERES. Biotin-labeled ALG-2 overlay assay to map ABS, stable cell lines with GFP-ALG-2 and Sec31A-RFP, FRAP (fluorescence recovery after photobleaching) in live cells Bioscience, Biotechnology, and Biochemistry High 20834162
2011 ALG-2 recognizes at least two distinct Pro-containing motifs in its hydrophobic pockets: type 1 (PPYPXnYP, as in ALIX) binds Pocket 1; type 2 (PXPGF, as in Sec31A) binds at a different surface. The alternatively spliced isoform ALG-2(ΔGF122) cannot bind ALIX (Pocket 1 closed) but retains Sec31A binding. X-ray crystallography, mutational analysis, binding assays summarized in review with structural validation Science China Life Sciences High 21786200
2013 ALG-2 attenuates COPII vesicle budding in vitro through Ca2+-dependent interaction with the ALG-2-binding domain in the Pro-rich region of Sec31A; ALG-2/Ca2+ increases recruitment of COPII proteins (Sec23/24, Sec13/31A) to liposomes and mediates Sec13/31A binding to Sec23, stabilizing the outer coat assembly. In vitro COPII budding assay, liposome recruitment assay, binding assay, ALG-2 EF-hand 1 mutant PloS ONE High 24069399
2013 Nuclear ALG-2 interacts Ca2+-dependently with CHERP (Ca2+ homeostasis ER protein) at nuclear speckles; ALG-2 is recruited to CHERP-localizing speckles upon Ca2+ mobilization. Knockdown of either CHERP or ALG-2 causes generation of alternatively spliced IP3R1 isoforms (inclusion of exons 41/42), establishing that the ALG-2/CHERP complex regulates alternative splicing of IP3R1 pre-mRNA. Co-immunoprecipitation, live-cell time-lapse imaging, siRNA knockdown, RT-PCR splicing analysis, RNA immunoprecipitation The Journal of Biological Chemistry High 24078636
2013 ALG2 mutations (including p.Val68Gly severely reducing ALG2 expression) cause congenital myasthenic syndrome; reduced ALG2 expression correlates with impaired asparagine-linked glycosylation at the neuromuscular junction. Linkage analysis, whole-exome/genome sequencing, Western blot of patient muscle and transfected cells Brain Medium 23404334
2013 ALG-2 bridges ALIX and ESCRT-I (containing VPS37B or VPS37C preferentially) as a Ca2+-dependent adaptor to form a ternary ESCRT-I/ALIX/ALG-2 complex; this was confirmed using purified recombinant proteins in in vitro binding assays. Far-Western blot with biotin-labeled ALG-2, pulldown of recombinant ESCRT-I complexes, in vitro binding with purified proteins Bioscience, Biotechnology, and Biochemistry High 23924735
2015 X-ray crystal structure of ALG-2 complexed with a Sec31A peptide (type 2 motif PXPGF) revealed that the peptide binds to a third hydrophobic pocket (Pocket 3), distinct from Pocket 1 (ALIX-binding); Phe85 mutation abolishes Sec31A binding without affecting ALIX binding; Tyr180 mutation abolishes ALIX but not Sec31A binding. X-ray crystallography of ALG-2/Sec31A peptide complex, site-directed mutagenesis of Pockets 1 and 3 International Journal of Molecular Sciences High 25667979
2015 Ca2+-dependent ALG-2 interaction with ALIX relieves the intramolecular autoinhibitory interaction of ALIX, promoting CHMP4-dependent ALIX membrane association and enabling ALIX to support MVB sorting of ubiquitinated EGFR; this activation is specific to MVB sorting and does not affect cytokinetic abscission or EIAV budding. Biochemical activation assays, membrane recruitment assay, EGFR sorting assay, inhibition of ALG-2 binding domain of ALIX Cell Discovery High 27462417
2016 ALG-2 promotes ER exit site (ERES) localization and Ca2+-dependent polymerization of TFG (Trk-fused gene protein); ALG-2 interacts with TFG via an ALG-2-binding motif (deletion of the motif reduces TFG half-life at ERES); overexpression of ALG-2 increases TFG accumulation at ERES; Ca2+-dependent in vitro cross-linking shows ALG-2 promotes TFG polymerization. Co-immunoprecipitation, time-lapse live-cell imaging, immunostaining, in vitro cross-linking assay, ERES half-life measurement The FEBS Journal High 27813252
2016 EF5 is the high-affinity Mg2+ binding site in ALG-2; D169A mutation (EF5 +x ligand) eliminates high-affinity Mg2+ binding and also reduces Ca2+ affinity at remaining sites (EF1 and EF3); Mg2+ binding in EF5 stabilizes the ALG-2 dimer. X-ray crystallography of Mg2+-bound ALG-2, site-directed mutagenesis of D169, calorimetry-based binding analysis Biochemistry High 27541325
2017 ALG-2 interacts with MISSL (MAPK1-interacting and spindle-stabilizing-like) protein Ca2+-dependently; MISSL relocates to ERES upon Ca2+ rise, colocalizing with ALG-2; MISSL or ALG-2 knockdown similarly attenuates SEAP secretion and delays ER-to-Golgi transport of procollagen type I; double knockdown is not additive, placing them in the same pathway. ALG-2 and MISSL interact with MAP1B, which negatively regulates secretion downstream. Co-immunoprecipitation, live-cell imaging, siRNA knockdown, secretion assay (SEAP), ER-to-Golgi transport assay (procollagen) The Journal of Biological Chemistry High 28864773
2018 MAP1B binds to ALG-2 in a Ca2+-dependent manner through a region lacking canonical ABM-1/ABM-2 motifs; MAP1B binding selectively competes with ABM-2-containing proteins (including Sec31A) for ALG-2 binding; in MAP1B KO cells, ALG-2/Sec31A co-localization increases; overexpression of wild-type (but not binding-defective) MAP1B disperses ALG-2 and Sec31A localization. Pulldown assays, co-immunoprecipitation, immunofluorescence in MAP1B KO cells, mutagenesis Biochemical and Biophysical Research Communications Medium 29432744
2018 ALG-2 participates in plasma membrane damage repair: ALG-2 KO cells (DT-40) are more sensitive to electroporation than wild-type; wild-type ALG-2 (but not Ca2+-binding-deficient mutant) partially protects HeLa cells from digitonin-induced death; a peptide containing the ALIX ALG-2-binding sequence inhibits the protective function. PDCD6 gene knockout by homologous recombination (DT-40), electroporation sensitivity assay, digitonin cell death assay, peptide competition PloS ONE Medium 30240438
2020 ALG-2 directly interacts with Rpn3 (a subunit of the 26S proteasome) and regulates proteasome activity in a Ca2+-dependent manner following T cell activation; this influences MCL1 (pro-survival Bcl-2 family member) stability and accelerates T cell apoptosis during contraction. Co-immunoprecipitation (ALG-2/Rpn3), proteasome activity assay with Ca2+ modulation, MCL1 stability assay (siRNA knockdown), T cell apoptosis assay Cell Death & Disease Medium 31919392
2020 ALG-2 interacts with FASLG (FAS ligand) and regulates its intracellular vesicular transport; ALG-2 involvement in FASLG trafficking contributes to T cell apoptosis pathway. Co-immunoprecipitation, vesicle transport assay The Biochemical Journal Low 32766719
2020 ALG-2 interacts with the cytosolic domain of SARAF (a negative SOCE regulator) Ca2+-dependently via an ABM-2 motif; ALG-2 overexpression interferes with SARAF ubiquitination in a manner requiring intact ALG-2-binding capacity (F228S mutant of SARAF abolishes this); ALG-2 dimer promotes Ca2+-dependent SARAF CytD-to-CytD bridging. Semi-quantitative in vitro binding assay, pulldown, ubiquitination analysis, half-life assay, mutagenesis International Journal of Molecular Sciences Medium 32878247
2021 ALG-2 is required for STING trafficking from the ER: ALG-2 associates with the C-terminal tail of STING Ca2+-dependently; ALG2 knockout markedly increases type I interferon production upon cGAMP/HSV-1; ALG2 inhibits STING translocation from ER to perinuclear region; Ca2+ coordination by ALG2 is required for regulation of STING trafficking. Co-immunoprecipitation, ALG2 KO (THP-1 monocytes), interferon reporter assay, HSV-1 infection, immunofluorescence of STING trafficking Journal of Cell Science Medium 34787301
2021 ALG-2 and peflin together constitute a hetero-bifunctional COPII regulator that responds to Ca2+ signaling: at steady-state Ca2+, ALG-2/peflin heterocomplexes at ERES confer a buffered (reduced) secretion rate, while peflin-lacking ALG-2 complexes stimulate secretion; Ca2+ signaling can either increase or decrease ER export depending on signal intensity/duration, cell type, and peflin availability. Secretion assays (constitutive and regulated), ERES localization analysis of COPII components, Ca2+ agonist stimulation in NRK and PC12 cells, ALG-2/peflin knockdown The Journal of Biological Chemistry High 34762908
2021 CDIP1 (pro-apoptotic p53 target) interacts with ALG-2 Ca2+-dependently; ALG-2 promotes the association between CDIP1 and ESCRT-I (preferentially containing VPS37B or VPS37C); ALG-2 and ESCRT-I together enhance CDIP1-induced caspase-3/7-mediated cell death. Co-immunoprecipitation, GFP-CDIP1 overexpression, caspase-3/7 activity assay, co-expression studies with ALG-2 and ESCRT-I variants International Journal of Molecular Sciences Medium 33503978
2022 Human Alg2 (hAlg2) has a single membrane-binding domain (not four as in yeast Alg2); under physiological conditions, hAlg2 prefers to transfer α1,3-mannose onto M1Gn2 before adding α1,6-mannose; this order preference is altered by excess GDP-Man or elevated M1Gn2, which triggers α1,6-Man addition first; both reactions occur on the cytosolic face of the ER. LC-MS quantitative kinetics assay with purified hAlg2, topology analysis, substrate competition assays Communications Biology High 35136180
2022 Ca2+-mediated ALG-2 recruitment to lysosomes participates in a JIP4-TRPML1-ALG2 pathway controlling lysosomal retrograde transport; oxidative stress (acrolein, H2O2) activates this pathway via TRPML1-mediated Ca2+ release; phosphorylation of JIP4 at T217 by CaMK2G in response to Ca2+ regulates this system. Lysosomal positioning assays, JIP4 KO cells, Ca2+ flux assays, phosphomimetic/KO mutants, pharmacological TRPML1 activation The EMBO Journal Medium 36394115
2024 ALG-2 binds directly to acidic phospholipid membranes in a Ca2+-dependent manner through electrostatic and hydrophobic interactions; charge-reversed mutations at membrane-binding residues reduce ERES localization upon Ca2+ release but still permit lysosomal localization (rescued by ESCRT-I binding); in vitro reconstitution shows ESCRT-I binding can rescue the ALG-2 membrane-binding defect for lysosomal function. Giant unilamellar vesicle (GUV) experiments, molecular dynamics simulations, charge-reversal mutagenesis, live-cell localization assay, in vitro reconstitution with purified components Proceedings of the National Academy of Sciences High 38386713
2024 ALG-2 recruits ESCRT proteins to lysosomes in response to Ca2+ release (from GPN-induced osmotic stress or TRPML1 activation) and enhances lysosomal membrane resilience; ALG-2 ΔGF122 splice variant (ESCRT-binding disabled) fails to protect lysosomes; ERES microautophagy during nutrient stress (mTOR inhibition/amino acid starvation) requires ALG-2, ubiquitinated SEC31, and ALIX; ALG2 KO prevents ERES engulfment by lysosomes. Lysosomal leakage/rupture assays, Ca2+ chelation, live-cell super-resolution imaging, FIB-SEM, ALG2 KO cells, TRPML1 pharmacological activation, in vitro reconstitution with lysosomal lipid-mimicking GUVs and purified recombinant components Proceedings of the National Academy of Sciences / Developmental Cell High 38593803 38781205

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Interfering with apoptosis: Ca(2+)-binding protein ALG-2 and Alzheimer's disease gene ALG-3. Science (New York, N.Y.) 451 8560270
1999 Alix, a novel mouse protein undergoing calcium-dependent interaction with the apoptosis-linked-gene 2 (ALG-2) protein. Cell death and differentiation 215 10200558
1999 Cloning of AIP1, a novel protein that associates with the apoptosis-linked gene ALG-2 in a Ca2+-dependent reaction. The Journal of biological chemistry 201 9880530
2000 The glioma-associated protein SETA interacts with AIP1/Alix and ALG-2 and modulates apoptosis in astrocytes. The Journal of biological chemistry 111 10858458
2013 Congenital myasthenic syndromes due to mutations in ALG2 and ALG14. Brain : a journal of neurology 108 23404334
2003 A new type of congenital disorders of glycosylation (CDG-Ii) provides new insights into the early steps of dolichol-linked oligosaccharide biosynthesis. The Journal of biological chemistry 94 12684507
2006 The Ca2+-binding protein ALG-2 is recruited to endoplasmic reticulum exit sites by Sec31A and stabilizes the localization of Sec31A. Molecular biology of the cell 86 16957052
2009 Identification of the penta-EF-hand protein ALG-2 as a Ca2+-dependent interactor of mucolipin-1. The Journal of biological chemistry 79 19864416
2006 ALG-2 directly binds Sec31A and localizes at endoplasmic reticulum exit sites in a Ca2+-dependent manner. Biochemical and biophysical research communications 76 17196169
2001 Structure of apoptosis-linked protein ALG-2: insights into Ca2+-induced changes in penta-EF-hand proteins. Structure (London, England : 1993) 74 11525164
2001 Peflin and ALG-2, members of the penta-EF-hand protein family, form a heterodimer that dissociates in a Ca2+-dependent manner. The Journal of biological chemistry 72 11278427
1999 Apoptosis-linked gene product ALG-2 is a new member of the calpain small subunit subfamily of Ca2+-binding proteins. Biochemistry 71 10360947
2007 Congenital Disorders of Glycosylation: CDG-I, CDG-II, and beyond. Current molecular medicine 69 17584079
2005 The penta-EF-hand protein ALG-2 interacts directly with the ESCRT-I component TSG101, and Ca2+-dependently co-localizes to aberrant endosomes with dominant-negative AAA ATPase SKD1/Vps4B. The Biochemical journal 69 16004603
2003 Up-regulation of ALG-2 in hepatomas and lung cancer tissue. The American journal of pathology 69 12819013
2013 MAN1B1 deficiency: an unexpected CDG-II. PLoS genetics 65 24348268
2012 Developmental characterization of the microRNA-specific C. elegans Argonautes alg-1 and alg-2. PloS one 65 22448270
2002 The penta-EF-hand domain of ALG-2 interacts with amino-terminal domains of both annexin VII and annexin XI in a Ca2+-dependent manner. Biochimica et biophysica acta 65 12445460
2004 The penta-EF-hand protein ALG-2 interacts with a region containing PxY repeats in Alix/AIP1, which is required for the subcellular punctate distribution of the amino-terminal truncation form of Alix/AIP1. Journal of biochemistry 62 14999017
2002 ALG-2 interacts with the amino-terminal domain of annexin XI in a Ca(2+)-dependent manner. Biochemical and biophysical research communications 60 11883939
2004 Physical interactions between the Alg1, Alg2, and Alg11 mannosyltransferases of the endoplasmic reticulum. Glycobiology 59 15044395
2011 Structure and function of ALG-2, a penta-EF-hand calcium-dependent adaptor protein. Science China. Life sciences 56 21786200
2008 Alix and ALG-2 are involved in tumor necrosis factor receptor 1-induced cell death. The Journal of biological chemistry 56 18936101
2006 Do Alix and ALG-2 really control endosomes for better or for worse? Biology of the cell 56 16354163
1998 Calcium-induced exposure of a hydrophobic surface of mouse ALG-2, which is a member of the penta-EF-hand protein family. Journal of biochemistry 55 9832622
2006 In vitro evidence for the dual function of Alg2 and Alg11: essential mannosyltransferases in N-linked glycoprotein biosynthesis. Biochemistry 54 16878994
2000 Two forms of the apoptosis-linked protein ALG-2 with different Ca(2+) affinities and target recognition. The Journal of biological chemistry 51 10744743
2016 Multifaceted Roles of ALG-2 in Ca(2+)-Regulated Membrane Trafficking. International journal of molecular sciences 50 27571067
2002 ALG-2: a Ca2+ -binding modulator protein involved in cell proliferation and in cell death. Biochimica et biophysica acta 49 12445461
2009 Penta-EF-hand protein ALG-2 functions as a Ca2+-dependent adaptor that bridges Alix and TSG101. Biochemical and biophysical research communications 47 19520058
1993 Biosynthesis of asparagine-linked oligosaccharides in Saccharomyces cerevisiae: the alg2 mutation. Glycobiology 47 8400550
1997 Dissociation of apoptosis and activation of IL-1beta-converting enzyme/Ced-3 proteases by ALG-2 and the truncated Alzheimer's gene ALG-3. Journal of immunology (Baltimore, Md. : 1950) 46 9164928
2007 The apoptosis linked gene ALG-2 is dysregulated in tumors of various origin and contributes to cancer cell viability. Molecular oncology 43 19383317
2013 ALG-2 attenuates COPII budding in vitro and stabilizes the Sec23/Sec31A complex. PloS one 41 24069399
2016 TMEM165 deficiencies in Congenital Disorders of Glycosylation type II (CDG-II): Clues and evidences for roles of the protein in Golgi functions and ion homeostasis. Tissue & cell 40 27401145
2013 Impact of disease-causing mutations on TMEM165 subcellular localization, a recently identified protein involved in CDG-II. Human molecular genetics 40 23575229
2006 POSH, a scaffold protein for JNK signaling, binds to ALG-2 and ALIX in Drosophila. FEBS letters 38 16698022
2024 Ca2+-sensor ALG-2 engages ESCRTs to enhance lysosomal membrane resilience to osmotic stress. Proceedings of the National Academy of Sciences of the United States of America 37 38781205
2006 ALG-2 oscillates in subcellular localization, unitemporally with calcium oscillations. Biochemical and biophysical research communications 37 17214967
2010 The ALG-2 binding site in Sec31A influences the retention kinetics of Sec31A at the endoplasmic reticulum exit sites as revealed by live-cell time-lapse imaging. Bioscience, biotechnology, and biochemistry 36 20834162
2015 ALG-2 activates the MVB sorting function of ALIX through relieving its intramolecular interaction. Cell discovery 35 27462417
2006 Nuclear translocation of the calcium-binding protein ALG-2 induced by the RNA-binding protein RBM22. Biochimica et biophysica acta 35 17045351
1999 Peflin, a novel member of the five-EF-hand-protein family, is similar to the apoptosis-linked gene 2 (ALG-2) protein but possesses nonapeptide repeats in the N-terminal hydrophobic region. Biochemical and biophysical research communications 35 10486255
2016 ALG-2 interacting protein-X (Alix) is essential for clathrin-independent endocytosis and signaling. Scientific reports 34 27244115
2004 ALG-2, a multifunctional calcium binding protein? Frontiers in bioscience : a journal and virtual library 34 14977589
2008 ALG-2 knockdown in HeLa cells results in G2/M cell cycle phase accumulation and cell death. Biochemical and biophysical research communications 33 19013425
2002 Interaction of ALG-2 with ASK1 influences ASK1 localization and subsequent JNK activation. FEBS letters 33 12372597
2016 The calcium-binding protein ALG-2 promotes endoplasmic reticulum exit site localization and polymerization of Trk-fused gene (TFG) protein. The FEBS journal 32 27813252
2006 The Caenorhabditis elegans Argonautes ALG-1 and ALG-2: almost identical yet different. Cold Spring Harbor symposia on quantitative biology 31 17381296
2015 Structural analysis of the complex between penta-EF-hand ALG-2 protein and Sec31A peptide reveals a novel target recognition mechanism of ALG-2. International journal of molecular sciences 30 25667979
2017 Chemo-enzymatic synthesis of lipid-linked GlcNAc2Man5 oligosaccharides using recombinant Alg1, Alg2 and Alg11 proteins. Glycobiology 29 28575298
2003 Properties of the co-chaperone protein p23 erroneously attributed to ALG-2 (apoptosis-linked gene 2). FEBS letters 29 14675759
2013 Nuclear ALG-2 protein interacts with Ca2+ homeostasis endoplasmic reticulum protein (CHERP) Ca2+-dependently and participates in regulation of alternative splicing of inositol trisphosphate receptor type 1 (IP3R1) pre-mRNA. The Journal of biological chemistry 28 24078636
2009 Biochemical characterization and membrane topology of Alg2 from Saccharomyces cerevisiae as a bifunctional alpha1,3- and 1,6-mannosyltransferase involved in lipid-linked oligosaccharide biosynthesis. The Journal of biological chemistry 28 19282279
2013 VPS37 isoforms differentially modulate the ternary complex formation of ALIX, ALG-2, and ESCRT-I. Bioscience, biotechnology, and biochemistry 26 23924735
2002 Both ALG-2 and peflin, penta-EF-hand (PEF) proteins, are stabilized by dimerization through their fifth EF-hand regions. Archives of biochemistry and biophysics 26 11883899
2009 Alix and ALG-2 make a link between endosomes and neuronal death. Biochemical Society transactions 24 19143631
2024 COPII with ALG2 and ESCRTs control lysosome-dependent microautophagy of ER exit sites. Developmental cell 22 38593803
2007 The calcium binding protein ALG-2 binds and stabilizes Scotin, a p53-inducible gene product localized at the endoplasmic reticulum membrane. Archives of biochemistry and biophysics 22 17889823
2000 Increased expression of apoptosis-linked gene 2 (ALG2) in the rat brain after temporary focal cerebral ischemia. Neuroscience 22 10683420
2022 Oxidative stress-induced phosphorylation of JIP4 regulates lysosomal positioning in coordination with TRPML1 and ALG2. The EMBO journal 21 36394115
2017 The calcium-binding protein ALG-2 regulates protein secretion and trafficking via interactions with MISSL and MAP1B proteins. The Journal of biological chemistry 21 28864773
2024 Mechanism and cellular function of direct membrane binding by the ESCRT and ERES-associated Ca2+-sensor ALG-2. Proceedings of the National Academy of Sciences of the United States of America 19 38386713
2017 ALG2 regulates glioblastoma cell proliferation, migration and tumorigenicity. Biochemical and biophysical research communications 18 28300556
2021 The Novel ALG-2 Target Protein CDIP1 Promotes Cell Death by Interacting with ESCRT-I and VAPA/B. International journal of molecular sciences 15 33503978
2021 Development and Initial Characterization of Cellular Models for COG Complex-Related CDG-II Diseases. Frontiers in genetics 15 34603392
2021 ALG-2 and peflin regulate COPII targeting and secretion in response to calcium signaling. The Journal of biological chemistry 15 34762908
2020 ALG-2 couples T cell activation and apoptosis by regulating proteasome activity and influencing MCL1 stability. Cell death & disease 15 31919392
2010 Molecular basis for defect in Alix-binding by alternatively spliced isoform of ALG-2 (ALG-2DeltaGF122) and structural roles of F122 in target recognition. BMC structural biology 15 20691033
1998 Characterization of alg2 encoding a mannosyltransferase in the zygomycete fungus Rhizomucor pusillus. Gene 13 9795208
2010 Stress induced subcellular distribution of ALG-2, RBM22 and hSlu7. Biochimica et biophysica acta 12 21122810
2008 ALG-2 interacting protein AIP1: a novel link between D1 and D3 signalling. The European journal of neuroscience 12 18380665
2022 ALG2 inhibits the epithelial-to-mesenchymal transition and stemness of ovarian granulosa cells through the Wnt/β-catenin signaling pathway in polycystic ovary syndrome. Reproductive biology 11 36327672
2018 ALG-2 participates in recovery of cells after plasma membrane damage by electroporation and digitonin treatment. PloS one 11 30240438
2009 The mechanism of Ca2+-dependent recognition of Alix by ALG-2: insights from X-ray crystal structures. Biochemical Society transactions 11 19143629
2021 ALG2 regulates type I interferon responses by inhibiting STING trafficking. Journal of cell science 10 34787301
2020 The Penta-EF-Hand ALG-2 Protein Interacts with the Cytosolic Domain of the SOCE Regulator SARAF and Interferes with Ubiquitination. International journal of molecular sciences 9 32878247
2013 Mammalian ESCRT-III-related protein IST1 has a distinctive met-pro repeat sequence that is essential for interaction with ALG-2 in the presence of Ca2+. Bioscience, biotechnology, and biochemistry 9 23649269
2021 The Argonaute Proteins ALG-1 and ALG-2 Are Linked to Stress Resistance and Proteostasis. microPublication biology 8 34723149
2021 Novel pathogenic ALG2 mutation causing congenital myasthenic syndrome: A case report. Neuromuscular disorders : NMD 8 34980536
2020 ALG2 Influences T cell apoptosis by regulating FASLG intracellular transportation. The Biochemical journal 8 32766719
2019 Structures and functions of penta-EF-hand calcium-binding proteins and their interacting partners: enigmatic relationships between ALG-2 and calpain-7. Bioscience, biotechnology, and biochemistry 8 31814542
2018 A microtubule-associated protein MAP1B binds to and regulates localization of a calcium-binding protein ALG-2. Biochemical and biophysical research communications 8 29432744
2018 Adaptor functions of the Ca2+-binding protein ALG-2 in protein transport from the endoplasmic reticulum. Bioscience, biotechnology, and biochemistry 8 30259798
2012 Prediction of a new ligand-binding site for type 2 motif based on the crystal structure of ALG-2 by dry and wet approaches. International journal of molecular sciences 8 22837710
2021 Mass spectrometry glycophenotype characterization of ALG2-CDG in Argentinean patients with a new genetic variant in homozygosis. Glycoconjugate journal 7 33644825
2021 A patient-based medaka alg2 mutant as a model for hypo-N-glycosylation. Development (Cambridge, England) 7 34106226
2013 Biochemical and immunological detection of physical interactions between penta-EF-hand protein ALG-2 and its binding partners. Methods in molecular biology (Clifton, N.J.) 7 23296612
2001 Mapping of the interaction sites between apoptosis linked gene ALG-2 and HEED. Molecules and cells 7 11804327
1999 Characterization of an alg2 mutant of the zygomycete fungus Rhizomucor pusillus. Glycobiology 7 10561453
2022 Topological and enzymatic analysis of human Alg2 mannosyltransferase reveals its role in lipid-linked oligosaccharide biosynthetic pathway. Communications biology 6 35136180
2003 ALG2, the Hansenula polymorpha isocitrate lyase gene. Yeast (Chichester, England) 6 12845606
2018 Thermodynamic Characterization of the Ca2+-Dependent Interaction Between SOUL and ALG-2. International journal of molecular sciences 5 30501057
2022 An Autographa californica nucleopolyhedrovirus-encoded microRNA, AcMNPV-miR-4, downregulates the expression of host gene alg-2. The Journal of general virology 3 35830328
2008 Crystallization and X-ray diffraction analysis of N-terminally truncated human ALG-2. Acta crystallographica. Section F, Structural biology and crystallization communications 3 18997320
2001 Crystallization and preliminary crystallographic studies of an apoptosis-linked calcium-binding protein ALG-2. Acta crystallographica. Section D, Biological crystallography 3 11468406
1998 Localization of mRNA for the apoptosis-linked gene ALG-2 in young and aged rat brain. Neuroreport 3 9674578
2024 Ca 2+ -sensor ALG-2 engages ESCRTs to enhance lysosomal membrane resilience to osmotic stress. bioRxiv : the preprint server for biology 2 38352356
2018 Ligation events influence ALG-2 dimerization. Biophysical chemistry 2 29758467
2016 EF5 Is the High-Affinity Mg(2+) Site in ALG-2. Biochemistry 2 27541325

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