Affinage

APPBP2

Amyloid protein-binding protein 2 · UniProt Q92624

Length
585 aa
Mass
66.9 kDa
Annotated
2026-06-09
18 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

APPBP2 is the substrate-recognition subunit of a CUL2-RING E3 ubiquitin ligase (CRL2APPBP2) that targets proteins bearing C-terminal R-x-x-G/C degron motifs for polyubiquitination and proteasomal degradation (PMID:35978186, PMID:37844242, PMID:37735597). Cryo-EM of the active complex shows that APPBP2 engages the degron through a bipartite pocket in which the arginine and glycine occupy distinct subsites spaced by two residues, accommodating motifs at or within three residues of the C-terminus, and that the ligase assembles into dimeric and tetrameric forms (PMID:37844242). Through this activity APPBP2 sets the abundance of specific substrates: it polyubiquitinates PRDM16, controlling its half-life and thereby beige adipocyte biogenesis and systemic metabolic homeostasis (PMID:35978186), and it degrades TSPYL2 to downregulate P21waf1/cip1 and delay senescence in human mesenchymal stem cells (PMID:38170390). Independently of its E3 ligase role, APPBP2 localizes to early endosomes, where it regulates Rab5/EEA1 vesicle number and transferrin receptor endocytosis and recycling (PMID:31139847). In non-small-cell lung cancer cells APPBP2 physically associates with PPM1D and supports proliferation, migration, and invasion, with PPM1D and SPOP acting downstream of its effects (PMID:31105033).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2009 Low

    An early interaction screen placed APPBP2 in a protein-binding context, identifying it as a microtubule-associated partner of the spermatid protein SLY1 before any enzymatic role was known.

    Evidence Yeast two-hybrid and co-immunoprecipitation

    PMID:19176879

    Open questions at the time
    • Single Y2H/Co-IP without reciprocal validation or functional consequence
    • No mechanistic role for APPBP2 established
    • Relevance of microtubule association to later E3 ligase function unresolved
  2. 2014 Low

    Transcriptional profiling showed APPBP2 is a thyroid-hormone-responsive gene in fetal cortex, addressing how its expression is regulated but not what the protein does.

    Evidence Expression microarray with thyroid hormone manipulation and TH response element confirmation in fetal mouse cortex

    PMID:24436321

    Open questions at the time
    • No downstream protein function established
    • Physiological role of TH-induced APPBP2 in brain development unknown
  3. 2019 Medium

    Two studies expanded APPBP2 function beyond a binding partner: one assigned it an early-endocytic role, the other linked it to cancer cell proliferation through PPM1D.

    Evidence Endosomal marker colocalization, transferrin uptake and domain-overexpression assays; and co-immunoprecipitation with shRNA knockdown, rescue, and xenograft assays in NSCLC

    PMID:31105033 PMID:31139847

    Open questions at the time
    • Endocytic role not mechanistically connected to E3 ligase activity
    • PPM1D interaction is a single Co-IP without reciprocal validation
    • Whether the PPM1D effect involves ubiquitin ligase activity is untested
  4. 2023 High

    APPBP2 was defined as a CUL2 substrate receptor and a physiological E3 ligase, with PRDM16 identified as a substrate whose degradation gates beige adipogenesis and metabolic health.

    Evidence Biochemical ubiquitination assays, protein half-life measurement, and adipocyte-specific CUL2-APPBP2 knockout mice with metabolic phenotyping

    PMID:35978186

    Open questions at the time
    • Degron in PRDM16 not yet defined in this study
    • Regulation of CRL2APPBP2 assembly/activity in adipocytes unknown
  5. 2023 High

    Structural and screening work established the molecular logic of substrate recognition, showing CRL2APPBP2 reads C-terminal R-x-x-G/C degrons via a bipartite pocket and identifying its substrate repertoire.

    Evidence Cryo-EM of CRL2APPBP2 bound to multiple degrons with binding and cell-based assays; and multiplex CRISPR screening with site-saturation mutagenesis

    PMID:37735597 PMID:37844242

    Open questions at the time
    • Functional significance of dimer/tetramer assembly states unresolved
    • Full physiological substrate set not enumerated
  6. 2023 Medium

    A second physiological substrate, TSPYL2, was identified, connecting CRL2APPBP2 activity to P21-dependent control of stem cell senescence.

    Evidence CRISPR/Cas9 CUL2 deletion, hESC-to-hMSC differentiation, proteasome inhibition, and senescence phenotyping

    PMID:38170390

    Open questions at the time
    • Direct degron in TSPYL2 not structurally mapped
    • Single-lab study without orthogonal substrate confirmation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How APPBP2's endosomal/microtubule-associated roles relate mechanistically to its CRL2 E3 ligase activity, and whether its cancer-promoting PPM1D interaction reflects ubiquitin ligase function, remain unresolved.
  • No unifying model linking endocytic and E3 ligase functions
  • Substrate dependence of cancer phenotypes untested
  • Tissue-specific regulation of CRL2APPBP2 assembly unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3 GO:0060090 molecular adaptor activity 2 GO:0016874 ligase activity 1
Localization
GO:0005768 endosome 1
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-5653656 Vesicle-mediated transport 1
Partners
CUL2PPM1DPRDM16SLY1TSPYL2
Complex memberships
CRL2APPBP2 (CUL2-RING E3 ubiquitin ligase)

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2023 CUL2-APPBP2 is the ubiquitin E3 ligase that determines PRDM16 protein stability by catalysing its polyubiquitination. Inhibition of CUL2-APPBP2 extended the half-life of PRDM16 protein and promoted beige adipocyte biogenesis. Adipocyte-specific deletion of CUL2-APPBP2 counteracted diet-induced obesity and metabolic dysfunction in mice. Biochemical ubiquitination assays, protein half-life measurement, adipocyte-specific CUL2-APPBP2 knockout mouse model with metabolic phenotyping Nature High 35978186
2023 APPBP2 (as part of CRL2APPBP2) specifically recognizes R-x-x-G/C-degrons at or near the C-terminus of substrate proteins via a bipartite mechanism, where arginine and glycine occupy distinct pockets spaced by two residues. The binding pocket accommodates the motif placed at or up to three residues upstream of the C-terminus. CRL2APPBP2 assembles as a dimer and tetramer. Cryo-EM structure determination of active CRL2APPBP2 bound with different R-x-x-G/C-degrons, complemented by binding experiments and cell-based assays Proceedings of the National Academy of Sciences of the United States of America High 37844242
2023 CRL2APPBP2 ubiquitin ligase targets TSPYL2 (a negative regulator of proliferation) for ubiquitin-proteasome-mediated degradation via APPBP2 as the substrate receptor. This degradation downregulates P21waf1/cip1 and delays senescence in human mesenchymal stem cells. CRISPR/Cas9-mediated CUL2 deletion, differentiation of hESCs into hMSCs, identification of TSPYL2 as substrate via APPBP2 substrate receptor, proteasome inhibition assays, senescence phenotype analysis Science China. Life sciences Medium 38170390
2023 A multiplex CRISPR screening platform identified substrates and degron motifs for Cul2APPBP2, refining understanding of the C-degron pathways it targets and confirming its substrate specificity within the ubiquitin-proteasome system. Multiplex CRISPR screening (~100 screens in a single experiment) with site-saturation mutagenesis for degron identification Nature cell biology Medium 37735597
2019 APPBP2 physically interacts with PPM1D (as shown by co-immunoprecipitation) and promotes NSCLC cell proliferation, migration, and invasion. Silencing APPBP2 decreases PPM1D and SPOP expression, and overexpression of PPM1D or SPOP rescues the inhibitory effects of APPBP2 knockdown. Co-immunoprecipitation, shRNA knockdown, overexpression rescue experiments, cell proliferation and invasion assays, xenograft tumor growth EBioMedicine Medium 31105033
2019 PAT1/APPBP2 colocalizes with early endosomal markers (Rab5, Rab4, EEA1, Rabaptin-5) but not with Rab11 or Rab7. PAT1 expression regulates the number of EEA1 and Rab5 vesicles and the endocytosis/recycling of transferrin receptor. Overexpression of the APP binding domain of PAT1 is sufficient to compromise endocytosis. Colocalization by fluorescence microscopy, live imaging, transferrin uptake assay, domain overexpression Cellular and molecular life sciences : CMLS Medium 31139847
2009 SLY1 (mouse Y-linked spermatid protein) interacts with the microtubule-associated protein APPBP2, as demonstrated by yeast two-hybrid and co-immunoprecipitation studies. Yeast two-hybrid assay, co-immunoprecipitation Biology of reproduction Low 19176879
2014 Appbp2 is a novel thyroid hormone (TH)-responsive gene in the fetal cerebral cortex, with thyroid hormone response elements confirmed in the Appbp2 gene. Gene expression microarray in fetal mouse cortex with TH manipulation, confirmation of TH response elements Cerebral cortex (New York, N.Y. : 1991) Low 24436321

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 PPM1D is a potential target for 17q gain in neuroblastoma. Cancer research 203 12702577
2007 An infectious retrovirus susceptible to an IFN antiviral pathway from human prostate tumors. Proceedings of the National Academy of Sciences of the United States of America 175 17234809
2006 Comprehensive genomic analysis of desmoplastic medulloblastomas: identification of novel amplified genes and separate evaluation of the different histological components. The Journal of pathology 105 16400626
2022 Post-translational control of beige fat biogenesis by PRDM16 stabilization. Nature 97 35978186
2010 Genome-wide mRNA and microRNA profiling of the NCI 60 cell-line screen and comparison of FdUMP[10] with fluorouracil, floxuridine, and topoisomerase 1 poisons. Molecular cancer therapeutics 74 21159603
2009 The multi-copy mouse gene Sycp3-like Y-linked (Sly) encodes an abundant spermatid protein that interacts with a histone acetyltransferase and an acrosomal protein. Biology of reproduction 55 19176879
2023 Defining E3 ligase-substrate relationships through multiplex CRISPR screening. Nature cell biology 53 37735597
2012 Structural analysis of the genome of breast cancer cell line ZR-75-30 identifies twelve expressed fusion genes. BMC genomics 40 23260012
2020 FOLFOX treatment response prediction in metastatic or recurrent colorectal cancer patients via machine learning algorithms. Cancer medicine 32 31893575
2023 MicroRNA-128 suppresses tau phosphorylation and reduces amyloid-beta accumulation by inhibiting the expression of GSK3β, APPBP2, and mTOR in Alzheimer's disease. CNS neuroscience & therapeutics 27 36880288
2014 Transient Maternal Hypothyroxinemia Potentiates the Transcriptional Response to Exogenous Thyroid Hormone in the Fetal Cerebral Cortex Before the Onset of Fetal Thyroid Function: A Messenger and MicroRNA Profiling Study. Cerebral cortex (New York, N.Y. : 1991) 22 24436321
2023 CRL2APPBP2-mediated TSPYL2 degradation counteracts human mesenchymal stem cell senescence. Science China. Life sciences 18 38170390
2023 Molecular basis for C-degron recognition by CRL2APPBP2 ubiquitin ligase. Proceedings of the National Academy of Sciences of the United States of America 14 37844242
2018 Analyzing the disease module associated with osteosarcoma via a network- and pathway-based approach. Experimental and therapeutic medicine 13 30210606
2021 Circ_SETD3 regulates gefitinib sensitivity and tumor progression by miR-873-5p-dependent regulation of APPBP2 in non-small cell lung cancer. Journal of chemotherapy (Florence, Italy) 9 34861803
2022 circBIRC6 contributes to the development of non-small cell lung cancer via regulating microRNA-217/amyloid beta precursor protein binding protein 2 axis. Chinese medical journal 8 35191420
2019 APPBP2 enhances non-small cell lung cancer proliferation and invasiveness through regulating PPM1D and SPOP. EBioMedicine 7 31105033
2019 Protein interacting with Amyloid Precursor Protein tail-1 (PAT1) is involved in early endocytosis. Cellular and molecular life sciences : CMLS 6 31139847

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