| ANAPC2 (APC2) functional annotation: evidence summary | Key points | Recent (2023–2024) evidence | Foundational/consensus evidence | Practical implications/applications |
|---|---|---|---|---|
| Identity/domains | Human ANAPC2 encodes APC2, the cullin-family catalytic scaffold subunit of APC/C; literature matches UniProt Q9UJX6 and cullin-family/domain annotation. APC2 contains a cullin-like C-terminal region with a WHB subdomain; 2024 cryo-EM additionally identified a zinc-binding module stabilizing APC2. | High-resolution human APC/C structures identified a previously unreported APC2 zinc-binding module and confirmed APC2 as part of the catalytic module in 2.9–3.2 Å maps (pqac-00000012, pqac-00000013). | APC2 has long been defined as the cullin-like APC/C subunit, partnering APC11 in the catalytic core; structural reviews describe flexible APC2 CTD/WHB regions and cullin homology (pqac-00000005, pqac-00000007, pqac-00000004). | Confirms the target is the human APC/C subunit rather than another APC2 symbol; domain knowledge supports functional annotation and variant interpretation in cell-cycle studies. |
| Catalytic role in APC/C | APC2 is the scaffold of the APC2–APC11 cullin–RING catalytic module, positioning APC11/RING and E2~Ub for ubiquitin transfer to APC/C substrates; APC2 itself is not the E2 or protease but a structural/catalytic organizer of the E3 ligase. | TR-EM directly visualized active APC/C with E2s and showed APC2 participates in E2/CTP engagement during substrate polyubiquitination (pqac-00000010, pqac-00000016). | Reconstitution showed APC2 plus APC11 is the minimal ubiquitin ligase module sufficient for ubiquitination with appropriate E2s; reviews consistently describe APC2 as the cullin scaffold of APC/C (pqac-00000003, pqac-00000001, pqac-00000002). | Central for interpreting APC/C-dependent proteolysis of cyclins, securin, and other cell-cycle substrates; useful when considering APC/C as a therapeutic vulnerability in proliferative disease. |
| E2/coactivator interactions | APC/C uses coactivators CDC20 or CDH1 for substrate recruitment and catalytic activation. APC2/APC11 engages initiating and elongating E2s, especially UBE2C/UBCH10 and UBE2S; APC10 and coactivators recognize degrons such as D-box/KEN/ABBA. | 2023 TR-EM showed UBE2C clasped by APC11 RING and APC2 WHB, while the UBE2S C-terminal peptide binds a groove formed by APC2–APC4; both E2s can be engaged in active complexes (pqac-00000009, pqac-00000010, pqac-00000015). 2024 structures reaffirmed that coactivators stimulate a catalytic-module change permitting UBE2C binding (pqac-00000012, pqac-00000013). | Reviews define APC/C substrate selection through CDC20/CDH1 plus APC10 and distinguish initiating E2s (UBE2C/UBCH10, sometimes UBE2D/UBCH5) from elongating UBE2S (pqac-00000004, pqac-00000006, pqac-00000008, pqac-00000024). | Explains substrate specificity and timing of mitotic exit; relevant to experimental design, degron engineering, and efforts to modulate APC/C signaling indirectly via E2s or coactivators. |
| Conformational regulation (CRL up/down) | APC2-containing catalytic module is mobile and switches between autoinhibited “CRL down” and active “CRL up” states; coactivators and UBE2S-linked interactions favor the active state and improve UBE2C recruitment/processivity. | CryoDRGN/TR-EM defined major CRL-down and CRL-up substates and showed UBE2S CTP allosterically stabilizes CRL-up, increasing UBE2C recruitment; APC2 CRL movements of ~15 Å and ~11 Å were quantified (pqac-00000009, pqac-00000011, pqac-00000030). | Earlier structural work established that APC2 WHB and APC11 RING are flexibly tethered and undergo conformational changes required for catalysis (pqac-00000005, pqac-00000007, pqac-00000019). | Mechanistic basis for APC/C activity tuning; suggests allosteric control points for chemical probes or inhibitors and helps explain processive ubiquitin-chain assembly. |
| Inhibition/regulation (MCC, EMI1, phosphorylation) | APC/C is inhibited by the spindle assembly checkpoint via MCC (CDC20, BUBR1, MAD2, BUB3), which blocks substrate access and E2 function. EMI1 acts as a pseudosubstrate/multivalent inhibitor contacting CDH1, APC10, APC11, APC2 WHB, and the APC2–APC4 groove. Phosphorylation promotes CDC20 loading and regulates coactivator exchange, while CDK1 phosphorylation restrains CDH1 in early mitosis. | 2024 structural work further clarified APC/C–CDH1:EMI1 organization and regulatory architecture (pqac-00000013). 2024 Cdc20 functional analysis reinforced SAC dependence on proper APC/C–MCC interactions (pqac-00000003). | Reviews consistently describe MCC-mediated inhibition, EMI1 blockade, and mitotic phosphorylation as core APC/C regulatory layers (pqac-00000017, pqac-00000019, pqac-00000020, pqac-00000023, pqac-00000024). | Relevant to anti-mitotic strategies, checkpoint biology, and explaining how APC/C remains inactive until chromosomes are properly attached. |
| Disease relevance (lung cancer DEPTOR axis; OpenTargets associations) | Direct ANAPC2 disease literature is limited, but APC2 function is implicated through APC/C-dependent oncogenic signaling. In lung cancer, APC/C^CDH1 with UBE2C requires APC2 for DEPTOR degradation, activating mTOR signaling. OpenTargets lists ANAPC2 associations with colorectal carcinoma, neurodegenerative disease, aplastic anemia, and skeletal phenotypes, though evidence depth is limited. | In Kras-driven lung cancer, knockdown of APC2 or CDH1 increased DEPTOR protein, supporting DEPTOR as an APC/C^CDH1 substrate; Ube2c deletion suppressed tumorigenesis and survival defects in vivo, placing APC/C catalytic function in a disease-relevant pathway (pqac-00000025, pqac-00000026, pqac-00000028). OpenTargets reports several ANAPC2 disease associations with modest evidence sizes (pqac-00000000). | APC/C dysregulation is broadly linked to tumorigenesis and genome instability in consensus reviews (pqac-00000005, pqac-00000008, pqac-00000013). | Supports using APC/C pathway readouts as cancer biomarkers or mechanistic stratifiers; suggests indirect therapeutic opportunities by targeting APC/C partners (e.g., UBE2C, checkpoint regulators) rather than APC2 directly. |
| Quantitative statistics highlighted | Recent studies provide structural and functional numbers that strengthen annotation: cryo-EM resolutions, particle counts, conformational fractions, biochemical recruitment windows, and cancer survival outcomes. | TR-EM used ~25,380 and 25,900 movies, yielding ~661,289 and 774,933 particle images and 3.5–4.0 Å maps; CRL-down particles were largely CDH1-lacking (~80%); timepoints included 0.5, 1.5, 5, 15 min; UBE2S CTP titrations 0–1.25 µM increased UBE2C recruitment; METRIS RP values included Ub–CycBN 0.21 ± 0.007 versus CycBN 0.15 ± 0.004 and UbV competition ~0.13 ± 0.003 (pqac-00000009, pqac-00000010, pqac-00000011, pqac-00000014, pqac-00000016). 2024 structures reached 2.9 and 3.2 Å (pqac-00000012, pqac-00000013). In KrasG12D lung cancer, Ube2c deletion extended median survival from ~130 to ~150 days and delayed 100% mortality from day 175 to day 210 (P = 0.0241; n = 10/group) (pqac-00000028). | Quantitative biochemical and structural measurements are consistent with long-standing APC/C models of dynamic catalytic activation and processive ubiquitination (pqac-00000001, pqac-00000005, pqac-00000008). | Useful for benchmarking structural quality, prioritizing recent evidence, and conveying effect sizes in translational or grant/reporting contexts. |


*Table: This table summarizes the strongest gathered evidence for human ANAPC2/APC2 function, mechanism, regulation, and disease relevance. It highlights both recent 2023–2024 structural advances and foundational consensus needed for functional annotation.*