Requested Falcon deep research was attempted with fallback:
just deep-research-falcon human ANAPC2 --fallback perplexity-lite
The Falcon provider timed out after the wrapper's 600 second timeout. The configured
perplexity-lite fallback then failed with a Perplexity API 401 quota error. No
ANAPC2-deep-research-falcon.md or fallback deep-research report was produced, so
this review uses the fetched UniProt record, cached publications, Reactome cache,
PANTHER family metadata, and project-local PN projection reports.
The PN projection report lists three ANAPC2 gene-GO projections:
GO:0005680 anaphase-promoting complex: already_in_goa_exact, so no newGO:0000151 ubiquitin ligase complex: entailed_by_goa_closure from existingGO:0005680 anaphase-promoting complex and GO:0031461 cullin-RING ubiquitin
ligase complex, so no new direct annotation is needed [projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv].GO:0160072 ubiquitin ligase complex scaffold activity: new_to_goa from theUbiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cullin|degenerate,
APC sununit [projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv].Conservative decision: ANAPC2 is not a canonical cullin like CUL1-CUL5, but the
cached literature supports a cullin-like APC/C scaffold role. UniProt describes
ANAPC2 as belonging to the cullin family and states that ANAPC2 with ANAPC11
constitutes the catalytic APC/C component [genes/human/ANAPC2/ANAPC2-uniprot.txt].
The structural papers describe the catalytic module as Apc2-Apc11 and the
cullin Apc2/RING Apc11 pair as the site where substrates are ubiquitinated
[PMID:16364912; PMID:26083744]. The biochemical reconstitution paper shows that
human APC2 with APC11 forms a minimal ligase module sufficient to ubiquitinate
securin and cyclin B1 with Ubc4 or UbcH10, while lacking substrate specificity
alone PMID:11739784. I therefore added GO:0160072 as a proposed NEW
annotation rather than automatically changing existing GOA.
Core ANAPC2 function is as the cullin-like scaffold subunit of the APC/C
E3 ubiquitin ligase catalytic module. It works with ANAPC11 and E2 enzymes to
ubiquitinate APC/C substrates, especially in mitotic cell-cycle transitions and
APC/C-dependent proteasomal degradation [PMID:16364912; PMID:18485873;
PMID:26083744; PMID:29033132].
Neuron-development annotations transferred from mammalian orthology were kept
as non-core only where they directly match the UniProt CDC20-APC/C
presynaptic-differentiation context. Broader or more specific axon, dendrite,
and synaptic-plasticity terms were marked as over-annotated because the local
support does not establish those exact process labels for human ANAPC2. Generic
protein binding annotations were not treated as core because they primarily
record individual physical interactions and are less informative than the APC/C
scaffold and ubiquitin ligase module interpretation.
A Falcon (Edison Scientific) deep research report was generated successfully on
2026-06-07 (the earlier timeout noted above has now been superseded). Synthesis of
KEY findings, flagged as CONFIRMS / NEW / PROVISIONAL relative to the existing
review:
CONFIRMS: ANAPC2/APC2 is the cullin-family catalytic scaffold subunit of the
APC/C, pairing with the RING subunit ANAPC11 to form the Apc2-Apc11 cullin-RING
catalytic core that recruits and activates ubiquitin-loaded E2 enzymes; APC/C is
a RING E3 that does not form a covalent E3~Ub intermediate. This matches the
existing core_functions and ACCEPT annotations [PMID:30449648 Watson 2019
"Posing the APC/C E3 ubiquitin ligase"; PMID:11739784 minimal Apc2-Apc11 module].
NEW (structural detail, mechanism): Time-resolved cryo-EM of active human APC/C
during substrate polyubiquitination shows a two-E2 division of labor where the
priming E2 UBE2C/UBCH10 is "clasped" by the APC11 RING and the APC2 WHB region,
while the elongation E2 UBE2S C-terminal peptide (CTP) binds a groove formed by
APC2-APC4; UBE2S CTP allosterically stabilizes a catalytically active "CRL up"
state and increases UBE2C recruitment. APC2 thus directly contributes E2-docking
surfaces (WHB; APC2-APC4 groove) and a mobile "CRL up/down" catalytic arm
[PMID:37735619 Bodrug 2023 "Time-resolved cryo-EM (TR-EM) analysis of substrate
polyubiquitination by the RING E3 APC/C", doi:10.1038/s41594-023-01105-5]. This
enriches but does not contradict the existing K11-ubiquitination / scaffold
annotations.
NEW (structural feature): High-resolution (2.9-3.2 A) cryo-EM of apo-APC/C and
APC/C^CDH1:EMI1 identified a previously unreported zinc-binding module in APC2
that confers structural stability, with zinc ions experimentally confirmed; the
same structures resolve EMI1 contacts and CDH1 N-terminal helix
[PMID:39567505 Hofler 2024, Nat Commun, doi:10.1038/s41467-024-54398-5]. NEW
domain-level detail for ANAPC2 not previously in the review.
NEW (disease link / substrate axis): In KrasG12D-driven lung tumorigenesis,
APC/C^CDH1 cooperates with UBE2C to ubiquitylate and degrade DEPTOR, activating
mTORC signaling; knockdown of APC2 (or CDH1) increased DEPTOR protein,
indicating APC2-containing APC/C is required for DEPTOR turnover. This adds a
specific human substrate (DEPTOR) and an oncogenic-pathway context (mTOR)
[PMID:36548081 Zhang 2023 "The UBE2C/CDH1/DEPTOR axis...", doi:10.1172/JCI162434].
Treated as substrate/pathway context, not a new core MF.
CONFIRMS/CONTEXT: APC/C is restrained by the spindle assembly checkpoint via the
mitotic checkpoint complex (MCC: CDC20, BUBR1, MAD2, BUB3) and by the EMI1
pseudo-substrate inhibitor, which contacts CDH1, APC10, APC11 RING, the APC2 WHB,
and the APC2-APC4 groove; phosphoregulation (CDK1, PLK1) controls coactivator
exchange. Consistent with existing Reactome-derived KEEP_AS_NON_CORE
localization/regulation annotations and PMID:23708001 (Emi1).
PROVISIONAL / low-confidence (NOT used to change annotations): OpenTargets lists
ANAPC2 disease associations (colorectal carcinoma, neurodegenerative disease,
aplastic anemia, skeletal phenotypes) with limited evidence depth; hypothesis-
generating only. Also note the report cites a bioRxiv preprint version of the
Hofler work (hofler2024newstructuralfeatures, doi:10.1101/2023.08.31.555674) —
the peer-reviewed Nat Commun version (PMID:39567505) is used instead.
Curation decision: incorporated the three peer-reviewed primary papers
(PMID:37735619, PMID:39567505, PMID:36548081) as statement-only references and
added one suggested question and one suggested experiment around the newly
described APC2 E2-docking surfaces and zinc-binding module. No existing annotation
action was changed, since all new findings enrich rather than contradict the
existing cullin-like scaffold / catalytic-module interpretation.