GCN1 (Stalled ribosome sensor GCN1 / GCN1L1) research notes

Identity

• UniProt Q92616; very large (~2671 aa) HEAT-repeat / alpha-solenoid ribosome-binding protein. GCN1 family. Has an RWD-binding domain (RWDBD).

Core function — two intertwined ribosome-surveillance roles

1. Ribosome collision/stall sensor that activates the eIF2alpha kinase GCN2 (EIF2AK4) -> integrated stress response (ISR).
2. [GCN1-uniprot.txt "Ribosome collision sensor that plays a key role in the RNF14-RNF25 translation quality control pathway"]
3. [GCN1-uniprot.txt "acts as a sentinel for colliding ribosomes"]
4. [GCN1-uniprot.txt "positive activator of the integrated stress response (ISR) by mediating activation of EIF2AK4/GCN2 in response to amino acid starvation"]
5. [GCN1-uniprot.txt "Interaction with EIF2AK4/GCN2 on translating ribosomes stimulates EIF2AK4/GCN2 kinase activity, leading to phosphorylation of eukaryotic translation initiation factor 2"]
6. Conserved from yeast: GCN1/GCN20 stimulate GCN2 on translating ribosomes. [PMID:9234705 title "Evidence that GCN1 and GCN20, translational regulators of GCN4, function on elongating ribosomes in activation of eIF2alpha kinase GCN2"]
7. GCN1 binds the RWD domain of GCN2; IMPACT competes. PMID:36638793
8. Ribosome collision sensor in the RNF14/RNF25 elongation-factor quality-control pathway (RQC).
9. [PMID:36638793 title "An E3 ligase network engages GCN1 to promote the degradation of translation factors on stalled ribosomes"]
10. PMID:36638793
11. GCN1 required for resolution of mRNA-RNA-protein crosslink (RPC) stalls (RNF14/RNF25). PMID:37951216
12. PMID:37651229

Localization

• Cytoplasm; associates with ribosomes / cytosolic ribosome (polysomes, 80S). [GCN1-uniprot.txt "Associates with ribosomes"; PMID:9234705]
• Membrane (HDA PMID:19946888) and cadherin binding (HDA PMID:25468996) and RNA binding (HDA PMID:22681889) are high-throughput proteomic/mRNA-interactome screens -> non-specific / over-annotation.

Annotation notes

• GO:0170011 stalled ribosome sensor activity (IDA, multiple papers) = CORE MF.
• GO:0043539 protein serine/threonine kinase activator activity (ISS/IEA) + GO:0019887 protein kinase regulator activity (IBA) = CORE MF (activates GCN2). Prefer the more specific kinase-activator term.
• GO:0060090 molecular adaptor activity (IDA PMID:36638793) — GCN1 scaffolds GCN2/RNF14/IMPACT via RWDBD; reasonable, keep (adaptor/scaffold).
• GO:0072344 rescue of stalled cytosolic ribosome (IDA x4) = CORE BP (RQC role).
• GO:0140469 GCN2-mediated signaling (IEA/ISS) + GO:0034198 cellular response to amino acid starvation (IBA/IEA) = CORE/near-core BP (ISR activation).
• GO:0006417 regulation of translation (IBA) — broad; keep non-core (the specific roles are GCN2 activation + RQC).
• GO:0160127 protein-RNA covalent cross-linking repair (IDA PMID:37951215) — GCN1's role in resolving formaldehyde RPC stalls; keep (RQC-adjacent), non-core relative to the sensor MF.
• protein binding IPI (PMID:17314511, 20936779, 38884001) all WITH MYC (P01106) — c-MYC interactome / adipocyte HaloMS screens; GCN1 is large & abundant; isolated HT, not core -> MARK_AS_OVER_ANNOTATED.
• GO:0045296 cadherin binding (HDA) — proximity/affinity proteomics artifact -> MARK_AS_OVER_ANNOTATED.
• GO:0016020 membrane (HDA) — over-annotation; GCN1 is cytosolic/ribosomal -> MARK_AS_OVER_ANNOTATED.
• GO:0003723 RNA binding (HDA mRNA-interactome) — GCN1 binds ribosomes/rRNA contextually; bare RNA binding from HT capture, keep non-core.
• GO:0008135 translation factor activity, RNA binding (NAS, 1997) — outdated framing; GCN1 is a sensor/scaffold, not a canonical translation factor -> MARK_AS_OVER_ANNOTATED.
• GO:0005840 ribosome / GO:0022626 cytosolic ribosome (NAS/IDA) — correct CC (ribosome-associated). Accept.