TULP3 (O75386) curation notes

Deep research status

just deep-research-falcon human TULP3 first failed (falcon timed out at 600 s; perplexity-lite fallback unavailable in this environment). Re-run with --timeout 2400 succeeded: see TULP3-deep-research-falcon.md.

Summary of function

• TULP3 binds IFT-A, which directs TULP3 into cilia [PMID:20889716 "We find that specific Tubby family proteins, notably Tubby-like protein 3 (TULP3), bind to the IFT-A complex."; "the IFT-A complex has a second role directing ciliary entry of TULP3"]; both IFT-A binding and phosphoinositide binding are needed for ciliary GPCR localization PMID:20889716.
• General adaptor for integral membrane cargo PMID:28154160, three-step model: PI(4,5)P2-dependent capture, IFT-A delivery, release into PI(4,5)P2-deficient ciliary membrane.
• Structure: TULP3 N-terminus binds IFT-A PMID:36775821.
• Negative regulator of Hh in neural tube PMID:20889716.
• Tubby domain binds PI(4,5)P2; Gq/PLC releases tubby/TULP3 to nucleus PMID:11375483.
• Reads ciliary phosphoinositides set by INPP5E PMID:26305592.
• Other reported roles (mouse, UniProt by similarity): lithocholic acid binding, SIRT1 activation, AMPK/TORC1 regulation; human TULP3-SIRT1 co-IP (PMID:35397207). Treated as non-core.

Key decisions

• 24 protein binding rows (interactome screens, SIRT1) REMOVE.
• Core MF: protein-macromolecule adaptor activity (GO:0030674), PI(4,5)P2 binding (GO:0005546), IFT-A binding (GO:0120160).
• protein-containing complex binding MODIFY -> GO:0120160.
• intraciliary anterograde transport: KEEP_AS_NON_CORE (cargo adaptor riding IFT, not IFT machinery).
• Transcription regulation and GPCR signalling pathway NAS: MARK_AS_OVER_ANNOTATED.

HPA cilium atlas vs module role

• Module (stage 5): "IFT-A membrane cargo adaptor", process protein localization to cilium (GO:0061512).
• HPA v25: Primary cilium (Supported), Primary cilium transition zone (Supported), Basal body (Uncertain); main locations Nucleoplasm; Primary cilium. GOA HPA rows: cilium, ciliary transition zone, plasma membrane, nucleoplasm, nucleolus.
• Interpretation: strong agreement. The cilium and transition-zone calls match entry of TULP3 with IFT-A through the ciliary base; the plasma membrane call matches the PI(4,5)P2-dependent cargo-capture step; the nucleoplasm call matches PLC-induced nuclear translocation. core_functions agree with the module role (adaptor activity; protein localization to non-motile cilium, a child of GO:0061512).

Additional points from deep research (falcon)

• TULP3 is an associated IFT-A adaptor, not an obligate IFT-A subunit [deep research: "depleting TULP3 did not itself dismantle IFT-A or IFT-B localization, supporting its classification as an associated adaptor rather than an obligate structural IFT-A subunit."]; IFT-A interface residues ~23-68 (K41, K42, R43, F47, V49) from human TULP3-IFT-A cryo-EM (PDB 8FH3).
• TULP3 also delivers lipidated ARL13B (tubby domain recognizes the ARL13B amphipathic helix; Palicharla et al. 2023, not cached), placing TULP3 upstream of ARL13B -> ARL3 -> UNC119B/PDE6D cargo release (NPHP3, CYS1, INPP5E). This links TULP3 to the other stage-5 members of the module.
• A 2025 study implicates a tubby-domain beta-barrel surface distinct from the PIP2 site in cargo recognition; patient variants R382W/R408H impair cargo trafficking.
• Human disease: biallelic TULP3 variants cause progressive liver, kidney and heart fibrosis (Devane et al. 2022, PMID:35397207, cached).