TIRAP (Mal) review notes — human, P58753

Identity and architecture

• 221 aa; disordered N-terminal region (1-82) and TIR domain (84-213) per UniProt; two intra-domain
  disulfides (C89-C134, C142-C174) seen in crystal structures.
• N-terminal PIP2-binding domain targets TIRAP to the plasma membrane
  PMID:16751103
  PMID:21873236

Core function: bridging/sorting adaptor for TLR2 and TLR4 -> MyD88

• PMID:11544529
• PMID:16751103
• PMID:17258210
• Mouse KO: PMID:12447441
  and not needed for TLR3/7/9: PMID:12447441
• D96N loses MyD88 binding but keeps TLR2/TLR4 binding, and is signaling-dead
  PMID:19509286
• IFN-beta induction by LPS is TIRAP-independent
  PMID:19509286
  (contrast: PMID:12062447 — abstract only, overexpression/DN era; not supported by KO data).
• TLR2: S180L loses TLR2 binding and attenuates TLR2 signaling
  PMID:17322885. Experiments used
  Malp2 (called "TLR2 ligand" in the paper), not a TLR1:TLR2-specific ligand, so the GOA TLR1:TLR2 IDA was
  generalized to GO:0034134.

Other partners

• RAGE (AGER): direct binding to phosphorylated RAGE tail PMID:21829704
• PI3K p85alpha after TLR2/6 stimulation PMID:19574958
• PKCdelta via TIR domain PMID:17161867
• IRAK2 via TIR domain PMID:11544529
• Pathogen mimics: Brucella TcpB PMID:24275656, HBeAg PMID:21334391.

Source tracing for ISS rows (mouse Q99JY1, QuickGO 2026-09-30)

• myeloid cell differentiation <- MGI IMP PMID:11526399 (DC maturation readout) -> over-annotation.
• regulation of IFN-beta production <- BHF IDA PMID:14630816 (not read) -> over-annotation given KO data.
• positive regulation of TLR3 signaling <- BHF IDA PMID:17322885 on mouse; the Khor paper does not test TLR3;
  contradicted by PMID:12447441 and PMID:19509286 -> REMOVE.
• neutrophil chemotaxis <- BHF IMP PMID:18039275 (not read) -> indirect via chemokines -> over-annotation.
• B cell proliferation, IL-12, CXCL1/2 <- mouse KO cytokine/proliferation phenotypes -> non-core.

Key decisions

• 'positive regulation of TLR2/TLR4 signaling' IMP rows -> MODIFY to pathway membership (TIRAP is a
  component, not a regulator).
• general adaptor MF (GO:0060090, GO:0030674) -> MODIFY to GO:0035591 signaling adaptor activity.
• protein binding: MODIFY to TLR4 binding / RAGE receptor binding / PI3K regulatory subunit binding /
  protein kinase binding / signaling adaptor activity where the paper supports it; REMOVE HT and pathogen rows.
• cell surface IDA (PMID:12447441, abstract-only, no localization data in abstract) -> MODIFY to GO:0031234;
  TIRAP is on the cytoplasmic face, not exposed at the cell surface.
• 3'-UTR mRNA stabilization -> over-annotation (distal consequence).
• GO-CAM index: TIRAP appears in 5 human models with GO:0035591 / GO:0060090 / GO:0030674 and TLR4 or
  TLR1:TLR2 pathways — consistent with the core function chosen.

Project questions (INNATE_IMMUNITY / TLR batch)

• TIRAP carries only vertebrate TLR-pathway terms (GO:0002224 branch); no GO:0008063 Toll signaling
  conflation. The TLR3 regulation row is the only ligand/receptor-specific term that is wrong.

Deep research (Falcon, completed 2026-09-30)

• TIRAP-deep-research-falcon.md arrived after the first draft of the review; it agrees with the core
  picture ("membrane-recruited bridging adaptor ... connects activated Toll-like receptors—principally TLR2
  and TLR4—to the downstream signaling adaptor MyD88"). No review action changed.
• New leads it raises (not in GOA, primary papers not cached here, so NOT used for annotations): endosomal
  PI3P binding for TLR9, 2025 bioRxiv cryo-EM of TIRAP filaments, TIR-domain acetylation by CBP (EMBO J
  2024), TIRAP-Cish control of M. tuberculosis phagosome acidification (PLoS Pathog 2023), and a 2026
  report of nuclear TIRAP in hepatic stellate cells. Recorded as suggested questions only.