IRAK3, also called IRAK-M, is an IRAK-family pseudokinase that regulates Toll-like and interleukin-1 receptor signaling. It participates in receptor-associated signaling assemblies and restrains inflammatory activation by stabilizing MyD88-associated IRAK complexes. Its death domain and kinase-like domain mediate protein interactions, and its effects depend on cellular context and stimulus history.
The 1999 discovery study observed negligible autophosphorylation yet restoration of an IL-1 response in IRAK-deficient cells. The 2002 genetic study established physiological negative regulation: IRAK-M prevents IRAK/IRAK4 release from MyD88 and restricts cytokine induction and endotoxin sensitivity. The 2021 human structure explains a noncanonical inactive catalytic site, a distinctive homodimer and a possible IRAK4-interaction surface. ATP-pocket retention or weak nucleotide binding cannot establish active kinase catalysis. The positive cell-reconstitution result and inhibitory physiological feedback should coexist in the synthesis rather than being flattened into an unconditional activator or inhibitor. The selected horse N-terminal deletion reaches its death-domain start, so receptor-complex assembly needs specific checking.
From PMID:12150927(https://pubmed.ncbi.nlm.nih.gov/12150927/):
We show here that IRAK-M is induced upon TLR stimulation and negatively regulates TLR signaling. IRAK-M prevented dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAK-TRAF6 complexes.
The exact target is A0A3Q2HDT6, not an arbitrary horse record with a matching name. The reproducible paired-sequence analysis records identity, coverage and internal gaps. It supports homology but is not a reciprocal orthology test. Molecular properties are transferred only with the relevant domain, targeting and paralog constraints. The prediction-time sequence is not independently verified.
The following annotation scopes need source-specific follow-up: cytokine-mediated signaling pathway, cytoplasm, magnesium ion binding, negative regulation of MAPK cascade, negative regulation of protein catabolic process, nucleus, plasma membrane, positive regulation of canonical NF-kappaB signal transduction, positive regulation of cytokine production, positive regulation of immune system process, protein binding, protein heterodimerization activity, protein phosphorylation, response to exogenous dsRNA, response to virus. Experimental annotations are not removed merely because a cached abstract omits the gene or a specific assay. High-throughput protein-binding rows require their actual partner or complex context before replacement with an informative molecular function.
Research provenance: external Falcon/Edison was attempted with Perplexity fallback. Some requests returned HTTP 429 and fallback returned insufficient-quota HTTP 401; successful external reports are preserved separately. Primary-source manual synthesis is explicitly labeled manual where no external report was available.