5t7q | pdb_00005t7q
TIRAP phosphoinositide-binding motif
Structural highlights
Function[TIRAP_HUMAN] Adapter involved in TLR2 and TLR4 signaling pathways in the innate immune response. Acts via IRAK2 and TRAF-6, leading to the activation of NF-kappa-B, MAPK1, MAPK3 and JNK, and resulting in cytokine secretion and the inflammatory response. Positively regulates the production of TNF-alpha and interleukin-6.[1] [2] Publication Abstract from PubMedPathogen-activated Toll-like receptors (TLRs), such as TLR2 and TLR4, dimerize and move laterally across the plasma membrane to phosphatidylinositol (4,5)-bisphosphate-enriched domains. At these sites, TLRs interact with the TIR domain-containing adaptor protein (TIRAP), triggering a signaling cascade that leads to innate immune responses. Membrane recruitment of TIRAP is mediated by its phosphoinositide (PI)-binding motif (PBM). We show that TIRAP PBM transitions from a disordered to a helical conformation in the presence of either zwitterionic micelles or monodispersed PIs. TIRAP PBM bound PIs through basic and nonpolar residues with high affinity, favoring a more ordered structure. TIRAP is phosphorylated at Thr28 within its PBM, which leads to its ubiquitination and degradation. We demonstrate that phosphorylation distorts the helical structure of TIRAP PBM, reducing PI interactions and cell membrane targeting. Our study provides the basis for TIRAP membrane insertion and the mechanism by which it is removed from membranes to avoid sustained innate immune responses. Membrane targeting of TIRAP is negatively regulated by phosphorylation in its phosphoinositide-binding motif.,Zhao X, Xiong W, Xiao S, Tang TX, Ellena JF, Armstrong GS, Finkielstein CV, Capelluto DG Sci Rep. 2017 Feb 22;7:43043. doi: 10.1038/srep43043. PMID:28225045[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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