Tollip (Toll-interacting protein) is a component of the IL-1RI pathway which contains an N-terminal C2 domain and a C-terminal CUE domain. Tollip binds to the cytoplasmic TIR domain of IL-1Rs after IL-1 stimulation. It is sufficient for recruitment of IRAK to IL-1Rs and negatively regulates IL-1-induced signaling by inhibiting IRAK phosphorylation. In addition, Tollip directly interacts with toll-like receptors TLR2 and TLR4, and plays an inhibitory role in TLR-mediated cell activation through suppressing phosphorylation and kinase activity of IRAK. Moreover, Tollip can associate with GAT domains of Tom1 and its related proteins Tom1L1 and Tom1L2, and facilitate the recruitment of clathrin onto endosomes [, ].
This domain promotes intramolecular monoubiquitination and has a dual role in mono- and poly-ubiquitination recognition, being involved in binding ubiquitin-conjugating enzymes (UBCs) [, , ]. CUE domains also occur in two proteins of the IL-1 signal transduction pathway, tollip and TAB2.
Tollip is a part of the Interleukin-1 receptor (IL-1R) signaling pathway. Tollip is proposed to link serine/threonine kinase IRAK to IL-1Rs as well as inhibiting phosphorylation of IRAK []. The TOLLIP-dependent selective autophagy pathway plays an important role in clearance of cytotoxic polyQ proteins aggregates []. There is a single C2 domain present in Tollip. C2 domains fold into an 8-standed β-sandwich that can adopt 2 structural arrangements, type I and type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide varietyof substances including phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions [, , , , , , , ].
