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The TIPE family is a newly known family of proteins which is responsible for the regulation of immunity and tumorigenesis. This family comprises of four members such as, TIPE or TNFAIP8 (tumor necrosis factor-α-induced protein 8), TIPE1 (TNFAIP8- like 1, or TNFAIP8L1), TIPE2 (TNFAIP8-like 2 or TNFAIP8L2), and TIPE3 (TNFAIP8-like 3 or TNFAIP8L3) (Goldsmith et al., 2017). Interestingly, although these four proteins of this family share a considerable sequence homology (~54%
sequence identity), but they are involved in diverse cell functions (Bordoloi et al., 2018).
1.9.1 TIPE
TIPE, the first and the most studied member of this family is a transcription factor nuclear factor- kappa B (NF-B) inducible, oncogenic molecule and cytoplasmic protein of 21 K-Da; initially identified in human head and neck squamous cell carcinoma (Bordoloi et al., 2018). It is expressed in various human normal tissues, however considerably higher expression was found in placenta and lymphoid tissues (Kumar et al., 2000). The open reading frame of this protein possess a sequence in the amino terminus which presents marked homology to the death effector domain II of the cell death regulatory protein, Fas-associated death domain-like interleukin-1beta- converting enzyme-inhibitory protein (FLIP) (Kumar et al., 2000). Further, the crystal structure of TIPE from Mus musculus (mTIPE) revealed it to posses similarity to a water dipper. Its cylindrical domain posses a dimension of 48 × 31 × 30 Å linked to an N-terminal grip-like domain, comprising of 20 residues and contains two long electron densities. It has a hydrophobic cavity lined with highly conserved hydrophobic residues, thereby aids in the binding of substrates inside the cavity or hydrophobic cofactors (Kim et al., 2017b).
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1.9.2. TIPE1
TIPE1 (tumor necrosis factor-α-induced protein 8-like 1) is a recently found member of the TIPE family which function as a cell death regulator. TIPE1 was predicted to interact with caspase-8 and FBXW5. Besides, different post-translational modifications were also prophesied to exist in case of TIPE1 (Shen et al., 2015; Bordoloi et al., 2018).
1.9.3 TIPE2
TIPE2 (tumor necrosis factor-α-induced protein 8-like 2), a cytoplasmic protein consisting of 184 amino acids and the third member of this family, is a latterly discovered negative regulator of innate and cellular immunity, with considerable sequence homology with the other members of the family (Bordoloi et al., 2018).
TIPE2 plays critical role in the maintenance of immune homeostasis. It was found to be highly expressed in inflamed but not normal nervous tissue (Zhang et al., 2009).
TIPE2 was found to be expressed in varied cell types such as neurons in the brain and brainstem, hepatocytes, squamous epithelial cells in the cervix and esophagus, glandular epithelial cells in the colon, stomach, and appendix and transitional epithelial cells in the ureter and bladder (Zhang et al., 2011). The crystal structure of human TIPE2 showed that it comprises of a total of six antiparallel α -helices. Among them, α5 helix bears a kink, due to Pro153, leading to its splitting into α5a and α5b, where the later forms the base of helical bundle. TIPE2 possess a cylindrical cavity located centrally which is mostly hydrophobic in nature whereas the outer surface of TIPE2 is found to be highly charged. The central cavity is predicted to be poised for cofactor binding and thus helps in immune homeostasis. Notably, the structure of TIPE2 differs from that of death effector domain (DED); firstly TIPE2 consists of around 150 amino acids which is relatively larger than that of DED and secondly, the topology of both are
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different. In fact, the topology of TIPE2 seems to be a mirror image of that of DED (Zhang et al., 2009) (Figure 1.4).
Figure 1.4. The structure of TIPE2 and TIPE3. A. The structure of TIPE2 defines a previously uncharacterized fold that is different from the DED. It is is shown in two perpendicular views. The six α-helices are rainbow colored.
Pro153, which breaks α5 into two helices, is indicated at right (Zhang et al., 2008), B. Cartoon presentation of TH-domain of human TIPE3 (trTIPE3, residues 21-204). Helices are rainbow-colored with α0 in blue and α6 in red (Fayngerts et al., 2014).
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1.9.4. TIPE3
TIPE3 (tumor necrosis factor-α-induced protein 8-like 3), the latest member of TIPE family acts as a transfer protein for lipid second messengers PIP2 (phosphatidylinositol 4,5-bisphosphate) and PIP3 (phosphatidylinositol 3,4,5-trisphosphate), and increases their level in the plasma membrane (Fayngerts et al., 2014; Bordoloi et al., 2018).
Further, TIPE3 is expressed in different human organs and is highly upregulated in certain cancer types such as cancers of the cervix, colon, esophagus and lung (Lian et al., 2017). In addition, the crystal structure of TIPE3 reveals that it consists of an N- terminal α0 helix, and six additional helices (α1-α6) which are similar to those of TIPE2. The most important feature of the TH fold of TIPE3 is the presence of a large centrally located hydrophobic cavity, possessing 20 Å depth and 10 Å diameter, which is speculated to serve as the binding site for a lipophilic molecule. Thus TIPE3 binds to phosphoinositides with the help of its TH domain, which essentially helps in its function as transfer protein for lipid second messengers. Further, the hydrophobic cavity in TIPE3 is occupied by two electron density tubes, which are connected at the surface opening of the cavity (Fayngerts et al., 2014) (Figure 1.4).