4. Problem to solve: Human ion channel TACAN isoform induced by tumor necrosis factor alpha
The transmembrane protein TMEM120A, also known as TACAN isoform 1, forms an ion channel involved in adipocite differentiation and in sensing mechanical pain in animals and plants. The structure of the homodimer purified or reconstituted in lipid nanodiscs has been modeled from cryo-EM data [Rong et al., 2021], [Xue et al., 2021], [Chen et al., 2022]. Map and atomic structure of this homodimer, unbound to any ligands is shown in Fig. 4.11. The complex displays C2 symmetry and shape of seesaw rocker. Each protomer is a relativelly small protein of 343 amino acids. The soluble N-terminal domain of each protein is located in the cytosolic side (horizontal helices in Fig. 4.11), and the transmembrane domain is embedded in the lipid bilayer (vertical helices in Fig. 4.11). Each protomer contains a pore putatively devoted to ion transport that seems to be closed at resting state [Chen et al., 2022]. Although different ligands have been identified bound to the dimer complex, such as the fatty acid metabolism cofactor CoASH, which occupies a small density in the intracellular funnel-like cavity of each monomer [Rong et al., 2021], [Xue et al., 2021], or cholesterol molecules at the flanks of the two protomers [Chen et al., 2022], they seem to dissociate using a detergent solution that allows to get the homodimer unbound to any ligands [Rong et al., 2021].
The volume of the first isoform of human TACAN complex, at 4 Å resolution, and its atomic interpretation (Fig. 4.11) are available in the Electron Microscopy Data Bank (EMDB) and Protein Data Bank (PDB) with accession numbers EMD-31441 and PDB 7F3U, respectively.
This tutorial will guide us in the model building of TACAN isoform 1 atomic structure using model-angelo [Jamali et al., 2023] in the Scipion framework. We are going to use the 3D map EMD-31441 as starting input, with and without the protein sequence (UniProtKB ID Q9BXJ8). We will finish with the comparison among the models generated and the atomic structure already traced (PDB 7F3U).