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    • A different mechanism has been suggested for the role of

    2023-05-29

    A different mechanism has been suggested for the role of TRX1 in ASK1 regulation based on disulfide bond-mediated ASK1 multimerization and its reduction through the thiol-reductase activity of TRX1 (Nadeau et al., 2007, Nadeau et al., 2009). In this model, oxidative stress induces intermolecular disulfide bond formation between ASK1 molecules. This, upon activation loop phosphorylation, generates an active and 64c mg competent form of ASK1, which is able to phosphorylate downstream MAP2Ks. Thus, the inhibitory function of TRX1 is based on the reduction of intermolecular disulfide bonds between ASK1 molecules.
    Central regulatory region of ASK1 (ASK1-CRR) The central regulatory region located between ASK1-TBD and ASK1-CD is responsible for TRAFs binding which presumably facilitates the homophilic interaction of the N-terminal part of ASK1, thereby activating the ASK1 signaling pathway (Fujino et al., 2007, Hoeflich et al., 1999, Liu et al., 2000, Lu et al., 2013, Nishitoh et al., 1998). The recently reported crystal structure of ASK1-CRR (residues 269–658) showed that it consists of 14 α-helices forming seven tetratricopeptide repeats (TPRs) followed by a pleckstrin homology domain (PH, Fig. 1B) (Weijman et al., 2017). The TPR domain of ASK1-CRR adopts a compact globular conformation, and the PH domain extensively interacts with TPRs 6 and 7 through a highly 64c mg interface. This suggested that the PH domain, which is directly adjacent to ASK1-CD, plays a key role in MAP2K docking and their consequent phosphorylation. Moreover, solution structural studies of constructs containing both ASK1-TBD and ASK1-CD (residues 88–658 and 88–941) suggested that ASK1-TBD is positioned in close proximity to ASK1-CD, thus indicating that TRX1 binding may inhibit ASK1 activity by blocking the surface involved in MAP2K docking and/or access to the active site of ASK1-CD (Weijman et al., 2017). Oxidative stress-induced TRX1 dissociation and TRAF binding, together with homo-oligomerization of the N-terminal part, may induce the opening of the closed, inhibited structure of ASK1, thus enabling MAP2k docking to the site within the PH domain. It has been previously suggested that the N-terminal part of ASK1 contains another coiled-coil motif (in addition to the C-terminal CC) responsible for the homo-oligomerization of the N-terminal part of ASK1 upon TRX dissociation from ASK1-TBD (Fujino et al., 2007). However, the crystal structure of ASK1-CRR revealed that the segment with the predicted CC motif (residues 297–324, shown in red in Fig. 1B) is an integral part of the TPR domain involved in numerous contacts with surrounding TPR helices (Weijman et al., 2017). Therefore, although this region is required for ASK1 activation (Fujino et al., 2007), Proto-oncogene will most unlikely mediate conventional coiled-coil associations. In addition, all three studied N-terminal fragments of ASK1 (residues 269–658, 88–658 and 88–941) have been reported as monomers in solution, which indicates that another mechanism is responsible for the homo-oligomerization of the N-terminal part of ASK1 during ASK1 activation (Weijman et al., 2017). Because TRAF2 and TRAF6 binding to ASK1-CRR is required for the homo-oligomerization of the N-terminal part of ASK1 (Fujino et al., 2007), it is possible that a trimeric nature of TRAFs (Fig. 1E) (Park et al., 1999, Zheng et al., 2010), together with the C-terminal CC and, possibly, the ASK1-CD (Bunkoczi et al., 2007, Tobiume et al., 2002), also contributes to this oligomerization process.
    Catalytic domain of ASK1 (ASK1-CD) ASK1-CD is located approximately in the middle of the ASK1 molecule flanked by the PH domain of ASK1-CRR and the 14-3-3 binding motif on the N- and C-termini, respectively (Fig. 1A). Crystallographic analysis showed that ASK1-CD has a typical protein kinase fold comprising of two lobes connected by a hinge region lining the catalytic ATP binding site (Fig. 1C) (Bunkoczi et al., 2007). The isolated ASK1-CD forms a tight head-to-tail dimer with a large interface spanning almost the entire side of ASK1-CD. However, whether the dimerization of ASK1-CD, which is independent of the C-terminal CC, participates in ASK1 oligomerization within the signalosome is unclear. As mentioned above, the larger constructs containing ASK1-CD together with ASK1-CRR and ASK1-TBD were reported as monomers (Weijman et al., 2017). We may speculate that these larger fragments remain as monomers because the dimerization interface is masked by the preceding ASK1-CRR and/or ASK1-TBD. Furthermore, ASK1 forms hetero-oligomers with a closely related kinase ASK2 (MAP3K6) within the signalosome and all residues located at the ASK1-CD dimer interface are conserved between these two kinases, thus suggesting that ASK1-CD and ASK2-CD may arrange in a similar fashion (Cockrell et al., 2010, Federspiel et al., 2016, Takeda et al., 2007). Therefore, evidence suggests that ASK1-CD homo- and/or hetero-dimerization may contribute to ASK1 oligomerization within the signalosome in a conformation-dependent manner.