UBL4A (also known as GdX) is a ubiquitously expressed ubiquitin-like (Ubl) protein that forms a complex with partner proteins and participates in the protein processing through endoplasmic reticulum (ER), acting as a chaperone. As a key component of the BCL2-associated athanogene 6 (BAG6) chaperone complex, UBL4A plays a role in mediating DNA damage signaling and cell death [, ]. UBL4A also regulates insulin-induced Akt plasma membrane translocation through promotion of Arp2/3-dependent actin branching []. Moreover, UBL4A specifically stabilises the TC45/STAT3 association and promotes dephosphorylation of STAT3 to repress tumorigenesis [].This is the ubiquitin-like domain of UBL4A and related proteins.
This is the C-terminal domain of Ubiquitin-like protein 4A, an orthologue of yeast Get5. In budding yeasts, Get proteins directly mediate the insertion of newly synthesized TA proteins into endoplasmic reticulum membranes. Similarly, mammalian BAG6, Ubl4a, and SGTA make up a trimeric complex that binds TA proteins post-translationally and then loads them onto the cytosolic ATPase TRC40, which in turn targets them to the endoplasmic reticulum. Structural studies show that this C-terminal TUGS domain of Ubl4a is essential for BAG6 tethering. Given that BAG6 mediates oligomeric complex formation of Ubl4a, TRC35, and TRC40 (mammalian counterparts of Get5, Get4, and Get3, respectively), the C-terminal TUGS domain might be crucial for supporting BAG6-mediated Ubl4a-TRC35 complexformation in humans as an alternative to the direct Get5-Get4 interaction in yeast [, ].
