E1-like enzyme which specifically catalyzes the first step in ufmylation (PubMed:15071506, PubMed:18442052, PubMed:25219498, PubMed:20368332, PubMed:27653677, PubMed:26929408, PubMed:27545674, PubMed:30412706, PubMed:27545681). Activates UFM1 by first adenylating its C-terminal glycine residue with ATP, and thereafter linking this residue to the side chain of a cysteine residue in E1, yielding a UFM1-E1 thioester and free AMP (PubMed:20368332, PubMed:27653677, PubMed:26929408, PubMed:30412706). Activates UFM1 via a trans-binding mechanism, in which UFM1 interacts with distinct sites in both subunits of the UBA5 homodimer (PubMed:27653677). Trans-binding also promotes stabilization of the UBA5 homodimer, and enhances ATP-binding (PubMed:29295865). Transfer of UFM1 from UBA5 to the E2-like enzyme UFC1 also takes place using a trans mechanism (PubMed:27653677). Ufmylation is involved in reticulophagy (also called ER-phagy) induced in response to endoplasmic reticulum stress (PubMed:32160526). Ufmylation is essential for erythroid differentiation of both megakaryocytes and erythrocytes (By similarity). Homodimer; homodimerization is required for UFM1 activation (PubMed:29295865, PubMed:27653677). Interacts (via UIS motif) with UFM1; binds UFM1 via a trans-binding mechanism in which UFM1 interacts with distinct sites in both subunits of the UBA5 homodimer (PubMed:29295865, PubMed:27653677, PubMed:26929408, PubMed:28360427, PubMed:30412706, PubMed:26872069). Interacts (via UIS motif) with GABARAPL2 and, with lower affinity, with GABARAP and GABARAPL1 (PubMed:26929408, PubMed:30990354). Interacts (via C-terminus) with UFC1 (PubMed:17825256, PubMed:29868776, PubMed:27653677). Localizes mainly in the cytoplasm, while it localizes to the nucleus in presence of SUMO2 (PubMed:18442052). Interaction with GABARAPL2 promotes localization to the endoplasmic reticulum membrane (PubMed:30990354). Widely expressed. The UFM1-interacting sequence (UIS) motif mediates interaction with both UFM1 and LC3/GABARAP proteins (GABARAP, GABARAPL1 and GABARAPL2). The N-terminus (1-56) contributes to the transfer of UFM1 from UBA5 to UFC1. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. Belongs to the ubiquitin-activating E1 family. UBA5 subfamily. Was initially reported to mediate activation of SUMO2 in addition to UFM1 (PubMed:18442052). However, it was later shown that it is specific for UFM1 (By similarity).