{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nUBA5 is a non‐canonical E1 enzyme that initiates the ufmylation cascade by activating the ubiquitin‐fold modifier UFM1. It catalyzes the adenylation of UFM1 using ATP and then forms a thioester bond via its catalytic cysteine—which, unusually, is embedded within the adenylation domain—to subsequently transfer UFM1 to the E2 enzyme UFC1. Structural and biochemical studies have delineated the minimal UBA5 regions required for high‐efficiency UFM1 activation, highlighted the critical role of its C‐terminal region for UFC1 binding, and revealed a unique trans‐binding mechanism that involves dimerization and the stabilization of ATP binding. These studies also uncovered additional functional motifs, including a linear LC3‐interacting region/UFM1‐interacting motif (LIR/UFIM) that modulates binding not only to UFM1 but also to autophagy‐related proteins, thereby integrating distinct cellular regulatory pathways."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDiverse genetic and experimental studies have firmly established the clinical importance of UBA5. Mutations in UBA5 have been implicated in a spectrum of severe neurodevelopmental disorders—including early‐onset epileptic encephalopathies, intellectual disability, movement disorders, microcephaly, and ataxia—underscoring its critical role in central nervous system development and function. Animal and cellular models further demonstrate that disruptions in UFM1 activation lead to abnormal endoplasmic reticulum morphology and impaired neurotransmission, linking defective ufmylation to both neuronal dysfunction and neurodegeneration."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its enzymatic role in ufmylation, UBA5 is emerging as a nexus in the regulation of cellular stress responses and protein homeostasis. Investigations into its activity have revealed that UBA5’s oligomeric state and ATP binding are modulated by UFM1, thereby affecting downstream signaling pathways. Furthermore, pharmacological inhibition studies and comprehensive genotype–phenotype evaluations have expanded our understanding of UBA5’s molecular regulation and its potential as a therapeutic target in disorders linked to defective post‐translational modifications."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "John-Paul Bacik, John R Walker, Mohsin Ali, et al. 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