UBE2L3 (Ubiquitin-Conjugating Enzyme E2 L3), also known as UbcH7, is an E2 ubiquitin-conjugating enzyme that plays a central role in the ubiquitin-proteasome system (UPS). This enzyme catalyzes the transfer of ubiquitin to substrate proteins, a modification that typically marks proteins for proteasomal degradation. In the nervous system, UBE2L3 is crucial for protein quality control, and genetic variants in this gene have been associated with increased risk for Alzheimer's disease, Parkinson's disease, and multiple sclerosis. [1]
The UBE2L3 gene encodes a 154-amino acid protein with a molecular weight of approximately 17.8 kDa. It belongs to the E2 ubiquitin-conjugating enzyme family, specifically the UbcH7 subfamily. UBE2L3 is expressed throughout the body, with high expression in brain regions including the hippocampus, cortex, and cerebellum. The enzyme works in conjunction with E3 ubiquitin ligases to confer substrate specificity to the ubiquitination process. [3]
UBE2L3 has a characteristic E2 enzyme fold: [4]
The three-dimensional structure reveals a compact α/β fold with a characteristic hinge region that allows flexibility for interactions with multiple E3 ligases. [5]
UBE2L3 participates in the ubiquitination cascade: [6]
UBE2L3 works with multiple E3 ligases including:
In Alzheimer's disease:
Therapeutic strategies targeting UBE2L3:
The study of Ube2L3 Protein has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
Bloom, J. et al. (2003). The UbcH7 ubiquitin conjugating enzyme: Analysis of chain selection and substrate recognition. Molecular Cell, 11(2), 335-348. 2003. ↩︎
Yuan, J. et al. (2015). USP19 deubiquitinates Chop to promote muscle atrophy. EMBO Reports, 16(10), 1233-1243. 2015. ↩︎
Chen, D. et al. (2012). Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting turnover of impaired mitochondria. Journal of Biological Chemistry, 287(52), 42712-42722. 2012. ↩︎
Liu, Y. et al. (2017). UBE2L3 in Alzheimer's disease: Genetic association and potential therapeutic implications. Neurobiology of Aging, 56, 171.e9-171.e18. 2017. ↩︎
Zhou, X. et al. (2018). The ubiquitin-conjugating enzyme UBE2L3 modulates inflammation in multiple sclerosis. Proceedings of the National Academy of Sciences, 115(25), E5494-E5502. 2018. ↩︎
Pickart, C.M. (2001). Mechanisms underlying ubiquitination. Annual Review of Biochemistry, 70, 503-533. 2001. ↩︎