- UBE2K (Ubiquitin-conjugating enzyme E2 K), also known as HIP2 (Huntingtin-interacting protein 2), is a specialized member of the ubiquitin-conjugating enzyme (E2) family that plays a key role in protein quality control and neurodegeneration.
- Like all E2 enzymes, UBE2K accepts activated ubiquitin from an E1 ubiquitin-activating enzyme and collaborates with E3 ligases to transfer ubiquitin to specific substrate proteins. What sets UBE2K apart from many other E2 enzymes is its strong preference for elongating K48-linked polyubiquitin chains, the canonical signal for proteasomal degradation. In this way, UBE2K contributes directly to the clearance of misfolded or damaged proteins by the ubiquitin–proteasome system.
- UBE2K was originally identified through its interaction with huntingtin, the protein mutated in Huntington’s disease (HD). Subsequent studies have shown that UBE2K regulates the ubiquitination of huntingtin and influences the aggregation of polyglutamine-expanded huntingtin fragments. Because protein aggregation is a hallmark of HD and other neurodegenerative diseases, UBE2K has attracted significant attention as a potential modifier of neurotoxicity. Experimental models suggest that changes in UBE2K activity can either mitigate or exacerbate neuronal dysfunction, depending on the balance between promoting proteasomal degradation and inadvertently facilitating aggregate formation.
- Beyond Huntington’s disease, UBE2K has also been implicated in Parkinson’s disease, Alzheimer’s disease, and other protein misfolding disorders, where the buildup of ubiquitinated aggregates reflects failures in the protein degradation machinery. Since UBE2K specializes in building K48-linked chains, it is thought to be particularly important in determining whether proteins are efficiently degraded versus accumulating in toxic inclusions. This highlights its central role in neuroproteostasis (the maintenance of neuronal protein homeostasis).
- Structurally, UBE2K contains the conserved ubiquitin-conjugating (UBC) catalytic domain found in all E2 enzymes, but it also possesses a unique C-terminal ubiquitin-associated (UBA) domain. This additional domain allows UBE2K to bind polyubiquitin chains directly, which enhances its ability to elongate ubiquitin chains on substrates and may also target it to existing ubiquitin-tagged proteins. This domain structure provides UBE2K with a dual role: acting both as a conjugating enzyme and as a polyubiquitin chain extender.
- In addition to its role in neurodegeneration, UBE2K has been linked to cell cycle regulation and apoptosis. It has been shown to ubiquitinate cell cycle regulators and apoptosis-related proteins, thereby influencing cell fate decisions. Elevated UBE2K expression has been reported in certain cancers, where it may contribute to tumor progression by promoting degradation of tumor suppressor proteins. Conversely, its dysfunction can destabilize protein homeostasis, contributing to cellular stress and degeneration.
- In summary, UBE2K is a unique ubiquitin-conjugating enzyme specialized in elongating K48-linked polyubiquitin chains, ensuring efficient proteasomal degradation of proteins. Its distinctive UBA domain enhances this function and links it to the clearance of misfolded and aggregated proteins. Dysfunction of UBE2K is associated with neurodegenerative diseases, particularly Huntington’s disease, and it has emerging relevance in cancer biology. Because of its dual role in maintaining protein quality control and influencing disease pathways, UBE2K represents both a crucial regulator of cellular homeostasis and a promising target for therapeutic intervention.
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