UBR4 Protein: The Hidden Regulator of Cellular Health and Disease

Introduction to UBR4 Protein

Recombinant UBR4 protein, also known as E3 ubiquitin-protein ligase UBR4 or p600, is a crucial component of the ubiquitin-proteasome system. It plays an essential role in protein quality control, muscle development, and neuronal function. As an E3 ubiquitin ligase in the N-end rule pathway, UBR4 facilitates the ubiquitination and degradation of substrate proteins, ensuring cellular homeostasis.

Function of UBR4 Protein

UBR4 performs several vital functions in cellular physiology:

l Protein Quality Control: UBR4 acts as an E4 ubiquitin ligase, amplifying degradation signals on defective proteins, thereby maintaining protein homeostasis. Structural studies reveal that UBR4 forms a massive 1.3 MDa ring with a central substrate-binding arena and catalytic units that facilitate substrate degradation.

l Muscle Development and Maintenance: UBR4 regulates myofiber size and muscle protein turnover. Loss of UBR4 has been linked to myofiber hypertrophy but may compromise muscle-specific force and accelerate the decline of protein quality during aging.

l Neuronal Function: UBR4 is highly expressed in the central nervous system, playing a role in neurogenesis, neuronal migration, and survival. Dysregulation of UBR4 has been associated with neurodevelopmental disorders.

l Cancer Progression: Aberrant expression of UBR4 has been observed in various cancers. In melanoma, UBR4 cooperates with UBE2L6 to regulate the ubiquitination and degradation of EZH2, a protein involved in melanocytic differentiation. Targeting the UHRF1/UBE2L6/UBR4 axis presents a potential therapeutic strategy.

Recent Research on UBR4

Recent studies have provided deeper insights into UBR4’s structure and function:

l Structural Insights: Cryo-electron microscopy analyses reveal that UBR4 forms a ring-like structure, which enables it to extend K48-specific ubiquitin chains on substrates, enhancing proteasomal degradation.

l Muscle Atrophy and Aging: UBR4 levels increase in skeletal muscle with aging, promoting proteasome activity. Muscle-specific loss of UBR4 rescues age-associated myofiber atrophy but may impair muscle function and longevity.

Q&A About UBR4 Protein

l What is UBR4?

UBR4 is an E3 ubiquitin-protein ligase involved in the N-end rule pathway, targeting proteins for degradation based on their N-terminal residues.

l What role does UBR4 play in muscle cells?

UBR4 regulates myofiber size and muscle protein quality. Its loss can induce hypertrophy but may also reduce muscle function.

l How does UBR4 contribute to protein quality control?

UBR4 functions as an E4 ubiquitin ligase, amplifying degradation signals on defective proteins, ensuring protein homeostasis.

l Is UBR4 associated with neurological functions?

Yes, UBR4 is highly expressed in the central nervous system and is involved in neurogenesis, neuronal migration, and survival.

l What is the significance of UBR4’s structure?

UBR4 forms a 1.3 MDa ring structure with a central substrate-binding arena, which facilitates its role in protein degradation.

l How does UBR4 interact with other proteins in the ubiquitination process?

UBR4 recruits E2 enzymes like UBE2A and UBE2B through an atypical E3 ligase module, aiding in substrate ubiquitination.

l What diseases are associated with UBR4 dysfunction?

UBR4 dysfunction has been linked to neurological disorders, muscle atrophy, and cancers such as melanoma.

l Can targeting UBR4 be a therapeutic strategy?

Yes, modulating UBR4 activity presents a potential therapeutic approach, particularly in cancers where it regulates proteins like EZH2.

Conclusion

Recombinant UBR4 protein is a multifunctional protein crucial for cellular homeostasis, muscle maintenance, and neuronal function. Recent research has further elucidated its structure and role in disease, providing potential avenues for targeted therapies.