UBR4

What is UBR4 Protein?

UBR4 is a massive protein that's got fingers in a lot of pies. It's a type of enzyme known as an E3 ligase, which plays a big role in tagging other proteins for destruction as part of the N-degron pathway. This pathway is vital for several processes in our bodies, like how our brains develop, how our muscles shrink as we get older, and even how some cancers progress. What's cool about UBR4 is its unique structure, which includes a 'hemiRING' zinc finger and a special N-terminal area that interacts with another enzyme, E2. This setup allows UBR4 to work specifically with E2 partners like UBE2A and UBE2B, making sure that only the right proteins get tagged and broken down at the right speed. It's a finely tuned system that's essential for maintaining cellular balance and function.

What is the Function of UBR4 Protein?

UBR4 is like a cellular handyman with a knack for keeping things tidy. Its main gig is working as an E3 ligase in the N-degron pathway, which involves marking certain proteins for cleanup. Think of it as attaching a "throw this out" sticker to old, worn-out proteins, signaling that it's time for them to be broken down and recycled. This process is crucial in a bunch of areas, such as making sure our brains develop properly, how our muscles behave as we age, and even in the dance of cell life and death in cancer. UBR4's unique structure lets it connect effectively with other enzymes, helping to control which proteins get tagged and when. By doing this, UBR4 helps maintain the right balance of proteins inside cells, ensuring everything runs smoothly and efficiently.

UBR4 Related Signaling Pathway

The UBR4-related signaling pathway is like a busy highway in our cells where proteins get the green light to head for recycling. At its core, it involves the N-degron pathway, with UBR4 acting as one of the main traffic cops. Its job is to tag specific proteins that need to be taken out of circulation. This tagging process tells the cell's clean-up crew it's time to break these proteins down and reuse their parts. It's a crucial part of cell maintenance, helping to regulate everything from brain development to muscle integrity as we age, and even playing roles in how cancer cells behave. By working in concert with other molecules and pathways, UBR4 ensures that proteins are properly managed, making sure the cell functions aren't disrupted by too many worn-out or unnecessary proteins lingering around. It's a sophisticated form of quality control that keeps our cellular machinery running smoothly.

UBR4 Related Diseases

UBR4 is connected to a variety of health issues because of its crucial role in managing protein life cycles within cells. When UBR4 doesn't work as it should, it can lead to a range of diseases. For instance, in neurodevelopmental disorders, if UBR4 fails to remove damaged proteins, it might interfere with how the brain forms and functions. As we age, issues in the UBR4 pathway could contribute to muscular atrophy, where muscles weaken and shrink because they're not getting rid of faulty proteins efficiently. In cancer, when UBR4 isn't doing its job right, it might mess up the process of normal cell death. This means cancer cells can stick around longer than they should, which could help tumors grow. Since UBR4 is involved in so many cellular tasks, problems with it can spread throughout the body, highlighting just how crucial it is for keeping us healthy.

Bioapplications of UBR4

UBR4 is proving to be quite the versatile player in the world of biotechnology and medicine. Given its role in tagging proteins for degradation, it's becoming a target of interest in developing therapies for conditions where protein regulation goes haywire. For instance, researchers are exploring ways to tweak UBR4 activity to help treat neurodegenerative diseases where protein build-up in brain cells leads to damage. In cancer research, since UBR4 can influence cell survival, scientists are looking into how modulating its activity might help in designing treatments that encourage cancer cells to self-destruct. Additionally, in regenerative medicine, understanding UBR4's role in cell growth and development could pave the way for novel approaches to tissue engineering and healing. By leveraging UBR4's functions, we could unlock a host of new bioapplications aimed at tackling some of the most challenging health problems.

Case Study 1: Nakatani Y. et al. Proc Natl Acad Sci U S A. 2005

This article examines p600, a unique protein binding with the retinoblastoma protein and calmodulin. In the nucleus, it forms a chromatin scaffold; in the cytoplasm, it structures with clathrin to shape the cytoskeleton and membranes. Reducing p600 disrupts integrin-aided ruffled membrane formation and survival pathways, making cells more prone to apoptosis when detached. These insights reveal how membrane activities might be regulated in tumor development.

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  Fig1. Silver staining of the purified RB complex.
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  Fig2. Analysis of FAK phosphorylation by Western blotting.

Case Study 2: Barnsby-Greer L. et al. Nat Struct Mol Biol. 2024

UBR4 is a key E3 ligase in the N-degron pathway, affecting brain development, age-related muscle loss, and cancer. Researchers identified an E3 module in human UBR4 with a 'hemiRING' zinc finger, a UZI subdomain, and an N-terminal area for E2 binding. The E2-E3 complex structure shows how hemiRING targets UBE2A/UBE2B. The UZI boosts the activity of the E2~Ub. This combo works with UBE2A's high lysine reactivity for precise substrate targeting and fast degradation. These findings explain how UBR4 functions and works with UBE2A, highlighting the diversity in its structure.

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  Fig3. Activity assessment of UBR4short and UBR4long with UBE2A.
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  Fig4. Quantitative UBR4 autoubiquitination assay comparing UBE2A WT with UBE2A Asn80Ser under single turnover E2∼Ub discharge conditions.

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  Fig1. Proposed model for UHRF1/UBE2L6/UBR4-mediated regulation of EZH2 and thereby melanocytic differentiation phenotypes in melanoma. (Gamze Kuser-Abali, 2023)
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  Fig2. A schematic model describing mitochondrial quality control mediated by UBR1/2/4 in response to the mitochondrial damage. (Jung Gi Kim, 2021)

UBR4 has several biochemical functions, for example, calmodulin binding,ligase activity,protein binding. Some of the functions are cooperated with other proteins, some of the functions could acted by UBR4 itself. We selected most functions UBR4 had, and list some proteins which have the same functions with UBR4. You can find most of the proteins on our site.

Function	Related Protein
ubiquitin-protein transferase activity	DZIP3,WWP2,HECTD3,FBXW2,RNF151,BRAP,FBXL5,RNF141,FBXO11,RCHY1
calmodulin binding	MYH10,CAMK2B1,PHKB,TRPC2,NRGNA,PHKG1A,MYH1E,REM1,PHKG1,TRPV5
protein binding	GAGE1,SFMBT1,CSNK2B,STAC3,UNC13A,CHCHD3,IRS4,ASB3,SAP30BP,GDAP2
ligase activity	TNFAIP3,UBR1,HECW1,CDC34A,RNF123,MARCH2,RAD18,HUWE1,RNF115,MUL1
zinc ion binding	PNMA3,AMFR,MMP28,SHARPIN,NR1H5,TRIM10,MORC1,ZSWIM3,MARCH5,TTF2

UBR4 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with UBR4 here. Most of them are supplied by our site. Hope this information will be useful for your research of UBR4.

E7;VCAM1;gag-pol;E7;E7;MCRS1;PRPF40A;SRGN;UBE2A;UBE2B;Smad6;Nsfl1c