UBE2D3: A Potential Drug Target and Biomarker for Ubiquitin-Conjugating Enzyme D3

Target Name: UBE2D3

NCBI ID: G7323

UBE2D3: A Potential Drug Target and Biomarker for Ubiquitin-Conjugating Enzyme D3

Introduction

Ubiquitin (U) is a protein that plays a crucial role in the regulation of protein stability and dynamics. Ubiquitin-conjugating enzyme D3 (UBE2D3) is a key enzyme that modifies the ubiquitin moiety on target proteins, which in turn affects protein stability and localization Abnormalities in UBE2D3 function have been implicated in a variety of diseases, including cancer, neurodegenerative diseases, and autoimmune disorders. As such, targeting UBE2D3 has emerged as a promising strategy for the development of new therapeutic approaches.

In this article, we will explore the biology of UBE2D3 and its potential as a drug target and biomarker. We will discuss the current understanding of UBE2D3 function and its relevance in disease, as well as the various approaches that have been taken to target UBE2D3 and the potential implications of these efforts.

Overview of UBE2D3 Function

UBE2D3 is a member of the ubiquitin-conjugating enzyme family 1 (UBE1-6) and is responsible for modifying the N-terminus of target proteins. This modification has important implications for protein stability and localization, as N-terminus modification is often associated with increased protein stability and localization to specific cellular compartments.

In addition to modifying the N-terminus of target proteins, UBE2D3 also plays a critical role in the regulation of protein ubiquitination, which is the process by which Ubiquitin is covalently attached to target proteins. regulation of Ubiquitin ubiquitination is critical for the regulation of protein stability, as changes in ubiquitination levels can affect protein localization, half-life, and interactions with other cellular components.

Approaches to Targeting UBE2D3

Several approaches have been taken to target UBE2D3 and modulate its function. These approaches can be broadly classified into three categories: inhibition of UBE2D3 activity, Blockade of UBE2D3-mediated signaling pathways, and modulation of UBE2D3 expression levels.

1. Inhibition of UBE2D3 activity:

One of the most effective approaches to targeting UBE2D3 is the inhibition of its activity. This can be achieved through various mechanisms, including the use of small molecules, antibodies, or genetic tools. One such approach is the use of inhibitors of UBE2D3-mediated ubiquitination , which can prevent the formation of Ubiquitin-protein conjugates and reduce the stability of target proteins.

2. Blockade of UBE2D3-mediated signaling pathways:

Another approach to targeting UBE2D3 is to blockade its-mediated signaling pathways. This can be achieved through the use of drugs or other compounds that inhibit the activity of UBE2D3, such as small molecules that inhibit Ubiquitin ubiquitination, antibodies that specifically bind to UBE2D3 and prevent its function, or genetic tools that disrupt UBE2D3 expression.

3. Modulation of UBE2D3 expression levels:

A third approach to targeting UBE2D3 is to modulate its expression levels. This can be achieved through the use of drugs or other compounds that modulate UBE2D3 expression levels, such as small molecules that induce Ubiquitin synthesis, antibodies that specifically bind to UBE2D3 and prevent its function , or genetic tools that disrupt UBE2D3 expression.

Potential Implications of Targeting UBE2D3

The potential implications of targeting UBE2D3 are vast and varied. If successful, these efforts could lead to the development of new therapeutic approaches for a variety of diseases, including cancer, neurodegenerative diseases, and autoimmune disorders.

For example, targeting

Protein Name: Ubiquitin Conjugating Enzyme E2 D3

Functions: Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-11'-, as well as 'Lys-48'-linked polyubiquitination. Cooperates with the E2 CDC34 and the SCF(FBXW11) E3 ligase complex for the polyubiquitination of NFKBIA leading to its subsequent proteasomal degradation. Acts as an initiator E2, priming the phosphorylated NFKBIA target at positions 'Lys-21' and/or 'Lys-22' with a monoubiquitin. Ubiquitin chain elongation is then performed by CDC34, building ubiquitin chains from the UBE2D3-primed NFKBIA-linked ubiquitin. Acts also as an initiator E2, in conjunction with RNF8, for the priming of PCNA. Monoubiquitination of PCNA, and its subsequent polyubiquitination, are essential events in the operation of the DNA damage tolerance (DDT) pathway that is activated after DNA damage caused by UV or chemical agents during S-phase. Associates with the BRCA1/BARD1 E3 ligase complex to perform ubiquitination at DNA damage sites following ionizing radiation leading to DNA repair. Targets DAPK3 for ubiquitination which influences promyelocytic leukemia protein nuclear body (PML-NB) formation in the nucleus. In conjunction with the MDM2 and TOPORS E3 ligases, functions ubiquitination of p53/TP53. Supports NRDP1-mediated ubiquitination and degradation of ERBB3 and of BRUCE which triggers apoptosis. In conjunction with the CBL E3 ligase, targets EGFR for polyubiquitination at the plasma membrane as well as during its internalization and transport on endosomes. In conjunction with the STUB1 E3 quality control E3 ligase, ubiquitinates unfolded proteins to catalyze their immediate destruction. Together with RNF135, catalyzes the viral RNA-dependent 'Lys-63'-linked polyubiquitination of RIGI to activate the downstream signaling pathway that leads to interferon beta production (PubMed:28469175)

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