ART1 - ADP-ribosyltransferase 1 |Elisa - Clia - Antibody - Protein

Background

ADP-ribosyltransferase 1 (ART1) is an enzyme that belongs to the ART superfamily of proteins, which catalyze the transfer of ADP-ribose from NAD+ (nicotinamide adenine dinucleotide) to target proteins, a process known as mono-ADP-ribosylation. This post-translational modification alters the function of target proteins, influencing various cellular processes, including signal transduction, immune responses, cell differentiation, and apoptosis. ART1 is primarily expressed in immune cells and skeletal muscle tissues and has been associated with immune modulation, inflammatory responses, and cell adhesion. As ART1 modifies proteins by adding an ADP-ribose moiety, it has significant roles in regulating interactions between cells and in modulating the immune response, making it an area of interest in immunology and cancer research.

Protein Structure

ART1 is a type I membrane-bound protein and part of the ecto-ADP-ribosyltransferase family, which is characterized by a conserved structure necessary for its enzymatic activity. ART1 consists of three primary domains:

Signal Peptide:

• ART1 has a short N-terminal signal peptide that directs the protein to the endoplasmic reticulum during its synthesis. After processing, ART1 is transported to the cell surface, where it is anchored by a glycosylphosphatidylinositol (GPI) anchor.

Catalytic Domain:

• The catalytic domain of ART1 is highly conserved within the ADP-ribosyltransferase family and consists of the NAD+ binding site and the active site responsible for the transfer of the ADP-ribose moiety. The catalytic activity requires a conserved arginine residue as the target for ADP-ribosylation. This domain is folded into an α/β structure with a distinct Rossmann fold, which is common among NAD+-binding proteins.
• The catalytic domain contains specific residues essential for NAD+ binding and the ADP-ribosyl transfer reaction. Glycine and aspartate residues play critical roles in positioning the NAD+ and facilitating the transfer of the ADP-ribose to substrate proteins.

Glycosylphosphatidylinositol (GPI) Anchor:

• ART1 is tethered to the outer leaflet of the cell membrane via a GPI anchor, which provides flexibility for the protein to interact with extracellular substrates. This anchor is crucial for ART1's localization and interaction with cell surface molecules.

Classification and Subtypes

ART1 belongs to the ART superfamily, which is further divided based on structure, cellular localization, and function. ART1 is classified as a GPI-anchored ecto-ADP-ribosyltransferase. Other members in this family include ART2, ART3, and ART4, which have similar functions but differ in tissue distribution, substrate specificity, and cellular localization. Among these, ART2 also plays an important role in immune modulation, particularly in T cells.

Function and Biological Significance

ART1 functions by transferring ADP-ribose from NAD+ to specific arginine residues on target proteins, a modification that impacts protein activity, localization, and interactions. The biological significance of ART1 stems from its ability to regulate immune functions, cell adhesion, and inflammation:

Modulation of Immune Response:

• ART1 is involved in the regulation of immune cell activity by modifying surface proteins on immune cells such as macrophages, neutrophils, and T cells. For example, ART1 can ADP-ribosylate CD8+ T cells and influence their activation, differentiation, and cytotoxic functions.
• This enzyme can also modulate immune tolerance by affecting the signaling pathways involved in immune cell interactions and responses to pathogens or inflammatory stimuli.

Cell Adhesion and Migration:

• ART1-mediated ADP-ribosylation of cell surface proteins, including integrins, affects cell adhesion and migration. In particular, ADP-ribosylation of the integrin β2 subunit can inhibit cell adhesion and migration, which is crucial in immune responses and wound healing. By modulating cell adhesion, ART1 influences the ability of immune cells to reach sites of infection or inflammation.

Inflammation and Tissue Repair:

• ART1 has a regulatory role in inflammatory responses. ADP-ribosylation can activate or inhibit pro-inflammatory cytokine release, and this modification can also affect inflammatory cell recruitment to injury sites. This modulation of inflammatory processes is essential in tissue repair, as controlled inflammation is crucial for the proper healing of damaged tissues.
• In some contexts, ART1 may have protective functions, limiting excessive inflammation by dampening immune cell activation through ADP-ribosylation of surface receptors, potentially reducing tissue damage in inflammatory diseases.

Signal Transduction:

• ART1 influences signal transduction pathways by modifying key signaling proteins, which can lead to changes in cellular responses to external stimuli. By modifying cell surface receptors, ART1 regulates pathways involved in cell growth, differentiation, and apoptosis, thus impacting cellular responses to the environment.

Clinical Issues

Autoimmune Disorders:

• Dysregulation of ART1 activity has been implicated in autoimmune diseases where improper ADP-ribosylation of immune cell surface receptors could lead to excessive immune activation and tissue damage. ART1 dysregulation may contribute to conditions like rheumatoid arthritis and multiple sclerosis, where immune responses are abnormally heightened.

Cancer:

• ART1 is expressed in some tumor cells, and ADP-ribosylation can influence cancer cell adhesion, proliferation, and immune evasion. For example, ART1 may promote cancer metastasis by modifying adhesion molecules, allowing tumor cells to detach and spread. The role of ART1 in modulating immune cell function may also contribute to the tumor’s ability to evade immune detection, impacting cancer progression.

Chronic Inflammatory Diseases:

• In diseases characterized by chronic inflammation, such as chronic obstructive pulmonary disease (COPD) or inflammatory bowel disease (IBD), ART1 expression and activity are often altered, contributing to persistent immune activation. ART1 could serve as a therapeutic target in these diseases, as inhibition of its activity may reduce inflammation and mitigate disease progression.

Muscle Disorders:

• Given its high expression in skeletal muscle, ART1 is implicated in certain muscular dystrophies and muscle wasting conditions. Abnormal ART1 activity may interfere with muscle cell repair mechanisms, leading to progressive muscle degeneration in diseases like Duchenne muscular dystrophy.

Summary

ART1, or ADP-ribosyltransferase 1, is an enzyme with critical functions in regulating immune responses, inflammation, and cell adhesion. It operates through the transfer of ADP-ribose to surface proteins on immune and other cell types, modifying protein functions and thereby impacting cellular processes essential for immune regulation, inflammation control, and cell communication. Structurally, ART1 is characterized by a signal peptide, a catalytic domain with a conserved ADP-ribosylation site, and a GPI anchor that localizes it to the cell surface, facilitating its interactions with extracellular substrates.

The enzyme’s function is significant in modulating immune responses, controlling inflammation, and regulating cell adhesion, which can affect wound healing, tissue repair, and immune surveillance. Clinically, ART1 dysregulation is associated with autoimmune diseases, chronic inflammatory conditions, and certain cancers, where its role in immune modulation and cell adhesion is often pathologically altered. Because of its involvement in these critical processes, ART1 presents a potential target for therapeutic interventions in various immune-mediated and inflammatory diseases, as well as in oncology.