ART4 - ADP-ribosyltransferase 4 |Elisa - Clia - Antibody - Protein

Background

ADP-ribosyltransferase 4 (ART4), also known as CD297, is an enzyme that belongs to the ART family of ADP-ribosyltransferases. These enzymes mediate the transfer of ADP-ribose from NAD+ (nicotinamide adenine dinucleotide) to specific target proteins, a modification that alters their functions. ADP-ribosylation is a post-translational modification that can impact a variety of cellular processes, such as signaling, immune regulation, and cell differentiation. ART4 is a GPI-anchored ectoenzyme, meaning it is attached to the outer surface of the plasma membrane and targets extracellular proteins. ART4 is particularly known for its association with the Dombrock (Do) blood group system, where variations in ART4 contribute to antigenic diversity on red blood cells. Its functions and expression are implicated in immune cell regulation, and it has been investigated for potential roles in immune and hematologic disorders.

Protein Structure

ART4 has a well-defined structure characteristic of the ecto-ADP-ribosyltransferase family. The structure consists of three main regions:

N-terminal Signal Peptide:

• The signal peptide is responsible for directing ART4 to the endoplasmic reticulum, where it is processed before being transported to the cell surface. After processing, ART4 is anchored to the plasma membrane via a GPI (glycosylphosphatidylinositol) linkage.

Catalytic Domain:

• The catalytic domain of ART4 is crucial for its ADP-ribosylation activity and contains conserved residues essential for NAD+ binding and catalysis. This domain is highly conserved across ART family members and consists of a Rossmann fold motif, which is typical for NAD+-binding proteins. This structure enables ART4 to bind NAD+ and transfer ADP-ribose to specific arginine residues on target proteins.
• Within the catalytic domain, specific amino acids (such as aspartate, glycine, and lysine residues) facilitate substrate binding and catalytic activity. These residues interact with NAD+ to position it correctly for ADP-ribose transfer.

GPI Anchor:

• ART4 is anchored to the outer leaflet of the plasma membrane by a GPI anchor, which provides mobility in the membrane and enables interactions with other cell surface molecules. This membrane anchoring is essential for ART4’s function as an ectoenzyme, as it can access and modify extracellular targets through ADP-ribosylation.

Classification and Subtypes

ART4 is classified within the ART superfamily, which encompasses several ADP-ribosyltransferase enzymes that differ based on their cellular location (ecto vs. intracellular) and functional roles. Among the ecto-ADP-ribosyltransferases, ART4 is distinct because of its expression pattern on hematopoietic cells and its involvement in blood group antigen expression.

• Subtypes: ART4 does not have multiple subtypes but exhibits polymorphisms responsible for various antigens in the Dombrock blood group system. These polymorphic forms are associated with antigenic variability on erythrocytes, affecting the immune response in blood transfusion and transplantation contexts.

Function and Biological Significance

ART4 functions by transferring ADP-ribose to arginine residues on target proteins, modifying their activity, stability, or interactions with other molecules. The biological significance of ART4 is primarily associated with immune cell regulation, cell adhesion, and blood group antigen expression:

Blood Group Antigen Expression:

• ART4 is responsible for the expression of the Dombrock blood group antigens (Doa, Dob) on red blood cells. These antigens arise from polymorphisms within the ART4 gene, leading to variations in ADP-ribosyltransferase activity and antigenic structure. The Doa and Dob antigens are important in blood transfusion compatibility, as they can trigger immune responses in individuals lacking specific Dombrock antigens.

Immune Modulation:

• ART4 is involved in immune regulation by modifying the surface proteins of immune cells such as natural killer (NK) cells and T cells. ADP-ribosylation can modulate the interactions between immune cells and target cells, impacting immune surveillance, cell-cell communication, and cytotoxic responses. This role in immune modulation has implications for cancer immunotherapy, where ART4 could potentially be targeted to enhance immune responses against tumors.

Cell Adhesion and Migration:

• ART4 contributes to cell adhesion by modifying integrins and other adhesion molecules on the cell surface. This modification can either promote or inhibit cell adhesion, impacting cell migration, immune cell trafficking, and wound healing. The modulation of adhesion molecules by ART4 is especially relevant in immune cell migration and in processes that require precise cellular localization.

Signal Transduction:

• ART4 influences signal transduction pathways by modifying cell surface receptors and other signaling molecules. Through ADP-ribosylation, ART4 can modulate the activity of signaling receptors, thereby altering cellular responses to external stimuli such as cytokines and growth factors. This function has implications for immune responses, inflammation, and cell proliferation.

Clinical Issues

Blood Transfusion and Hemolytic Reactions:

• Variants of ART4 associated with the Dombrock blood group antigens are clinically significant in blood transfusion compatibility. Individuals with differing ART4 polymorphisms may exhibit antibodies against certain Dombrock antigens, leading to hemolytic transfusion reactions. This makes ART4 genotyping an important consideration in blood banks to ensure transfusion compatibility.

Autoimmune Disorders:

• Dysregulation of ART4 activity has been linked to autoimmune diseases. Abnormal ADP-ribosylation of cell surface proteins may alter immune cell activity, leading to the improper activation of immune responses and tissue damage. ART4’s role in modifying immune receptors and adhesion molecules may be implicated in conditions like autoimmune hemolytic anemia and other immune-mediated disorders.

Cancer and Immunotherapy:

• ART4 has been studied for its potential role in cancer, particularly in modulating immune responses against tumors. By altering the activity of immune cells, ART4 may contribute to immune evasion by cancer cells. The regulation of ART4 expression or activity is being explored as a therapeutic strategy to enhance immune cell recognition and destruction of cancer cells.

Inherited Hemolytic Disorders:

• Genetic mutations or polymorphisms in ART4 can lead to inherited hemolytic disorders due to the presence of incompatible Dombrock antigens on red blood cells. These conditions are relatively rare but can pose challenges in clinical settings where repeated blood transfusions are required, such as in patients with sickle cell anemia or thalassemia.

Summary

ADP-ribosyltransferase 4 (ART4) is an ectoenzyme that transfers ADP-ribose to target proteins, primarily impacting immune cell function and blood group antigen expression. ART4 plays a pivotal role in the Dombrock blood group system, where its polymorphisms contribute to antigenic variability on erythrocytes, impacting blood transfusion compatibility and immune recognition. Structurally, ART4 is composed of a signal peptide, a catalytic domain with a Rossmann fold for NAD+ binding, and a GPI anchor that localizes it to the plasma membrane. Through its catalytic activity, ART4 modulates immune cell function, cell adhesion, and signaling, impacting processes like immune modulation, wound healing, and cell migration.

Clinically, ART4 has significant implications in blood transfusion reactions, autoimmune disorders, and potentially in cancer immunotherapy. Its polymorphisms in the Dombrock blood group system can lead to hemolytic reactions during transfusions, and its role in immune modulation makes it a potential target in conditions characterized by immune dysregulation. ART4’s importance in immune response and cell adhesion highlights its potential as a therapeutic target for enhancing immune responses in cancer and managing autoimmune conditions.