ACKR - Atypical chemokine receptor | Elisa - Clia - Antibody - Protein

Background

Atypical chemokine receptors (ACKRs) are a group of receptors that are structurally related to conventional chemokine receptors but have distinct functions in regulating chemokine signaling. ACKRs share structural similarities with conventional chemokine receptors, including seven transmembrane domains characteristic of GPCRs. However, they may lack certain conserved motifs or exhibit variations in their intracellular domains that affect signaling capabilities. Unlike conventional chemokine receptors, which typically signal through G-protein coupled receptor (GPCR) pathways to promote cell migration and activation, ACKRs often act as scavengers or decoy receptors for chemokines, modulating the availability and activity of these signaling molecules without inducing classical chemokine signaling responses. ACKRs are capable of binding to specific chemokines, but they typically do not induce downstream signaling cascades associated with cell activation or migration. Instead, ACKRs often internalize bound chemokines or sequester them on cell surfaces, thereby regulating the availability and distribution of chemokines in tissues. By scavenging or sequestering chemokines, ACKRs can modulate the formation and maintenance of chemokine gradients within tissues. This can influence the directional migration of immune cells and other cell types in physiological and pathological contexts, such as inflammation and immune surveillance. ACKRs are involved in immune regulation and contribute to the modulation of immune responses. They can affect the trafficking and activation of immune cells, as well as the development of immune cell-mediated inflammatory responses. Dysregulation of ACKRs has been implicated in various diseases, including inflammatory disorders, cancer, and infectious diseases. Altered expression or function of ACKRs can disrupt chemokine gradients and immune cell trafficking, contributing to disease pathogenesis.

Protein Structure

ACKRs share structural similarities with classical chemokine receptors but have unique features that differentiate them:

• Seven Transmembrane Domains: Like other GPCRs, ACKRs have seven transmembrane alpha-helices.
• Lack of Traditional Signaling Motifs: ACKRs often lack the DRYLAIV motif found in classical chemokine receptors, which is crucial for G-protein activation.
• Cytoplasmic Tail: The C-terminal tail of ACKRs can interact with β-arrestins and other proteins, facilitating chemokine uptake and receptor recycling.

Classification and Subtypes

The main members of the ACKR family include:

• ACKR1 (DARC - Duffy Antigen/Receptor for Chemokines): Expressed on erythrocytes and endothelial cells, involved in clearing chemokines from circulation.
• ACKR2 (D6): Primarily expressed in lymphatic endothelial cells and involved in the regulation of inflammatory chemokines.
• ACKR3 (CXCR7): Binds to CXCL12 and CXCL11, modulating their availability and function in various tissues.
• ACKR4 (CCRL1): Binds CCL19, CCL21, and CCL25, regulating their levels and impacting immune cell migration.

Function and Biological Significance

ACKRs play several critical roles in the immune system and homeostasis:

1. Chemokine Scavenging: ACKRs bind and internalize chemokines, removing them from the extracellular space to regulate their availability and gradient formation.
2. Immune Cell Positioning: By modulating chemokine levels, ACKRs help position immune cells appropriately within tissues and organs, ensuring effective immune surveillance and response.
3. Inflammation Regulation: ACKRs play a role in resolving inflammation by clearing pro-inflammatory chemokines, thus controlling the extent and duration of inflammatory responses.
4. Developmental Roles: Some ACKRs are involved in developmental processes, particularly in the formation and function of lymphoid tissues.

Interactions

ACKRs interact with various molecules and cellular components:

1. Chemokines: Bind to specific chemokines with high affinity, facilitating their internalization and degradation.
2. β-Arrestins: Interact with β-arrestins to mediate receptor internalization and chemokine uptake.
3. GPCR Pathways: While they do not signal through traditional GPCR pathways, ACKRs can modulate the function of classical chemokine receptors indirectly by regulating chemokine availability.
4. Immune Cells and Endothelial Cells: Expressed on various immune and endothelial cells, impacting their function and behavior.

Clinical Significance

Dysregulation or mutations in ACKRs can lead to various pathological conditions:

1. Inflammatory Diseases: Impaired function of ACKRs can result in excessive or prolonged inflammation, contributing to conditions like chronic inflammatory diseases, autoimmune disorders, and atherosclerosis.
2. Cancer: ACKRs can influence tumor progression by modulating the tumor microenvironment, affecting tumor growth, metastasis, and immune evasion.
3. Infectious Diseases: Certain pathogens exploit ACKRs to evade the immune system or facilitate their spread, making these receptors potential targets for therapeutic intervention.
4. Hematological Disorders: Mutations in ACKR1 (DARC) can lead to conditions like the Duffy-null phenotype, which is associated with resistance to Plasmodium vivax malaria but also linked to certain blood disorders.

Summary

Atypical chemokine receptors (ACKRs) are a unique class of chemokine receptors that primarily function as chemokine scavengers, regulating chemokine levels and gradients to modulate immune responses and maintain homeostasis. Unlike classical chemokine receptors, ACKRs do not signal through traditional GPCR pathways but play crucial roles in inflammation resolution, immune cell positioning, and developmental processes. Dysregulation of ACKRs is associated with various diseases, including inflammatory disorders, cancer, and infectious diseases, highlighting their importance in health and disease. Understanding the structure, function, and clinical implications of ACKRs provides valuable insights into their roles in immune regulation and potential therapeutic targets.