# CXCR4

## Overview
The CXCR4 gene encodes the C-X-C motif chemokine receptor 4, a G protein-coupled receptor (GPCR) that plays a pivotal role in various physiological and pathological processes. As a transmembrane receptor, CXCR4 is primarily involved in mediating cell migration and homing by binding to its ligand, CXCL12, also known as stromal cell-derived factor 1 (SDF-1) (Bianchi2020The; Kawaguchi2019Involvement). This interaction is crucial for the trafficking and retention of hematopoietic stem/progenitor cells in the bone marrow and is essential for embryonic development, immune surveillance, and homeostasis (Karpova2015Concise; Zou1998Function). CXCR4's involvement extends to various tissues, influencing processes such as epithelial cell renewal and maintenance (Jordan1999Expression). Clinically, mutations in the CXCR4 gene are linked to disorders like WHIM syndrome and Waldenström macroglobulinemia, and the receptor is implicated in cancer metastasis, making it a target for therapeutic interventions (Milanesi2020Aberrant; Hernandez2003Mutations).

## Structure
The CXCR4 protein is a G protein-coupled receptor (GPCR) characterized by a canonical bundle of seven transmembrane alpha-helices, which is typical of GPCRs (Wu2010Structures). The primary structure of CXCR4 includes specific amino acid residues critical for its function, such as Asp (D20A) and Tyr (Y21A) in the N-terminal domain, and Glu (E268A) in extracellular loop 3 (ECL3), which are involved in ligand binding (Zhou2001Structural). The secondary structure features include transmembrane helices with unique configurations, such as helix VII, which is two turns longer on the extracellular side, allowing for strategic disulfide bond formation (Wu2010Structures).

The tertiary structure of CXCR4 reveals a ligand-binding pocket shaped by disulfide bonds that constrain the extracellular loops, crucial for ligand interaction (Wu2010Structures). The receptor can form homodimers and higher-order oligomers, such as trimers and tetramers, which are significant for its quaternary structure and function (Saotome2024Structural). These oligomeric forms are stabilized by hydrophobic interactions and specific amino acid residues (Wu2010Structures). Post-translational modifications, such as phosphorylation and glycosylation, play roles in modulating CXCR4's function and signaling (Wescott2016Signal).

## Function
CXCR4 (C-X-C motif chemokine receptor 4) is a G protein-coupled receptor that plays a crucial role in various physiological processes in healthy human cells. It primarily binds to its ligand CXCL12, also known as stromal cell-derived factor 1 (SDF-1), to mediate cell migration, homing, and retention, particularly in hematopoietic and immune system cells (Bianchi2020The; Kawaguchi2019Involvement). This receptor is essential for the trafficking and retention of hematopoietic stem/progenitor cells (HSPCs) in the bone marrow, influencing their survival and expansion (Karpova2015Concise; Majka2024Biological).

CXCR4 is involved in embryonic development, playing a significant role in cardiovascular development, cerebellar neuron migration, and hematopoiesis. Mice deficient in CXCR4 exhibit severe developmental defects, highlighting its non-redundant functions (Karpova2015Concise). In the central nervous system, CXCR4 is crucial for the proper migration and positioning of granule cells in the cerebellum, preventing premature migration and ensuring normal cerebellar structure (Zou1998Function).

In the immune system, CXCR4 is involved in the migration of resting leukocytes and hematopoietic progenitors, contributing to immune surveillance and homeostasis (Zou1998Function). It is also expressed in various tissues, including the colon, where it plays a role in epithelial cell renewal and maintenance (Jordan1999Expression).

## Clinical Significance
Mutations in the CXCR4 gene are associated with several diseases, most notably WHIM syndrome and Waldenström macroglobulinemia (WM). WHIM syndrome is a rare immunodeficiency disorder characterized by warts, hypogammaglobulinemia, infections, and myelokathexis. It results from heterozygous mutations in CXCR4, such as the R334X mutation, which lead to delayed receptor internalization and prolonged signaling. This causes neutrophil retention in the bone marrow and increased susceptibility to infections, particularly HPV (Milanesi2020Aberrant; Hernandez2003Mutations; McDermott2011AMD3100).

In Waldenström macroglobulinemia, CXCR4 mutations are found in a significant portion of patients and are often associated with the MYD88 L265P mutation. These mutations contribute to the disease's pathogenesis by disrupting the CXCR4/SDF1 signaling pathway, leading to increased receptor expression on tumor cells and altered cell migration (Poulain2016Genomic; Milanesi2020Aberrant). CXCR4 is also implicated in cancer metastasis, where its high expression is linked to increased risk and decreased survival in certain cancers, such as breast carcinoma (Kawaguchi2019Involvement). Targeting the CXCR4 pathway with antagonists like Plerixafor is being explored as a therapeutic strategy for these conditions (Milanesi2020Aberrant; Scala2020New).

## Interactions
CXCR4, a chemokine receptor, engages in various interactions with other proteins, forming complexes that influence its signaling pathways. It can form a functional receptor complex with CD74 and heterodimers with the chemokine receptor ACKR3, modulating CXCL12/CXCR4 signaling. CXCR4 also oligomerizes with CCR5 and CCR2, which are significant for HIV infection (Pawig2015Diversity). Upon stimulation with CXCL12, CXCR4 forms a heterodimer with the T-cell receptor (TCR), leading to cellular outcomes such as ERK activation and increased Ca2+ levels (Pawig2015Diversity). In endothelial cells, CXCR4 interacts with TLR2 to mediate pro-angiogenic effects (Pawig2015Diversity).

CXCR4 also interacts with the androgen receptor, regulating cellular motility in prostate tumor cells, and with α1A/B-adrenergic GPCR, CD4, and the lipopolysaccharide receptor (Pawig2015Diversity). The receptor's interaction with the Epstein-Barr virus-encoded GPCR BILF1, kappa-type opioid receptor, and delta-type opioid receptor has been noted (Pawig2015Diversity). CXCL12, the natural ligand of CXCR4, interacts with high mobility group box 1 (HMGB1), affecting CXCR4 activation and inflammatory cell recruitment (Pawig2015Diversity). The MIF/CXCR4 axis is involved in cell migration, proliferation, and survival, and is implicated in inflammatory diseases and cancer cell behavior (Pawig2015Diversity).


## References


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