CCR5

What is CCR5 protein?

CCR5 gene (C-C motif chemokine receptor 5) is a protein coding gene which situated on the short arm of chromosome 3 at locus 3p21. This gene encodes a member of the beta chemokine receptor family, which is predicted to be a seven transmembrane protein similar to G protein-coupled receptors. This protein is expressed by T cells and macrophages, and is known to be an important co-receptor for macrophage-tropic virus, including HIV, to enter host cells. Defective alleles of this gene have been associated with the HIV infection resistance. The ligands of this receptor include monocyte chemoattractant protein 2 (MCP-2), macrophage inflammatory protein 1 alpha (MIP-1 alpha), macrophage inflammatory protein 1 beta (MIP-1 beta) and regulated on activation normal T expressed and secreted protein (RANTES). Expression of this gene was also detected in a promyeloblastic cell line, suggesting that this protein may play a role in granulocyte lineage proliferation and differentiation. This gene is located at the chemokine receptor gene cluster region. The CCR5 protein is consisted of 352 amino acids and CCR5 molecular weight is approximately 40.5 kDa.

What is the function of CCR5 protein?

CCR5 is the principal coreceptor for the entry of R5 strains of human immunodeficiency virus (HIV-1, HIV-2) into the host cells. The binding of chemokines to CCR5 leads to cellular activation through G proteins and can also trigger G protein-independent signaling pathways. Furthermore, CCR5 is implicated in inflammatory responses and has been shown to be essential for HIV pathogenesis. It binds to multiple chemokines such as macrophage inflammatory protein (MIP-1α, also known as CCL3) and RANTES (regulated on activation, normal T cell expressed and secreted, also known as CCL5), which are involved in the migration and positioning of immune cells during infection and inflammation. CCR5 also participates in the response to bacteria and bacterial products, like lipopolysaccharide (LPS) and heat-shock proteins, highlighting its role in the innate immune response.

CCR5 Related Signaling Pathway

In the chemokine signaling pathway, CCR5 binds to ligands such as MIP-1α (Macrophage inflammatory protein-1α) and RANTES (regulated on activation, normal T cell expressed and secreted), It can activate G protein signal transduction, and then activate downstream intracellular signal cascade, and promote the activation and proliferation of immune cells. In addition to the GPCR pathway, CCR5 may also induce rapid phosphorylation of tyrosine residues in CCR5 through its ligand, CCL5 (RANTES), activating GPCR-independent signaling.

CCR5 Related Diseases

Immune-related inflammatory diseases, such as multiple sclerosis, rheumatoid arthritis, atherosclerosis, transplant rejection, and autoimmune diseases. CCR5 is one of the main co-receptors for HIV-1 virus to enter host cells and is closely related to the development of AIDS. CCR5 may play a role in the pathogenesis of neurological diseases, including stroke, Alzheimer's disease, Parkinson's disease and HIV encephalopathy. Associated with inflammatory storms, abnormal activation of CCR5 in certain pathological states may be related to the regulatory axis of regulatory signaling pathways in inflammatory cells.

Fig1. Mechanisms of the CCL5/CCR5 axis in the pathogenesis of AD. (Weijiang Ma, 2023)

Bioapplications of CCR5

As the main co-receptor for HIV-1 virus to enter host cells, CCR5 is an important target for the development of anti-HIV drugs, and there are already drugs such as Maraviroc that are used as HIV treatments. CCR5 may play a role in the pathogenesis of certain neurological diseases, and CCR5 inhibitors are being tested as neuroprotective agents in clinical trials. CCR5 plays a role in the migration and localization of immune cells, and CCR5 antagonists may be used to treat autoimmune and inflammatory diseases. In certain viral diseases, CCR5 may serve as a potential target for vaccine design to prevent disease by modulating the host immune response.

Case Study 1: I Scurci, 2021

Chemokine receptor tyrosine sulfation plays a key role in the binding of chemokines. It has been suggested that receptor sulfation is heterogeneous, but no experimental evidence has been provided so far. The potent anti-HIV chemokine analog 5P12-RANTES has been proposed to owe its inhibitory activity to a capacity to bind a larger pool of cell surface CCR5 receptors than native chemokines such as CCL5, but the molecular details underlying this phenomenon have not been elucidated. Here researchers investigated the CCR5 sulfation heterogeneity and the sensitivity of CCR5 ligands to receptor sulfation by performing ELISA assays on synthetic N-terminal sulfopeptides and by performing binding assays on CCR5-expressing cells under conditions that modulate CCR5 sulfation levels. The results showed CCR5 sulfation is heterogeneous and this affects the binding properties of both native chemokines and antibodies. Enhanced capacity to bind to CCR5 is a component of the inhibitory mechanism of 5P12-RANTES.

Fig1. Competition binding assays.

Fig2. Evidence for CCR5 heterogeneity on primary human T cells.

Case Study 2: Pierre Calmet, 2020

The chemokine CCR5 receptor is target of maraviroc, a negative allosteric modulator of CCR5 that blocks the HIV protein gp120 from associating with the receptor, thereby inhibiting virus cellular entry. As noted with other G-protein-coupled receptor family members, the role of the lipid environment in CCR5 signaling remains obscure and very modestly investigated. To address this aim, the approach chosen was to employ reconstituted model lipid systems of controlled lipid composition containing CCR5 from two distinct expression systems: Pichia pastoris and cell-free expression. The characterization of receptor/ligand interaction in terms of total binding or competition binding assays was independently performed by plasmon waveguide resonance and fluorescence anisotropy, respectively. Maraviroc, a potent receptor antagonist, was the ligand investigated. Additionally, coarse-grained molecular dynamics simulation was employed to investigate Chol impact in the receptor-conformational flexibility and dynamics. Results obtained with receptor produced by different expression systems and using different biophysical approaches clearly demonstrate a considerable impact of Chol in the binding affinity of maraviroc to the receptor and receptor-conformational dynamics. Chol considerably decreases maraviroc binding affinity to the CCR5 receptor.

Fig3. Coomassie blue staining of CCR5 after purification of sucrose gradient.

Fig4. Binding competition between a fluorescent CCR5 agonist and maraviroc to the CCR5 reconstituted in the absence and in the presence of Chol, respectively.

CCR5 has several biochemical functions, for example, C-C chemokine binding,C-C chemokine receptor activity,actin binding. Some of the functions are cooperated with other proteins, some of the functions could acted by CCR5 itself. We selected most functions CCR5 had, and list some proteins which have the same functions with CCR5. You can find most of the proteins on our site.

CCR5 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with CCR5 here. Most of them are supplied by our site. Hope this information will be useful for your research of CCR5.

CD4;PRAF2;CCL5;CXCR4;ARL6IP5;CCL4;MYH9;CREB3;ETV5;CTBP2;IL24