Abstract
CXCL12 activates CXCR4 and is involved in embryogenesis, hematopoiesis, and angiogenesis. It has pathological roles in HIV-1, WHIM disease, cancer, and autoimmune diseases. An antagonist, AMD3100, is used for the release of CD34+ hematopoietic stem cells from the bone marrow for autologous transplantation for lymphoma or multiple myeloma patients. Adverse effects are tolerated due to its short-term treatment, but AMD3100 is cardiotoxic in clinical studies for HIV-1. In an effort to determine whether Saccharomyces cerevisiae expressing a functional human CXCR4 could be used as a platform for identifying a ligand from a library of less ∼1,000 compounds, a high-throughput screening was developed. We report that 2-carboxyphenyl phosphate (fosfosal) up-regulates CXCR4 activation only in the presence of CXCL12. This is the first identification of a compound that increases CXCR4 activity by any mechanism. We mapped the fosfosal binding site on CXCL12, described its mechanism of action, and studied its chemical components, salicylate and phosphate, to conclude that they synergize to achieve the functional effect.
Highlights
CXC chemokine receptor 2 (CXCR4) is a G protein-coupled receptor (GPCR) with physiological roles in cellular homeostasis and a variety of immune response functions, and is activated by the chemokine agonist CXC chemokine ligand 12 (CXCL12)
Other studies are consistent with CXCL12-CXCR4 cardioprotection during pre- and post-myocardial ischemia, which is prevented by AMD3100 or a CXCR4 inducible knockout in cardiac myocytes (Hu et al, 2007; Huang et al, 2011; Dong et al, 2012; LaRocca et al, 2019)
We studied the mechanism of a constitutively active mutant (CAM) of CXCR4 and small molecules that bound to the CXCR4 CAM in the same strain of S. cerevisiae (Rosenberg et al, 2019)
Summary
CXCR4 is a GPCR with physiological roles in cellular homeostasis and a variety of immune response functions, and is activated by the chemokine agonist CXCL12. HTPS of CXCL12-CXCR4 in S. cerevisiae interactions of the various oligomeric states with glycoaminoglycans play a role in establishing a concentration gradient in tissues that allows immune cells expressing CXCR4 to migrate in response to increased CXCL12 concentrations (Fernandez and Lolis, 2002; Handel et al, 2005; Allen et al, 2007). Due to the importance of the monomer in activating the receptor and the oligomers in establishing this concentration gradient, most biophysical studies have investigated this monomer–dimer equilibrium, including factors that alter the equilibrium such as pH, phosphate or sulfate ions, and heparin (Veldkamp et al, 2005; Murphy et al, 2007). The effects of CXCL12-CXCR4 on the cardiovascular system are complicated by varied cell types and cardiac events, indicating more studies are necessary to define mechanisms where activation or antagonism of CXCR4 are beneficial (Bernhagen et al, 2007; Zernecke et al, 2008; Doring et al, 2017, 2019)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
