title: Allosteric peptide regulators of chemokine receptors CXCR4 and CXCR7.
abstract: The chemokine CXCL12 and its shared seven-transmembrane receptors CXCR4 and CXCR7 regulate diseases including cancer, atherosclerosis, autoimmunity, and HIV infection, making these molecules promising drug targets. These molecules also control key processes in normal development and physiology, suggesting the need to selectively modulate CXCR4 and/or CXCR7 functions and signaling to reduce potential complications of long-term therapy. We previously identified two peptides that functioned as allosteric agonists driving CXCR4-dependent chemotaxis, providing key structural information to design a small number of additional peptides to investigate determinants of CXCL12 interactions and signaling through CXCR4 and CXCR7. In the current study, we show that the previously identified peptides only minimally activated CXCR4 signaling through the cytosolic adapter protein β-arrestin 2 and do not initiate signaling to ERK1/2. By comparison, peptides with diverse N-terminal amino acid sequences effectively activated CXCR7 signaling to β-arrestin 2. One peptide, designated as GSLW based on its N-terminal amino acids, activated CXCR7 signaling and potentiated CXCL12-CXCR7 signaling without blocking the scavenger function of CXCR7 to internalize CXCL12. These results advance our understanding of CXCR7 ligand recognition and signaling, and provide structural information to target allosteric binding sites on this receptor as chemical probes and potential therapeutic agents.
authors: Center for Molecular Imaging, Department of Radiology, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA.
authors: Anna
authors: A
authors: Ehrlich
authors: Paramita
authors: P
authors: Ray
authors: Kathryn E
authors: KE
authors: Luker
authors: Elias J
authors: EJ
authors: Lolis
authors: Gary D
authors: GD
authors: Luker
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019390:Arrestins / Q000378:metabolism; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy / Q000379:methods; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D054387:Receptors, CXCR / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C501896:ACKR3 protein, human; C000605254:ARRB2 protein, human; D019390:Arrestins; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D008024:Ligands; D010455:Peptides; D054387:Receptors, CXCR; D019718:Receptors, CXCR4; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: Bioluminescence; Chemokine; Chemokine receptor; Luciferase; Peptide
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