Faculty Collaboration Database

Constitutive activity of an atypical chemokine receptor revealed by inverse agonistic nanobodies. bioRxiv 2024 Nov 04

Date

11/22/2024

Pubmed ID

39574661

Pubmed Central ID

PMC11580867

DOI

10.1101/2024.11.04.621790

Abstract

Chemokine stimulation of atypical chemokine receptor 3 (ACKR3) does not activate G proteins but recruits arrestins. It is a chemokine scavenger that indirectly influences responses by restricting the availability of CXCL12, an agonist shared with the canonical receptor CXCR4. ACKR3 is upregulated in numerous disorders. Due to limited insights in chemokine-activated ACKR3 signaling, it is unclear how ACKR3 contributes to pathological phenotypes. One explanation may be that high constitutive activity of ACKR3 drives non-canonical signaling through a basal receptor state. Here we characterize the constitutive action of ACKR3 using novel inverse agonistic nanobodies to suppress basal activity. These new tools promote an inactive receptor conformation which decreased arrestin engagement and inhibited constitutive internalization. Basal, non-chemotactic, breast cancer cell motility was also suppressed, suggesting a role for ACKR3 in this process. The basal receptor activity in pathophysiology may provide a new therapeutic approach for targeting ACKR3.

Author List

Perez Almeria CV, Otun O, Schlimgen R, Lamme TD, Crudden C, Youssef N, Musli L, Jenjak S, Bobkov V, Drube J, Hoffmann C, Volkman BF, Granier S, Bechara C, Siderius M, Heukers R, Schafer CT, Smit MJ

Author

Brian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin