A non-GPCR-binding partner interacts with a novel surface on ?-arrestin1 to mediate GPCR signaling.

The multifaceted adaptor protein ?-arr1 (?-arrestin1) promotes activation of focal adhesion kinase (FAK) by the chemokine receptor CXCR4, facilitating chemotaxis. This function of ?-arr1 requires the assistance of the adaptor protein STAM1 (signal-transducing adaptor molecule 1) because disruption of the interaction between STAM1 and ?-arr1 reduces CXCR4-mediated activation of FAK ...
and chemotaxis. To begin to understand the mechanism by which ?-arr1 together with STAM1 activates FAK, we used site-directed spin-labeling EPR spectroscopy-based studies coupled with bioluminescence resonance energy transfer-based cellular studies to show that STAM1 is recruited to activated ?-arr1 by binding to a novel surface on ?-arr1 at the base of the finger loop, at a site that is distinct from the receptor-binding site. Expression of a STAM1-deficient binding ?-arr1 mutant that is still able to bind to CXCR4 significantly reduced CXCL12-induced activation of FAK but had no impact on ERK-1/2 activation. We provide evidence of a novel surface at the base of the finger loop that dictates non-GPCR interactions specifying ?-arrestin-dependent signaling by a GPCR. This surface might represent a previously unidentified switch region that engages with effector molecules to drive ?-arrestin signaling.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Chemokine CXCL12, Endosomal Sorting Complexes Required for Transport, Focal Adhesion Kinase 1, HEK293 Cells, Humans, MAP Kinase Signaling System, Phosphoproteins, Protein Structure, Secondary, Receptors, CXCR4, beta-Arrestin 1
J Biol Chem
Date: Dec. 09, 2019
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