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A non-GPCR-binding partner interacts with a novel surface on β-arrestin1 to mediate GPCR signaling. J Biol Chem 2020 10 09;295(41):14111-14124



Pubmed ID


Pubmed Central ID




Scopus ID

2-s2.0-85092803357   2 Citations


The multifaceted adaptor protein β-arr1 (β-arrestin1) promotes activation of focal adhesion kinase (FAK) by the chemokine receptor CXCR4, facilitating chemotaxis. This function of β-arr1 requires the assistance of the adaptor protein STAM1 (signal-transducing adaptor molecule 1) because disruption of the interaction between STAM1 and β-arr1 reduces CXCR4-mediated activation of FAK and chemotaxis. To begin to understand the mechanism by which β-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 β-arr1 by binding to a novel surface on β-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 β-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 β-arrestin-dependent signaling by a GPCR. This surface might represent a previously unidentified switch region that engages with effector molecules to drive β-arrestin signaling.

Author List

Zhuo Y, Gurevich VV, Vishnivetskiy SA, Klug CS, Marchese A


Candice S. Klug PhD Professor in the Biophysics department at Medical College of Wisconsin
Adriano Marchese PhD Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adaptor Proteins, Signal Transducing
Chemokine CXCL12
Endosomal Sorting Complexes Required for Transport
Focal Adhesion Kinase 1
HEK293 Cells
MAP Kinase Signaling System
Protein Structure, Secondary
Receptors, CXCR4
beta-Arrestin 1