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Regulator of G protein signaling (RGS) proteins are negative modulators of G protein signaling that have emerged as promising drug targets to improve specificity and reduce side effects of G protein-coupled receptor-related therapies. Several small molecule RGS protein inhibitors have been identified; however, enhancing RGS protein function is often more clinically desirable but presents a challenge. Low protein levels of RGS2 are associated with various pathologies, including hypertension and heart failure. For this reason, RGS2 is a prominent example wherein enhancing its function would be beneficial. RGS2 is rapidly ubiquitinated and proteasomally degraded, providing a point of intervention for small molecule RGS2-stabilizing compounds. We previously identified a novel cullin-RING E3 ligase utilizing F-box only protein 44 (FBXO44) as the substrate recognition component. Here, we demonstrate that RGS2 associates with FBXO44 through a stretch of residues in its N terminus. RGS2 contains four methionine residues close to the N terminus that can act as alternative translation initiation sites. The shorter translation initiation variants display reduced ubiquitination and proteasomal degradation as a result of lost association with FBXO44. In addition, we show that phosphorylation of Ser 3 may be an additional mechanism to protect RGS2 from FBXO44-mediated proteasomal degradation. These findings contribute to elucidating mechanisms regulating steady state levels of RGS2 protein and will inform future studies to develop small molecule RGS2 stabilizers. These would serve as novel leads in pathologies associated with low RGS2 protein levels, such as hypertension, heart failure, and anxiety. SIGNIFICANCE STATEMENT: E3 ligases provide a novel point of intervention for therapeutic development, but progress is hindered by the lack of available information about specific E3-substrate pairs. Here, we provide molecular detail on the recognition of regulator of G protein signaling protein 2 (RGS2) by its E3 ligase, increasing the potential for rational design of small molecule RGS2 protein stabilizers. These would be clinically useful in pathologies associated with low RGS2 protein levels, such as hypertension, heart failure, and anxiety.

N-Terminal Targeting of Regulator of G Protein Signaling Protein 2 for F-Box Only Protein 44–Mediated Proteasomal Degradation