Deep mutational scanning of the GPCR rhodopsin reveals pleiotropic mutational effects and their roles in modulating receptor signaling.

Deep mutational scanning of rhodopsin across ~2,000 single-residue substitutions reveals asymmetric pleiotropic constraints that restrict mutational tolerance in the retinal binding pocket and G protein interface.

• Why it matters: Biophysical pleiotropy is linked to genetic disease and protein evolution, but how it shapes GPCR receptor-function evolution and signaling remains unclear, limiting therapeutic and synthetic-biology design.
• What they did: A cell-based assay simultaneously measured basal activity, ligand-dependent signaling, and cellular receptor abundance, and was combined with ~6,000 phenotype measurements from deep mutational scanning.
• The result: Dose-response analysis indicates the constraints stem from the chromophore’s dual role as an agonist in light-driven isomerization and an inverse agonist in darkness, shaping receptor signaling evolution.

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