Disease-causing mutations in the G protein β5 β-propeller disrupt its chaperonin-mediated folding trajectory
Abstract
The Chaperonin Containing Tailless polypeptide 1 (CCT or TRiC) is an essential cytosolic chaperone that folds multiple protein substrates, including many with β-propeller folds. One β-propeller substrate is the G protein β5subunit (Gβ5) of Regulator of G protein Signaling (RGS) complexes that determine the duration of G protein signals in neurons. In recent work, we used cryo-electron microscopy (cryo-EM) to visualize the complete CCT-mediated folding trajectory for Gβ5, from an initiating electrostatic interaction of a single β-strand in Gβ5with CCT5 to a completely folded β-propeller structure. Here, we used biochemistry and cryo-EM to determine how missense mutations in Gβ5, including those that cause severe neurological diseases, alter the Gβ5folding trajectory and lead to incompletely folded, trapped intermediates. These findings highlight how defects in chaperonin-mediated folding contribute to disease and suggest potential strategies for stabilizing misfolded proteins to restore function.
Significance
Certain missense mutations in the G protein β5subunit (Gβ5) lead to protein misfolding and are associated with neurological disorders. Using cryo-EM, we tracked how these mutations disrupt the normal folding of Gβ5by the CCT chaperonin complex. Although mutant Gβ5still binds the complex, folding stalls mid-process, leaving the protein trapped in partially folded, non-functional states. These defects arise from disrupted side chain interactions needed to form the closed, functional structure. Our findings reveal a molecular basis for Gβ5misfolding in disease and suggest that pharmacological chaperones that stabilize the folded state could help restore proper function.
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