Hedgehog regulates smoothened activity by inducing a conformational switch.

Area of Science:

• Developmental Biology
• Molecular Cell Biology
• Signal Transduction

Background:

• The Hedgehog (HH) morphogen pathway is crucial for animal development.
• The seven-transmembrane protein Smoothened (SMO) mediates HH signal transduction but its activation mechanism is unclear.

Purpose of the Study:

• To elucidate the molecular mechanism by which HH signaling activates SMO.
• To investigate the role of phosphorylation and arginine clusters in SMO regulation.

Main Methods:

• Investigated SMO activation in Drosophila melanogaster.
• Analyzed the effects of phosphorylation and mutations in SMO's cytoplasmic tail.
• Examined conformational changes and dimerization of SMO.

Main Results:

• HH signaling induces phosphorylation of the SMO carboxy-terminal tail.
• Phosphorylation antagonizes inhibitory Arg clusters, relieving SMO autoinhibition.
• This leads to a conformational switch, SMO dimerization, and cell surface accumulation, activating the pathway.

Conclusions:

• SMO activation involves a phosphorylation-dependent conformational switch that releases autoinhibition.
• The SMO protein functions as a rheostat, translating graded HH signals into distinct developmental responses via differential phosphorylation of Arg clusters.