Gβγ engages PLCβ3 at multiple sites to reorient and facilitate its activation.

Gβγ binds multiple sites on PLCβ3 to facilitate activation and reorient the enzyme for maximal PI(4,5)P2 hydrolysis in concert with Gα q.

• Why it matters: Understanding Gβγ-dependent activation of PLCβ3 is important because it complements the well-known Gα q mechanism, revealing how Gβγ enhances phospholipase activity at the plasma membrane.
• What they did: The study used cryo-electron microscopy, functional assays, and bioluminescence resonance energy transfer to show that Gβγ binds multiple surfaces of PLCβ3 and acts as a positive allosteric modulator, promoting enzyme activation in the presence of Gα q.
• The result: Gβγ is essential for maximal PLCβ3 activation, even when Gα q is present, enabling effective PI(4,5)P2 hydrolysis and downstream calcium release, which advances understanding of G protein regulation of phospholipase activity.