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A model for activation of Nedd4 in cells. Cellular signaling elevates the cytoplasmic concentration of calcium, which binds to the C2 domain and enables the C2 domain to interact with the cellular membrane. Calcium-dependent binding of the C2 domain to the membrane results in dissociation of the C2 domain from the HECT domain, and release of the C2 domain-mediated auto-inhibition thus activates Nedd4 E3 ligase activity.
