Fig. 6.

Variations in accessible cholesterol affect the function of Ptch1 and Smo at the ciliary membrane: A cilium is shown at the top, with a rectangle representing a ciliary pocket magnified below. a In model 1: Ptch1 utilizes its energy-driven transporter function to remove cholesterol from the ciliary membrane, transporting it to an extracellular or intracellular acceptor. By this function, the accessible cholesterol level falls below the threshold needed for Smo activation, and the level of sphingomyelin increases at the ciliary membrane (left panel). In the presence of Hh ligand, inactivated Ptch1 allows an influx of cholesterol into the ciliary membrane thus accessible ciliary cholesterol increases and activates Smo (right panel). b In model 2: The extracellular domain of Ptch1 directly accepts cholesterol from Smo-CRD, transferring it to the membrane, and directly inactivates Smo (left panel). In the presence of Hh ligand, inactivation of Ptch1 increases accessible ciliary cholesterol and promotes cholesterol interaction with Smo-CRD, resulting in activation of Smo (right panel)