2.A.6.6.13
Patched, PTCH1, Ptc1 or PTCH, SLC65 family) of 1447 aas and 12 TMSs.  RND transporter-like receptor, regulates the activity of Smoothened of 7 TMSs via the Hedgehog (HH) pathway. The Na⁺ gradient may provide the energy for Patched activity (Myers et al. 2017). Possibly Patched1, chemiosmotically driven by the transmembrane Na⁺ gradient, regulates Smoothened. 3-d structures have been solved at ~ 3.5 Å resolution by cryoEM (Qi et al. 2018). This protein seems to have both transport and signalling functions, exporting cholesterol from the inner leaflet of the membrane out to the external environment. It displays a tunnel going through the membrane with a lateral opening, all large enough to accomodate cholesterol (Qi et al. 2018; Sommer and Lemmon 2018). The distrutribution of Smoothened on the primary cillium surface has been studied (Yoon et al. 2019).
Hedgehog protein signals mediate tissue patterning and maintenance by binding to and inactivating their common receptor Patched that suppresses the activity of the 7-TMS protein Smoothened. Loss of Patched function, the most common cause of basal cell carcinoma, permits unregulated activation of Smoothened and of the Hedgehog pathway. A cryo-EM structure of Patched revealed striking transmembrane domain similarities to prokaryotic RND transporters in whick a central hydrophobic conduit with cholesterol-like contents courses through the extracellular domain and resembles that used by other RND proteins to transport substrates, suggesting that Patched catalyzes cholesterol transport (Zhang et al. 2018). Cholesterol in the inner leaflet of the plasma membrane is reduced by PTCH1 expression but rapidly restored by Hedgehog stimulation, suggesting that PTCH1 regulates Smoothened by controlling cholesterol availability.
Key proteins in the Hedgehog-signalling pathway dynamically localize in primary cilia, antenna-like solitary organelles present on most cells. The secreted Hedgehog ligand Sonic Hedgehog (SHH) binds to its receptor Patched1 (PTCH1) in primary cilia, causing its inactivation and delocalization from cilia. At the same time, the transmembrane protein Smoothened (SMO or SMOH; TC# 9.A.14.16.4) is released of its inhibition by PTCH1 and accumulates in cilia. PTCH1 inactivation by SHH changes the diffusive motion of PTCH1 (Weiss et al. 2019). PTCH1 is mutated in the nevoid basal cell carcinoma syndrome (NBCCS) (Nakase et al. 2020). Patched (Ptc1) acts as a suppressor for Hedgehog (Hh) signaling by depleting sterols in the cytoplasmic membrane leaflet that are required for the activation of downstream regulators. The positive modulator Hh inhibits Ptc1's transport function by binding to Ptc1 and its co-receptors, which are locally concentrated in invaginated microdomains known as caveolae. Luo et al. 2021 reconstituted the mouse Ptc1 into lipid nanodiscs and determined its structure by cryoEM. The structure is  similar to those in amphipol and detergents but displays various conformational differences in the transmembrane region. Although most particles are monomers, Ptc1 dimers were also observed with distinct interaction patterns and different membrane curvatures, some of which are reminiscent of caveolae. An extramembranous "hand-shake" region, rich in hydrophobic and aromatic residues, mediates inter-Ptc1 interactions under conditions of different membrane curvature, providing a plausible framework for Ptc1 clustering in the highly curved caveolae (Luo et al. 2021). Cholesterol regulates reception of the Hedgehog (Hh) signal in target cells. In vertebrates, cell-surface organelles called primary cilia function as compartments for the propagation of Hh signals. Various studies have led to the model that Patched-1 (PTCH1), the receptor for Hh ligands, uses its transporter-like activity to lower cholesterol accessibility in the membrane surrounding primary cilia (Kinnebrew et al. 2022). PTCH1 depletes accessible cholesterol in the outer leaflet of the membrane in a manner regulated by its ligand Sonic Hedgehog and the transmembrane potassium gradient. Kinnebrew et al. 2021 proposed that PTCH1 moves cholesterol from the outer to the inner leaflet of the membrane in exchange for potassium ion export.