Patched, PTCH1, Ptc1 or PTCH, 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).
|Protein Name:||Protein patched homolog 1|
|Species:||Homo sapiens (Human)  |
|Number of TMSs:||12|
|Location1 / Topology2 / Orientation3:
Membrane1 / Multi-pass membrane protein2
1: MASAGNAAEP QDRGGGGSGC IGAPGRPAGG GRRRRTGGLR RAAAPDRDYL HRPSYCDAAF
61: ALEQISKGKA TGRKAPLWLR AKFQRLLFKL GCYIQKNCGK FLVVGLLIFG AFAVGLKAAN
121: LETNVEELWV EVGGRVSREL NYTRQKIGEE AMFNPQLMIQ TPKEEGANVL TTEALLQHLD
181: SALQASRVHV YMYNRQWKLE HLCYKSGELI TETGYMDQII EYLYPCLIIT PLDCFWEGAK
241: LQSGTAYLLG KPPLRWTNFD PLEFLEELKK INYQVDSWEE MLNKAEVGHG YMDRPCLNPA
301: DPDCPATAPN KNSTKPLDMA LVLNGGCHGL SRKYMHWQEE LIVGGTVKNS TGKLVSAHAL
361: QTMFQLMTPK QMYEHFKGYE YVSHINWNED KAAAILEAWQ RTYVEVVHQS VAQNSTQKVL
421: SFTTTTLDDI LKSFSDVSVI RVASGYLLML AYACLTMLRW DCSKSQGAVG LAGVLLVALS
481: VAAGLGLCSL IGISFNAATT QVLPFLALGV GVDDVFLLAH AFSETGQNKR IPFEDRTGEC
541: LKRTGASVAL TSISNVTAFF MAALIPIPAL RAFSLQAAVV VVFNFAMVLL IFPAILSMDL
601: YRREDRRLDI FCCFTSPCVS RVIQVEPQAY TDTHDNTRYS PPPPYSSHSF AHETQITMQS
661: TVQLRTEYDP HTHVYYTTAE PRSEISVQPV TVTQDTLSCQ SPESTSSTRD LLSQFSDSSL
721: HCLEPPCTKW TLSSFAEKHY APFLLKPKAK VVVIFLFLGL LGVSLYGTTR VRDGLDLTDI
781: VPRETREYDF IAAQFKYFSF YNMYIVTQKA DYPNIQHLLY DLHRSFSNVK YVMLEENKQL
841: PKMWLHYFRD WLQGLQDAFD SDWETGKIMP NNYKNGSDDG VLAYKLLVQT GSRDKPIDIS
901: QLTKQRLVDA DGIINPSAFY IYLTAWVSND PVAYAASQAN IRPHRPEWVH DKADYMPETR
961: LRIPAAEPIE YAQFPFYLNG LRDTSDFVEA IEKVRTICSN YTSLGLSSYP NGYPFLFWEQ
1021: YIGLRHWLLL FISVVLACTF LVCAVFLLNP WTAGIIVMVL ALMTVELFGM MGLIGIKLSA
1081: VPVVILIASV GIGVEFTVHV ALAFLTAIGD KNRRAVLALE HMFAPVLDGA VSTLLGVLML
1141: AGSEFDFIVR YFFAVLAILT ILGVLNGLVL LPVLLSFFGP YPEVSPANGL NRLPTPSPEP
1201: PPSVVRFAMP PGHTHSGSDS SDSEYSSQTT VSGLSEELRH YEAQQGAGGP AHQVIVEATE
1261: NPVFAHSTVV HPESRHHPPS NPRQQPHLDS GSLPPGRQGQ QPRRDPPREG LWPPPYRPRR
1321: DAFEISTEGH SGPSNRARWG PRGARSHNPR NPASTAMGSS VPGYCQPITT VTASASVTVA
1381: VHPPPVPGPG RNPRGGLCPG YPETDHGLFE DPHVPFHVRC ERRDSKVEVI ELQDVECEER