Structural basis for catalyzed assembly of the Sonic hedgehog–Patched1 signaling complex

The energetics and ion coupling of cholesterol transport through Patched1

“…The exact mechanism of PTCH1-mediated SMO inhibition remains ambiguous, despite decades of biochemical and cellular studies (1) and a handful of recent PTCH1 structures (5)(6)(7)(8)(9)(10)(11)(12)(13). Current models suggest that PTCH1 may function as a cholesterol transporter to modulate the abundance of accessible membrane cholesterol available to bind and activate SMO (14).…”

Lipid-membrane protein interaction visualised by cryo-EM: A review

“…LptC binding is destabilized by LPS and leaves the complex, allowing for the cleft between both subunits LptF to close down and push the LPS up (figure 6 D-E) so that it may interact with other periplasmic partners for its ascension to the OM. The LPS binding site of 6M8H overlaps with that of Patched1 structure from Xenopus calcaratus [30] and we chose it to illustrate this review. The monomer model shows three cholesterol molecules (black on figure 7 A) and the map shows additional annular lipids in the membrane area (off-white colour on figure 7 B).…”

Hedgehog acyltransferase catalyzes a random sequential reaction and utilizes multiple fatty acyl-CoA substrates

“…Furthermore, while interaction of SCUBE2 with the palmitate moiety is not absolutely required for Shh binding and secretion from cells, the presence of palmitate enhances these activities (49). After secretion, GAS1 acts as the final agent (in a sequence with other preceding hand-off proteins CDON/BOC) to deliver dually lipidated Shh to Ptch1 on the receiving cell surface (48,50). Although not absolutely required for binding of Shh to Ptch1 and subsequent signaling, GAS1-mediated handoff of Shh greatly enhances these activities, and interaction between GAS1 and Shh requires a Shh N-terminal fatty acid (48,50).…”

“…After secretion, GAS1 acts as the final agent (in a sequence with other preceding hand-off proteins CDON/BOC) to deliver dually lipidated Shh to Ptch1 on the receiving cell surface (48,50). Although not absolutely required for binding of Shh to Ptch1 and subsequent signaling, GAS1-mediated handoff of Shh greatly enhances these activities, and interaction between GAS1 and Shh requires a Shh N-terminal fatty acid (48,50). Importantly, the affinity of GAS1 for Shh is ~10-fold higher when palmitate is the N-terminal modification compared to octanoate (8:0) (50).…”