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

Huang, Peiying; Wierbowski, Bradley M.; Lian, Tengfei; Chan, Charlene; García‐Linares, Sara; Jiang, Junchen

doi:10.1016/j.devcel.2022.02.008

Cited by 16 publications

(14 citation statements)

References 114 publications

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“…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).…”

Section: Introductionmentioning

confidence: 99%

The energetics and ion coupling of cholesterol transport through Patched1

Ansell,

Corey,

Viti

et al. 2023

Sci. Adv.

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Patched1 (PTCH1) is a tumor suppressor protein of the mammalian Hedgehog (HH) signaling pathway, implicated in embryogenesis and tissue homeostasis. PTCH1 inhibits the G protein–coupled receptor Smoothened (SMO) via a debated mechanism involving modulating ciliary cholesterol accessibility. Using extensive molecular dynamics simulations and free energy calculations to evaluate cholesterol transport through PTCH1, we find an energetic barrier of ~15 to 20 kilojoule per mole for cholesterol export. In silico data are coupled to in vivo biochemical assays of PTCH1 mutants to probe coupling between cation binding sites, transmembrane motions, and PTCH1 activity. Using complementary simulations of Dispatched1, we find that transition between “inward-open” and solvent “occluded” states is accompanied by Na + -induced pinching of intracellular helical segments. Thus, our findings illuminate the energetics and ion coupling stoichiometries of PTCH1 transport mechanisms, whereby one to three Na + or two to three K + couple to cholesterol export, and provide the first molecular description of transitions between distinct transport states.

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Section: Introductionmentioning

confidence: 99%

The energetics and ion coupling of cholesterol transport through Patched1

Ansell,

Corey,

Viti

et al. 2023

Sci. Adv.

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“…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).…”

Section: Lipopolysaccharide Transport Complex Lptmentioning

confidence: 99%

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

Biou

2023

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…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).…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

“…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).…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%