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

Huang P, Wierbowski BM, Lian T, Chan C, García-Linares S, Jiang J, Salic A
Dev Cell 57 670-685.e8 (2022)
Cited: 11 times
EuropePMC logo PMID: 35231446

Abstract

The dually lipidated Sonic hedgehog (SHH) morphogen signals through the tumor suppressor membrane protein Patched1 (PTCH1) to activate the Hedgehog pathway, which is fundamental in development and cancer. SHH engagement with PTCH1 requires the GAS1 coreceptor, but the mechanism is unknown. We demonstrate a unique role for GAS1, catalyzing SHH-PTCH1 complex assembly in vertebrate cells by direct SHH transfer from the extracellular SCUBE2 carrier to PTCH1. Structure of the GAS1-SHH-PTCH1 transition state identifies how GAS1 recognizes the SHH palmitate and cholesterol modifications in modular fashion and how it facilitates lipid-dependent SHH handoff to PTCH1. Structure-guided experiments elucidate SHH movement from SCUBE2 to PTCH1, explain disease mutations, and demonstrate that SHH-induced PTCH1 dimerization causes its internalization from the cell surface. These results define how the signaling-competent SHH-PTCH1 complex assembles, the key step triggering the Hedgehog pathway, and provide a paradigm for understanding morphogen reception and its regulation.

Articles - 7rhr mentioned but not cited (1)

  1. Structural basis for catalyzed assembly of the Sonic hedgehog-Patched1 signaling complex. Huang P, Wierbowski BM, Lian T, Chan C, García-Linares S, Jiang J, Salic A. Dev Cell 57 670-685.e8 (2022)


Reviews citing this publication (4)

  1. Cellular and molecular mechanisms of Hedgehog signalling. Zhang Y, Beachy PA. Nat Rev Mol Cell Biol 24 668-687 (2023)
  2. Establishing Hedgehog Gradients during Neural Development. Douceau S, Deutsch Guerrero T, Ferent J. Cells 12 225 (2023)
  3. The biology of SCUBE. Lin YC, Sahoo BK, Gau SS, Yang RB. J Biomed Sci 30 33 (2023)
  4. The Inseparable Relationship Between Cholesterol and Hedgehog Signaling. Siebold C, Rohatgi R. Annu Rev Biochem 92 273-298 (2023)

Articles citing this publication (6)

  1. Genomic alterations of oligodendrogliomas at distant recurrence. Liu G, Bu C, Guo G, Zhang Z, Sheng Z, Deng K, Wu S, Xu S, Bu Y, Gao Y, Wang M, Liu G, Kong L, Li T, Li M, Bu X. Cancer Med 12 17171-17183 (2023)
  2. Hedgehog acyltransferase catalyzes a random sequential reaction and utilizes multiple fatty acyl-CoA substrates. Schonbrun AR, Resh MD. J Biol Chem 298 102422 (2022)
  3. Detection of various fusion genes by one-step RT-PCR and the association with clinicopathological features in 242 cases of soft tissue tumor. Song L, Zhang Y, Wang Y, Xia Q, Guo D, Cao J, Xin X, Cheng H, Liu C, Jia X, Li F. Front Cell Dev Biol 11 1214262 (2023)
  4. Extracellular carriers control lipid-dependent secretion, delivery, and activity of WNT morphogens. de Almeida Magalhaes T, Liu J, Chan C, Borges KS, Zhang J, Kane AJ, Wierbowski BM, Ge Y, Liu Z, Mannam P, Zeve D, Weiss R, Breault DT, Huang P, Salic A. Dev Cell 59 244-261.e6 (2024)
  5. Identifying therapeutic targets for cancer among 2074 circulating proteins and risk of nine cancers. Smith-Byrne K, Hedman Å, Dimitriou M, Desai T, Sokolov AV, Schioth HB, Koprulu M, Pietzner M, Langenberg C, Atkins J, Penha RC, McKay J, Brennan P, Zhou S, Richards BJ, Yarmolinsky J, Martin RM, Borlido J, Mu XJ, Butterworth A, Shen X, Wilson J, Assimes TL, Hung RJ, Amos C, Purdue M, Rothman N, Chanock S, Travis RC, Johansson M, Mälarstig A. Nat Commun 15 3621 (2024)
  6. The energetics and ion coupling of cholesterol transport through Patched1. Ansell TB, Corey RA, Viti LV, Kinnebrew M, Rohatgi R, Siebold C, Sansom MSP. Sci Adv 9 eadh1609 (2023)


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