Two Patched molecules engage distinct sites on Hedgehog yielding a signaling-competent complex

Science
Xiaofeng QiXiaochun Li

Abstract

Aberrant Hedgehog (HH) signaling leads to various types of cancer and birth defects. N-terminally palmitoylated HH initiates signaling by binding its receptor Patched-1 (PTCH1). A recent 1:1 PTCH1-HH complex structure visualized a palmitate-mediated binding site on HH, which was inconsistent with previous studies that implied a distinct, calcium-mediated binding site for PTCH1 and HH co-receptors. Our 3.5-angstrom resolution cryo-electron microscopy structure of native Sonic Hedgehog (SHH-N) in complex with PTCH1 at a physiological calcium concentration reconciles these disparate findings and demonstrates that one SHH-N molecule engages both epitopes to bind two PTCH1 receptors in an asymmetric manner. Functional assays using PTCH1 or SHH-N mutants that disrupt the individual interfaces illustrate that simultaneous engagement of both interfaces is required for efficient signaling in cells.

References

Dec 2, 1994·Science·J J LeeP A Beachy
Feb 1, 1996·Critical Reviews in Biochemistry and Molecular Biology·S Hurwitz
Nov 14, 1996·Nature·V MarigoC J Tabin
Jun 5, 1998·The Journal of Biological Chemistry·R B PepinskyA Galdes
Sep 29, 1999·Proceedings of the National Academy of Sciences of the United States of America·N FuseP A Beachy
Feb 7, 2001·The Journal of Biological Chemistry·R B PepinskyE A Garber
May 18, 2001·Nature·J Taipale, P A Beachy
Dec 4, 2001·Genes & Development·P W Ingham, A P McMahon
Jun 5, 2002·Nature Reviews. Cancer·Ariel Ruiz i AltabaNadia Dahmane
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
May 1, 1997·Acta Crystallographica. Section D, Biological Crystallography·G N MurshudovE J Dodson
Oct 4, 2005·BMC Developmental Biology·Rebecca J DawberMarcel van den Heuvel
Feb 16, 2006·Proceedings of the National Academy of Sciences of the United States of America·Deborah J StauberIan A Wilson
Oct 3, 2006·Journal of Structural Biology·J Bernard Heymann, David M Belnap
Dec 2, 2006·Nature Reviews. Drug Discovery·Lee L Rubin, Frederic J de Sauvage
Aug 8, 2007·Journal of Molecular Biology·Evgeny Krissinel, Kim Henrick
Dec 17, 2008·Developmental Cell·Jin Jiang, Chi-Chung Hui
Jun 30, 2009·Nature Structural & Molecular Biology·Ivan BosanacRobert A Lazarus
Jun 30, 2009·Nature Structural & Molecular Biology·Benjamin BishopChristian Siebold
Jan 9, 2010·Acta Crystallographica. Section D, Biological Crystallography·Vincent B ChenDavid C Richardson
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
May 28, 2010·The Journal of Biological Chemistry·Henry R MaunSarah G Hymowitz
Sep 17, 2010·Genes & Development·Philip A BeachyChristian Siebold
Jul 21, 2011·Cancer Research·Ciara Metcalfe, Frederic J de Sauvage
May 4, 2012·Nucleic Acids Research·Karel BerkaMichal Otyepka
Sep 25, 2012·Journal of Structural Biology·Sjors H W Scheres
May 31, 2013·Nature Reviews. Molecular Cell Biology·James Briscoe, Pascal P Thérond
Jan 24, 2015·Acta Crystallographica. Section D, Biological Crystallography·Alan BrownGarib Murshudov
Apr 8, 2015·Developmental Biology·Jane Y SongBenjamin L Allen
Aug 19, 2015·Journal of Structural Biology·Alexis Rohou, Nikolaus Grigorieff

❮ Previous
Next ❯

Citations

Feb 3, 2019·The Journal of Biological Chemistry·Suzanne R Pfeffer
Sep 27, 2019·Science Advances·Chao QiVolodymyr M Korkhov
Jan 4, 2020·Regenerative Medicine Research·Lu ZhengYing Xiao
Nov 7, 2019·Acta Crystallographica. Section D, Structural Biology·Rachel Bonn-BreachJoseph Wedekind
Jan 11, 2020·Nature Communications·Tao LongXiaochun Li
May 28, 2019·Nature Communications·Hongwu QianXin Gong
Sep 25, 2019·Nature Chemical Biology·Amalie F RudolfChristian Siebold
May 17, 2019·Development·Jennifer H KongRajat Rohatgi
Aug 4, 2019·Journal of Cell Science·Peter Satir, Birgit H Satir
Jun 5, 2020·Science Advances·Fabien CannacVolodymyr M Korkhov
Jul 11, 2020·Life Science Alliance·Hongwen ChenXiaochun Li
Sep 16, 2020·Nature Chemical Biology·Xiaofeng QiXiaochun Li
Apr 6, 2019·Nature Reviews. Molecular Cell Biology·Maxence V Nachury, David U Mick
Oct 6, 2018·Science·Anselm Sommer, Mark A Lemmon
Oct 8, 2019·Annals of the New York Academy of Sciences·Jessica KobylkaKlaas M Pos
Apr 26, 2020·International Journal of Molecular Sciences·Nadia Elghobashi-Meinhardt
Jun 17, 2020·Seminars in Cell & Developmental Biology·Daniel KopinkeSaikat Mukhopadhyay
Sep 24, 2019·Cell·Mikael B L WinklerBjørn Panyella Pedersen
Feb 2, 2021·Physical Chemistry Chemical Physics : PCCP·Sandra KovachkaPaolo Ruggerone
Nov 4, 2020·Proceedings of the National Academy of Sciences of the United States of America·Yunxiao ZhangPhilip A Beachy
Oct 24, 2020·Current Pathobiology Reports·Rachel CarterAmanda Haymond
Nov 18, 2020·Nature Chemical Biology·Arun RadhakrishnanChristian Siebold
Feb 3, 2021·Proceedings of the National Academy of Sciences of the United States of America·Kostadin PetrovAdrian Salic
Feb 20, 2021·The Journal of Cell Biology·Karin M Reinisch, William A Prinz
Mar 11, 2019·Trends in Cell Biology·Eric T HallStacey K Ogden
Apr 10, 2021·Seminars in Cancer Biology·Jin Jiang
Apr 18, 2021·BMC Molecular and Cell Biology·Carina Jägers, Henk Roelink
Jun 11, 2021·Biochemical Pharmacology·Vikas DaggubatiNavdar Sever
Aug 14, 2021·Nature Communications·Carla E Cadena Del CastilloAnne Spang
Aug 28, 2021·Biochimica Et Biophysica Acta. Molecular and Cell Biology of Lipids·Zhi-Ping QiuBao-Liang Song
Aug 28, 2021·Cells·Jie ZhangJianhang Jia

❮ Previous
Next ❯

Related Concepts

Related Feeds

Calcium & Bioenergetics

Bioenergetic processes, including cellular respiration and photosynthesis, concern the transformation of energy by cells. Here is the latest research on the role of calcium in bioenergetics.

Birth Defects

Birth defects encompass structural and functional alterations that occur during embryonic or fetal development and are present since birth. The cause may be genetic, environmental or unknown and can result in physical and/or mental impairment. Here is the latest research on birth defects.