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The morphogen Sonic hedgehog inhibits its receptor Patched by a pincer grasp mechanism

DOI: 10.1038/s41589-019-0370-y DOI Help

Authors: Amalie F. Rudolf (Wellcome Centre for Human Genetics, University of Oxford) , Maia Kinnebrew (Stanford University School of Medicine) , Christiane Kowatsch (Wellcome Centre for Human Genetics, University of Oxford) , T. Bertie Ansell (University of Oxford) , Kamel El Omari (Diamond Light Source) , Benjamin Bishop (Wellcome Centre for Human Genetics, University of Oxford) , Els Pardon (Vrije Universiteit Brussel (VUB); VIB-VUB Center for Structural Biology) , Rebekka A. Schwab (Wellcome Centre for Human Genetics, University of Oxford) , Tomas Malinauskas (Wellcome Centre for Human Genetics, University of Oxford) , Mingxing Qian (Washington University School of Medicine) , Ramona Duman (Diamond Light Source) , Douglas F. Covey (Washington University School of Medicine) , Jan Steyaert (Vrije Universiteit Brussel (VUB); VIB-VUB Center for Structural Biology) , Armin Wagner (Diamond Light Source) , Mark S. P. Sansom (University of Oxford) , Rajat Rohatgi (Stanford University School of Medicine) , Christian Siebold (Wellcome Centre for Human Genetics, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Chemical Biology , VOL 15 , PAGES 975 - 982

State: Published (Approved)
Published: October 2019

Abstract: Hedgehog (HH) ligands, classical morphogens that pattern embryonic tissues in all animals, are covalently coupled to two lipids—a palmitoyl group at the N terminus and a cholesteroyl group at the C terminus. While the palmitoyl group binds and inactivates Patched 1 (PTCH1), the main receptor for HH ligands, the function of the cholesterol modification has remained mysterious. Using structural and biochemical studies, along with reassessment of previous cryo-electron microscopy structures, we find that the C-terminal cholesterol attached to Sonic hedgehog (Shh) binds the first extracellular domain of PTCH1 and promotes its inactivation, thus triggering HH signaling. Molecular dynamics simulations show that this interaction leads to the closure of a tunnel through PTCH1 that serves as the putative conduit for sterol transport. Thus, Shh inactivates PTCH1 by grasping its extracellular domain with two lipidic pincers, the N-terminal palmitate and the C-terminal cholesterol, which are both inserted into the PTCH1 protein core.

Journal Keywords: Cell signalling; Lipids; Structural biology; X-ray crystallography

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I23-Long wavelength MX

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