Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling

Sigrid Nachtergaele, Daniel M. Whalen, Laurel K. Mydock, Zhonghua Zhao, Tomas Malinauskas, Kathiresan Krishnan, Philip W. Ingham, Douglas F. Covey, Christian Siebold, Rajat Rohatgi

Research output: Contribution to journalArticlepeer-review

113 Scopus citations

Abstract

The Hedgehog (Hh) signal is transduced across the membrane by the heptahelical protein Smoothened (Smo), a developmental regulator, oncoprotein and drug target in oncology. We present the 2.3 Å crystal structure of the extracellular cysteine rich domain (CRD) of vertebrate Smo and show that it binds to oxysterols, endogenous lipids that activate Hh signaling. The oxysterol-binding groove in the Smo CRD is analogous to that used by Frizzled 8 to bind to the palmitoleyl group of Wnt ligands and to similar pockets used by other Frizzled-like CRDs to bind hydrophobic ligands. The CRD is required for signaling in response to native Hh ligands, showing that it is an important regulatory module for Smo activation. Indeed, targeting of the Smo CRD by oxysterol-inspired small molecules can block signaling by all known classes of Hh activators and by clinically relevant Smo mutants.

Original languageEnglish
Article numbere01340
JournaleLife
Volume2013
Issue number2
DOIs
StatePublished - Oct 29 2013

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