Structural insight into the recognition between Sufu and fused in the Hedgehog signal transduction pathway

J Struct Biol. 2020 Nov 1;212(2):107614. doi: 10.1016/j.jsb.2020.107614. Epub 2020 Sep 8.

Abstract

Hedgehog signaling plays a crucial role in embryogenesis and adult tissue homeostasis, and mutations of its key components such as Suppressor of fused (Sufu) are closely associated with human diseases. The Ser/Thr kinase Fused (Fu) promotes Hedgehog signaling by phosphorylating the Cubitus interruptus (Ci)/Glioma-associated oncogene homologue (Gli) family of transcription factors. Sufu associates with both Fu and Ci/Gli, but the recognition mechanism between Sufu and Fu remains obscure. Here, our structure of the N-terminal domain (NTD) of Drosophila Sufu (dSufu) in complex with the Sufu-binding site (SBS) of Fu reveals that both main-chain β sheet formation and side-chain hydrophobic interactions contribute to the recognition between Sufu and Fu, and point mutations of highly conserved interface residues eliminated their association. Structural comparison suggests that Fu and Ci/Gli bind on opposite sides of dSufu-NTD, allowing the formation of a Fu-dSufu-Ci ternary complex which facilitates the phosphorylation of Ci/Gli by Fu. Hence, our results provide insights into the Sufu-Fu recognition mechanism.

Keywords: Ci; Crystal structure; Fu; Hedgehog; Sufu.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA-Binding Proteins / genetics
  • Drosophila / genetics
  • Drosophila Proteins / genetics*
  • Hedgehog Proteins / genetics*
  • Protein Binding / genetics
  • Protein Conformation, beta-Strand / genetics
  • Protein Serine-Threonine Kinases / genetics
  • Repressor Proteins / genetics*
  • Signal Transduction / genetics*

Substances

  • DNA-Binding Proteins
  • Drosophila Proteins
  • Hedgehog Proteins
  • Repressor Proteins
  • Su(fu) protein, Drosophila
  • fu protein, Drosophila
  • Protein Serine-Threonine Kinases