Regulation of Cholesterol Binding to the Receptor Patched1 by its interactions With the Ligand Sonic Hedgehog (Shh).

Changqing Zhong,Beibei Wang

doi:10.3389/fmolb.2022.831891

Abstract

The Hedgehog (Hh) signaling pathway is essential in cell development and regeneration, which is activated by the ligand Sonic hedgehog (Shh). The binding of Shh to its receptor Patched1 (PTCH1) releases the inhibitory effect on the downstream protein Smoothened (SMO), a G-protein-coupled-receptor (GPCR) protein. Cholesterol was supposed to function as a secondary messenger between PTCH1 and SMO. However, the molecular mechanism of this regulation process is still unclear. Therefore, microsecond coarse-grained molecular dynamics simulations were performed to investigate the protein-lipid interactions of the PTCH1 monomer and dimer-Shh complex. It was observed that the binding of cholesterols to the monomer is more stable than that to the dimer-Shh complex. It is regulated by the enrichment of Ganglioside lipids around proteins and the conformation of Y446, a residue in the sterol-sensing domain (SSD). The regulation of Shh on the dynamics of PTCH1 was further analyzed to explore the allosteric communication pathways between the Shh and the SSD. Our study provides structural and dynamic details of an additional perspective on the regulation of Hh signaling pathway through the lipid micro-environments of PTCH1.

Highlights

The Hedgehog (Hh) signaling pathway transmits information between cells, and is critical for embryogenesis and tissue regeneration (Ingham et al, 2011; Briscoe and Therond, 2013)
Our study provides structural and dynamic details of an additional perspective on the regulation of Hh signaling pathway through the lipid micro-environments of Patched 1 (PTCH1)
Defects in Hh pathway may lead to birth defects such as holoprosencephaly (Roessler et al, 1996), whereas abnormally activated Hh pathway leads to cancers, most commonly basal cell carcinoma and medulloblastoma (Teglund and Toftgard, 2010)

Summary

INTRODUCTION

The Hedgehog (Hh) signaling pathway transmits information between cells, and is critical for embryogenesis and tissue regeneration (Ingham et al, 2011; Briscoe and Therond, 2013). The structures of the 2:1 PTCH1 and Shh complex (termed dimer-Shh here) (Qi et al, 2018a; Qian et al, 2019; Rudolf et al, 2019) show that Shh binds ECDs of two PTCH1s with its C-terminal CHOL bound in the ECD1, and the N-terminal palmitate and 15 residues inserted into the ECD cavity of PTCH1-A (Figure 1A). Shh, lacking of the N-terminal palmitate and C-terminal CHOL, can inhibit PTCH1, the potency is significantly reduced (Pepinsky et al, 1998; Chen et al, 2004). It indicates that the PTCH1-Shh interactions play a role in the regulation of Hh signaling pathway.

METHODS

RESULTS

DATA AVAILABILITY STATEMENT