A5039917706- Lipid Membrane Structure and Behavior
- Drug Transport and Resistance Mechanisms
- Cholesterol and Lipid Metabolism
- Hedgehog Signaling Pathway Studies
- Congenital Ear and Nasal Anomalies
- Genomics and Chromatin Dynamics
- Ocular Disorders and Treatments
Centre for Human Genetics
2021-2023
University of Oxford
2021
A long-standing mystery in vertebrate Hedgehog signaling is how Patched 1 (PTCH1), the receptor for ligands, inhibits activity of Smoothened, protein that transmits signal across membrane. We previously proposed (Kinnebrew et al., 2019) PTCH1 Smoothened by depleting accessible cholesterol from ciliary Using a new imaging-based assay to directly measure transport PTCH1, we find depletes outer leaflet plasma This terminated binding ligands or dissipation transmembrane potassium gradient. These...
Patched1 (PTCH1) is a tumor suppressor protein of the mammalian Hedgehog (HH) signaling pathway, implicated in embryogenesis and tissue homeostasis. PTCH1 inhibits G protein–coupled receptor Smoothened (SMO) via debated mechanism involving modulating ciliary cholesterol accessibility. Using extensive molecular dynamics simulations free energy calculations to evaluate transport through PTCH1, we find an energetic barrier ~15 20 kilojoule per mole for export. In silico data are coupled vivo...
Patched1 (PTCH1) is the principal tumour suppressor protein of mammalian Hedgehog (HH) signalling pathway, implicated in embryogenesis and tissue homeostasis. PTCH1 inhibits Class F G protein-coupled receptor Smoothened (SMO) via a debated mechanism involving modulating accessible cholesterol levels within ciliary membranes. Using extensive molecular dynamics (MD) simulations free energy calculations to evaluate transport through PTCH1, we find an energetic barrier ~15-20 kJ mol