TY  - JOUR
AU  - Methorst, Jeroen
AU  - Verwei, Nino
AU  - Hoffmann, Christian
AU  - Chodnicki, Paweł
AU  - Sansevrino, Roberto
AU  - Pyne, Partha
AU  - Wang, Han
AU  - van Hilten, Niek
AU  - Aschmann, Dennis
AU  - Kros, Alexander
AU  - Andreas, Loren
AU  - Czub, Jacek
AU  - Milovanovic, Dragomir
AU  - Risselada, Herre Jelger
TI  - Physics-based evolution of transmembrane helices reveals mechanisms of cholesterol attraction.
JO  - Nature Communications
VL  - 16
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - DZNE-2025-01185
SP  - 9275
PY  - 2025
AB  - The existence of linear cholesterol-recognition motifs in transmembrane domains has long been debated. Evolutionary molecular dynamics (Evo-MD) simulations-genetic algorithms guided by (coarse-grained) molecular force-fields-reveal that thermodynamic optimal cholesterol attraction in isolated alpha-helical transmembrane domains occurs when multiple consecutive lysine/arginine residues flank a short hydrophobic segment. These findings are supported by atomistic simulations and solid-state NMR experiments. Our analyses illustrate that linear motifs in transmembrane domains exhibit weak binding affinity for cholesterol, characterized by sub-microsecond residence times, challenging the predictive value of linear CRAC/CARC motifs for cholesterol binding. Membrane protein database analyses suggest even weaker affinity for native linear motifs, whereas live cell assays demonstrate that optimizing cholesterol binding restricts transmembrane domains to the endoplasmic reticulum post-translationally. In summary, these findings contribute to our understanding of cholesterol-protein interactions and offer insight into the mechanisms of protein-mediated cholesterol regulation within membranes.
KW  - Cholesterol: metabolism
KW  - Cholesterol: chemistry
KW  - Molecular Dynamics Simulation
KW  - Membrane Proteins: chemistry
KW  - Membrane Proteins: metabolism
KW  - Humans
KW  - Thermodynamics
KW  - Cell Membrane: metabolism
KW  - Cell Membrane: chemistry
KW  - Protein Binding
KW  - Endoplasmic Reticulum: metabolism
KW  - Amino Acid Motifs
KW  - Hydrophobic and Hydrophilic Interactions
KW  - Cholesterol (NLM Chemicals)
KW  - Membrane Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41115860
DO  - DOI:10.1038/s41467-025-63769-5
UR  - https://pub.dzne.de/record/281795
ER  -