281795 20260105130600.0 pmc:PMC12537875 pmc 10.1038/s41467-025-63769-5 doi pmid:41115860 pmid DZNE-2025-01185 English 500 Methorst, Jeroen 0000-0003-4507-4882 0 Physics-based evolution of transmembrane helices reveals mechanisms of cholesterol attraction. [London] 2025 Springer Nature article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1765545640_25185 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote 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. 351 - Brain Function (POF4-351) G:(DE-HGF)POF4-351 POF4-351 POF IV 0 Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de Cholesterol 97C5T2UQ7J NLM Chemicals Membrane Proteins NLM Chemicals Cholesterol: metabolism MeSH Cholesterol: chemistry MeSH Molecular Dynamics Simulation MeSH Membrane Proteins: chemistry MeSH Membrane Proteins: metabolism MeSH Humans MeSH Thermodynamics MeSH Cell Membrane: metabolism MeSH Cell Membrane: chemistry MeSH Protein Binding MeSH Endoplasmic Reticulum: metabolism MeSH Amino Acid Motifs MeSH Hydrophobic and Hydrophilic Interactions MeSH Verwei, Nino 0000-0003-2464-6896 1 Hoffmann, Christian P:(DE-2719)9000582 2 Chodnicki, Paweł 0000-0003-4563-2469 3 Sansevrino, Roberto P:(DE-2719)9000736 4 Pyne, Partha 5 Wang, Han P:(DE-2719)9001572 6 van Hilten, Niek 0000-0003-1204-2489 7 Aschmann, Dennis 8 Kros, Alexander 0000-0002-3983-3048 9 Andreas, Loren 10 Czub, Jacek 0000-0003-3639-6935 11 Milovanovic, Dragomir P:(DE-2719)9000670 12 Risselada, Herre Jelger 0000-0003-1410-6570 13 10.1038/s41467-025-63769-5 Vol. 16, no. 1, p. 9275 PERI:(DE-600)2553671-0 1 9275 Nature Communications 16 2025 2041-1723 http://pub.dzne.de/record/281795/files/DZNE-2025-01185%20SUP.zip http://pub.dzne.de/record/281795/files/DZNE-2025-01185.pdf OpenAccess http://pub.dzne.de/record/281795/files/DZNE-2025-01185.pdf?subformat=pdfa pdfa OpenAccess oai:pub.dzne.de:281795 openaire open_access VDB driver dnbdelivery Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 2 P:(DE-2719)9000582 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 4 P:(DE-2719)9000736 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 6 P:(DE-2719)9001572 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 12 P:(DE-2719)9000670 DE-HGF Gesundheit Neurodegenerative Diseases G:(DE-HGF)POF4-350 G:(DE-HGF)POF4-351 G:(DE-HGF)POF4 G:(DE-HGF)POF4-300 G:(DE-HGF)POF Brain Function 0 2025 DBCoverage StatID:(DE-HGF)0200 StatID SCOPUS 2025-01-02 DBCoverage StatID:(DE-HGF)0160 StatID Essential Science Indicators 2025-01-02 DBCoverage StatID:(DE-HGF)1050 StatID BIOSIS Previews 2025-01-02 DBCoverage StatID:(DE-HGF)1190 StatID Biological Abstracts 2025-01-02 OpenAccess StatID:(DE-HGF)0510 StatID DBCoverage StatID:(DE-HGF)1040 StatID Zoological Record 2025-01-02 IF >= 15 StatID:(DE-HGF)9915 StatID NAT COMMUN : 2022 2025-01-02 JCR StatID:(DE-HGF)0100 StatID NAT COMMUN : 2022 2025-01-02 DBCoverage StatID:(DE-HGF)0501 StatID DOAJ Seal 2024-01-30T07:48:07Z DBCoverage StatID:(DE-HGF)0500 StatID DOAJ 2024-01-30T07:48:07Z DBCoverage StatID:(DE-HGF)1030 StatID Current Contents - Life Sciences 2025-01-02 Fees StatID:(DE-HGF)0700 StatID 2025-01-02 DBCoverage StatID:(DE-HGF)0150 StatID Web of Science Core Collection 2025-01-02 Creative Commons Attribution CC BY 4.0 LIC:(DE-HGF)CCBY4 HGFVOC WoS StatID:(DE-HGF)0113 StatID Science Citation Index Expanded 2025-01-02 Peer Review StatID:(DE-HGF)0030 StatID DOAJ : Peer review 2024-01-30T07:48:07Z Article Processing Charges StatID:(DE-HGF)0561 StatID 2025-01-02 DBCoverage StatID:(DE-HGF)1060 StatID Current Contents - Agriculture, Biology and Environmental Sciences 2025-01-02 DBCoverage StatID:(DE-HGF)0300 StatID Medline 2025-01-02 DBCoverage StatID:(DE-HGF)1150 StatID Current Contents - Physical, Chemical and Earth Sciences 2025-01-02 DBCoverage StatID:(DE-HGF)0199 StatID Clarivate Analytics Master Journal List 2025-01-02 I:(DE-2719)1813002 AG Milovanovic (Berlin) Molecular Neuroscience 0 journal VDB I:(DE-2719)1813002 UNRESTRICTED FullTexts