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000281795 1001_ $$00000-0003-4507-4882$$aMethorst, Jeroen$$b0
000281795 245__ $$aPhysics-based evolution of transmembrane helices reveals mechanisms of cholesterol attraction.
000281795 260__ $$a[London]$$bSpringer Nature$$c2025
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000281795 520__ $$aThe 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.
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000281795 650_7 $$097C5T2UQ7J$$2NLM Chemicals$$aCholesterol
000281795 650_7 $$2NLM Chemicals$$aMembrane Proteins
000281795 650_2 $$2MeSH$$aCholesterol: metabolism
000281795 650_2 $$2MeSH$$aCholesterol: chemistry
000281795 650_2 $$2MeSH$$aMolecular Dynamics Simulation
000281795 650_2 $$2MeSH$$aMembrane Proteins: chemistry
000281795 650_2 $$2MeSH$$aMembrane Proteins: metabolism
000281795 650_2 $$2MeSH$$aHumans
000281795 650_2 $$2MeSH$$aThermodynamics
000281795 650_2 $$2MeSH$$aCell Membrane: metabolism
000281795 650_2 $$2MeSH$$aCell Membrane: chemistry
000281795 650_2 $$2MeSH$$aProtein Binding
000281795 650_2 $$2MeSH$$aEndoplasmic Reticulum: metabolism
000281795 650_2 $$2MeSH$$aAmino Acid Motifs
000281795 650_2 $$2MeSH$$aHydrophobic and Hydrophilic Interactions
000281795 7001_ $$00000-0003-2464-6896$$aVerwei, Nino$$b1
000281795 7001_ $$0P:(DE-2719)9000582$$aHoffmann, Christian$$b2
000281795 7001_ $$00000-0003-4563-2469$$aChodnicki, Paweł$$b3
000281795 7001_ $$0P:(DE-2719)9000736$$aSansevrino, Roberto$$b4
000281795 7001_ $$aPyne, Partha$$b5
000281795 7001_ $$0P:(DE-2719)9001572$$aWang, Han$$b6
000281795 7001_ $$00000-0003-1204-2489$$avan Hilten, Niek$$b7
000281795 7001_ $$aAschmann, Dennis$$b8
000281795 7001_ $$00000-0002-3983-3048$$aKros, Alexander$$b9
000281795 7001_ $$aAndreas, Loren$$b10
000281795 7001_ $$00000-0003-3639-6935$$aCzub, Jacek$$b11
000281795 7001_ $$0P:(DE-2719)9000670$$aMilovanovic, Dragomir$$b12
000281795 7001_ $$00000-0003-1410-6570$$aRisselada, Herre Jelger$$b13
000281795 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-025-63769-5$$gVol. 16, no. 1, p. 9275$$n1$$p9275$$tNature Communications$$v16$$x2041-1723$$y2025
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