biostudies-literatureFry MYNational Institutes of HealthNIGMS NIH HHS306-318https://www.ebi.ac.uk/biostudies/studies/S-EPMC8380732biostudies-literatureUnknown22(9)The correct targeting and insertion of tail-anchored (TA) integral membrane proteins is critical for cellular homeostasis. TA proteins are defined by a hydrophobic transmembrane domain (TMD) at their C-terminus and are targeted to either the ER or mitochondria. Derived from experimental measurements of a few TA proteins, there has been little examination of the TMD features that determine localization. As a result, the localization of many TA proteins are misclassified by the simple heuristic of overall hydrophobicity. Because ER-directed TMDs favor arrangement of hydrophobic residues to one side, we sought to explore the role of geometric hydrophobic properties. By curating TA proteins with experimentally determined localizations and assessing hypotheses for recognition, we bioinformaticaTraffic (Copenhagen, Denmark)Sequence-based features that are determinant for tail-anchored membrane protein sorting in eukaryotes.PMC8380732R01GM097572R01 GM097572DP1 GM1053855T32GM07616T32 GM007616Cunha AClemons WMSaladi SMFry MYfalseSequence-based features that are determinant for tail-anchored membrane protein sorting in eukaryotes.The correct targeting and insertion of tail-anchored (TA) integral membrane proteins is critical for cellular homeostasis. TA proteins are defined by a hydrophobic transmembrane domain (TMD) at their C-terminus and are targeted to either the ER or mitochondria. Derived from experimental measurements of a few TA proteins, there has been little examination of the TMD features that determine localization. As a result, the localization of many TA proteins are misclassified by the simple heuristic of overall hydrophobicity. Because ER-directed TMDs favor arrangement of hydrophobic residues to one side, we sought to explore the role of geometric hydrophobic properties. By curating TA proteins with experimentally determined localizations and assessing hypotheses for recognition, we bioinformatica2021-01-01T00:00:00Z2021 Sep2025-04-18T15:25:20.886Z2025-04-07T02:00:48.192ZS-EPMC83807323428828910.1111/tra.12809