Proline <i>cis</i>/<i>trans</i> Conformational Selection Controls 14-3-3 Binding.

ABSTRACT: Intrinsically disordered protein regions (IDRs) are structurally dynamic yet functional, often interacting with other proteins through short linear motifs (SLiMs). Proline residues in IDRs introduce conformational heterogeneity on a uniquely slow time scale arising from cis/trans isomerization of the Xaa-Pro peptide bond. Here, we explore the role of proline isomerization in the interaction between the prolactin receptor (PRLR) and 14-3-3. Using NMR spectroscopy, thermodynamic profiling, and molecular dynamics (MD) simulations, we uncover a unique proline isomer-dependent binding, with a cis conformation affinity 3 orders of magnitude higher than the trans. MD simulations identify structural constraints in the narrow 14-3-3 binding groove that provide an explana

SUBMITTER: Theisen FF 

PROVIDER: S-EPMC11848828 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature