BPS2026 – Sequence-encoded multivalent interactions tune the conformational ensembles of intrinsically disordered proteins

Intrinsically disordered proteins play important roles in cellular signaling and regulation. The intrinsically disordered protein CITED2 is a fully disordered protein that is essential for transcriptional regulation in various cellular contexts. The context-dependent biological functions of CITED2 have been attributed to its ability to engage a diverse set of molecular partners. However, little is known about the mechanistic basis of these interactions. We are studying CITED2 as a model for understanding how differences in sequence, arrangement of binding motifs, and dynamics influence protein-protein interactions. Using solution NMR spectroscopy in combination with complementary biophysical techniques, we have identified that long-range interactions between the N- and C-terminal regions of CITED2 bias the conformational ensemble toward more compact states. These dynamic, multivalent interactions are mediated by regions of compositional bias and transient helicity and regulate the accessibility of conserved interaction motifs. We anticipate that long-range interactions in CITED2 are essential for fine-tuning the CITED2 conformational ensemble and modulating its interactions and functions in transcriptional regulation.