This mini review discusses the protein complexes comprised of the universal Notch signaling transcription factor, CSL (CBF1/Su(H)/Lag-1), and its activating or repressing transcriptional coregulation partners. Many of these complex structures have been solved crystallographically as well as undergoing extensive binding studies with wild-type and mutant variants. Notch signaling is critically important in a large variety of basic biological processes: cell proliferation, differentiation, cell cycle control to name a few. Aberrant Notch thus remains a coveted target for pharmaceutical intervention. To that end, we provide a molecular-level summary of the similarities and differences in the Notch coregulator complexes that ultimately govern these processes. We highlight a conserved binding motif that multiple superficially unrelated proteins have adopted to become involved in Notch target gene regulation. As CSL-interacting small molecules begin to be characterized, this review will provide insight to potential binding sites and differential complex disruption.
Impact statement: Proper Notch signaling regulation is informed by many distinct protein complexes involving a single nuclear effector. A decade of research into these protein complexes yields multiple crystal structures and a wealth of binding data to guide drug development for Notch-related diseases – cancer, cardiovascular, development disorders.
Keywords: Notch signaling; Structural biology; X-ray crystallography; isothermal titration calorimetry; protein–protein interactions; transcription.